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Targeted therapy in Cancer
Dr TRI WIDYAWATI MSi
Bagian Farmakologi dan Terapeutik
Fakultas Kedokteran
Universitas Sumatera Utara
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Introductionbull Surgery radiation and chemotherapy have led to
increase survival rates for certain types of cancer
However there are some types of cancer eg lung andGIT (liver cancer) cancers often do not respond well tosuch type of treatment in addition to the marked sideeffects that have been observedTherefore additionalcancer thera is stron l recommendedThe latter
should be targeting therapy based on biochemical andbiological approachbull Novel promissing biological ndashbiochemical therapy for
cancer
bull 1-Bio-immunotherapybull 2-Anti-angiogenesis amp anti-metastasis inducerbiomolecules
bull 3-Apoptosis inducer therapy
bull 4-Gene therapy 5-differentiation inducer therapy
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ChemotherapyShortcomingsA Nature of cytotoxin
B Lack of in vivo selectivity
C The mechanism of anti-proliferation on cells cycle rather than
specific toxicity directed towards particular cancer cell
D Host toxixity treatment discontinued most of them had badside-effects such as no appetites omit lose hair
Side Effects of Chemotherapy
Immediate Early Delayed Late(hours - days) (days - weeks) (weeks- months) (months - yrs)
Extravasation Myelosuppression Cardiotoxicity Second CancerEmesis Mucositis Lung fibrosis EncephalopathyHypersensitivity Alopecia P Neuropathy SterilityTumour lysis Cystitis Hepatotoxicity Teratogenicity
Nephrotoxicity
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Changing of the Guard
bull There is a paradigm shift in thetreatment of cancer
bull with DNA to prevent cell replication butare not specific to cancer cells
bull We are moving to targeted therapieswhich specifically target cancer cells
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The Paradigm Shift
bull The use of these drugs is giving
clinicians a glimmer of the paradigmshift that will occur in the treatment of
bull One or several new targeted therapiesoffer the prospect of cancer being
treated as a chronic disease
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Targeted Therapy A definitionbull Drugs targeted at pathways processes and
physiology which are uniquely disrupted incancer cells
ndash Receptors
ndash Genes ndash Angiogenesis
ndash Tumor pH
bull Get real these pathways etc are not so distinct
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Targeted therapiesbull With targeted therapy the specific
mechanism of action of the drug results in anincrease in its therapeutic index
bull However the advantages of the specificity
and safety of the are offset by the smallernumber of susceptible tumour types
bull Increasing numbers of these innovative and
expensive anti-cancer drugs may exceed thecapacity of the public purse to pay for them
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The Need to Identify the Targetbull Appropriate use of newly approved and
expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample
bull urren y e wo ma or c asses o arge etherapy are
= the small molecule tyrosine kinase
inhibitors (TKIs) and= monoclonal antibodies (mAbs)
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
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Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
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983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Introductionbull Surgery radiation and chemotherapy have led to
increase survival rates for certain types of cancer
However there are some types of cancer eg lung andGIT (liver cancer) cancers often do not respond well tosuch type of treatment in addition to the marked sideeffects that have been observedTherefore additionalcancer thera is stron l recommendedThe latter
should be targeting therapy based on biochemical andbiological approachbull Novel promissing biological ndashbiochemical therapy for
cancer
bull 1-Bio-immunotherapybull 2-Anti-angiogenesis amp anti-metastasis inducerbiomolecules
bull 3-Apoptosis inducer therapy
bull 4-Gene therapy 5-differentiation inducer therapy
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ChemotherapyShortcomingsA Nature of cytotoxin
B Lack of in vivo selectivity
C The mechanism of anti-proliferation on cells cycle rather than
specific toxicity directed towards particular cancer cell
D Host toxixity treatment discontinued most of them had badside-effects such as no appetites omit lose hair
Side Effects of Chemotherapy
Immediate Early Delayed Late(hours - days) (days - weeks) (weeks- months) (months - yrs)
Extravasation Myelosuppression Cardiotoxicity Second CancerEmesis Mucositis Lung fibrosis EncephalopathyHypersensitivity Alopecia P Neuropathy SterilityTumour lysis Cystitis Hepatotoxicity Teratogenicity
Nephrotoxicity
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Changing of the Guard
bull There is a paradigm shift in thetreatment of cancer
bull with DNA to prevent cell replication butare not specific to cancer cells
bull We are moving to targeted therapieswhich specifically target cancer cells
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The Paradigm Shift
bull The use of these drugs is giving
clinicians a glimmer of the paradigmshift that will occur in the treatment of
bull One or several new targeted therapiesoffer the prospect of cancer being
treated as a chronic disease
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Targeted Therapy A definitionbull Drugs targeted at pathways processes and
physiology which are uniquely disrupted incancer cells
ndash Receptors
ndash Genes ndash Angiogenesis
ndash Tumor pH
bull Get real these pathways etc are not so distinct
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Targeted therapiesbull With targeted therapy the specific
mechanism of action of the drug results in anincrease in its therapeutic index
bull However the advantages of the specificity
and safety of the are offset by the smallernumber of susceptible tumour types
bull Increasing numbers of these innovative and
expensive anti-cancer drugs may exceed thecapacity of the public purse to pay for them
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The Need to Identify the Targetbull Appropriate use of newly approved and
expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample
bull urren y e wo ma or c asses o arge etherapy are
= the small molecule tyrosine kinase
inhibitors (TKIs) and= monoclonal antibodies (mAbs)
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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ChemotherapyShortcomingsA Nature of cytotoxin
B Lack of in vivo selectivity
C The mechanism of anti-proliferation on cells cycle rather than
specific toxicity directed towards particular cancer cell
D Host toxixity treatment discontinued most of them had badside-effects such as no appetites omit lose hair
Side Effects of Chemotherapy
Immediate Early Delayed Late(hours - days) (days - weeks) (weeks- months) (months - yrs)
Extravasation Myelosuppression Cardiotoxicity Second CancerEmesis Mucositis Lung fibrosis EncephalopathyHypersensitivity Alopecia P Neuropathy SterilityTumour lysis Cystitis Hepatotoxicity Teratogenicity
Nephrotoxicity
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Changing of the Guard
bull There is a paradigm shift in thetreatment of cancer
bull with DNA to prevent cell replication butare not specific to cancer cells
bull We are moving to targeted therapieswhich specifically target cancer cells
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The Paradigm Shift
bull The use of these drugs is giving
clinicians a glimmer of the paradigmshift that will occur in the treatment of
bull One or several new targeted therapiesoffer the prospect of cancer being
treated as a chronic disease
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Targeted Therapy A definitionbull Drugs targeted at pathways processes and
physiology which are uniquely disrupted incancer cells
ndash Receptors
ndash Genes ndash Angiogenesis
ndash Tumor pH
bull Get real these pathways etc are not so distinct
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Targeted therapiesbull With targeted therapy the specific
mechanism of action of the drug results in anincrease in its therapeutic index
bull However the advantages of the specificity
and safety of the are offset by the smallernumber of susceptible tumour types
bull Increasing numbers of these innovative and
expensive anti-cancer drugs may exceed thecapacity of the public purse to pay for them
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The Need to Identify the Targetbull Appropriate use of newly approved and
expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample
bull urren y e wo ma or c asses o arge etherapy are
= the small molecule tyrosine kinase
inhibitors (TKIs) and= monoclonal antibodies (mAbs)
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Changing of the Guard
bull There is a paradigm shift in thetreatment of cancer
bull with DNA to prevent cell replication butare not specific to cancer cells
bull We are moving to targeted therapieswhich specifically target cancer cells
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The Paradigm Shift
bull The use of these drugs is giving
clinicians a glimmer of the paradigmshift that will occur in the treatment of
bull One or several new targeted therapiesoffer the prospect of cancer being
treated as a chronic disease
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Targeted Therapy A definitionbull Drugs targeted at pathways processes and
physiology which are uniquely disrupted incancer cells
ndash Receptors
ndash Genes ndash Angiogenesis
ndash Tumor pH
bull Get real these pathways etc are not so distinct
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Targeted therapiesbull With targeted therapy the specific
mechanism of action of the drug results in anincrease in its therapeutic index
bull However the advantages of the specificity
and safety of the are offset by the smallernumber of susceptible tumour types
bull Increasing numbers of these innovative and
expensive anti-cancer drugs may exceed thecapacity of the public purse to pay for them
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The Need to Identify the Targetbull Appropriate use of newly approved and
expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample
bull urren y e wo ma or c asses o arge etherapy are
= the small molecule tyrosine kinase
inhibitors (TKIs) and= monoclonal antibodies (mAbs)
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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The Paradigm Shift
bull The use of these drugs is giving
clinicians a glimmer of the paradigmshift that will occur in the treatment of
bull One or several new targeted therapiesoffer the prospect of cancer being
treated as a chronic disease
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Targeted Therapy A definitionbull Drugs targeted at pathways processes and
physiology which are uniquely disrupted incancer cells
ndash Receptors
ndash Genes ndash Angiogenesis
ndash Tumor pH
bull Get real these pathways etc are not so distinct
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Targeted therapiesbull With targeted therapy the specific
mechanism of action of the drug results in anincrease in its therapeutic index
bull However the advantages of the specificity
and safety of the are offset by the smallernumber of susceptible tumour types
bull Increasing numbers of these innovative and
expensive anti-cancer drugs may exceed thecapacity of the public purse to pay for them
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The Need to Identify the Targetbull Appropriate use of newly approved and
expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample
bull urren y e wo ma or c asses o arge etherapy are
= the small molecule tyrosine kinase
inhibitors (TKIs) and= monoclonal antibodies (mAbs)
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Targeted Therapy A definitionbull Drugs targeted at pathways processes and
physiology which are uniquely disrupted incancer cells
ndash Receptors
ndash Genes ndash Angiogenesis
ndash Tumor pH
bull Get real these pathways etc are not so distinct
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Targeted therapiesbull With targeted therapy the specific
mechanism of action of the drug results in anincrease in its therapeutic index
bull However the advantages of the specificity
and safety of the are offset by the smallernumber of susceptible tumour types
bull Increasing numbers of these innovative and
expensive anti-cancer drugs may exceed thecapacity of the public purse to pay for them
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The Need to Identify the Targetbull Appropriate use of newly approved and
expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample
bull urren y e wo ma or c asses o arge etherapy are
= the small molecule tyrosine kinase
inhibitors (TKIs) and= monoclonal antibodies (mAbs)
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Targeted therapiesbull With targeted therapy the specific
mechanism of action of the drug results in anincrease in its therapeutic index
bull However the advantages of the specificity
and safety of the are offset by the smallernumber of susceptible tumour types
bull Increasing numbers of these innovative and
expensive anti-cancer drugs may exceed thecapacity of the public purse to pay for them
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The Need to Identify the Targetbull Appropriate use of newly approved and
expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample
bull urren y e wo ma or c asses o arge etherapy are
= the small molecule tyrosine kinase
inhibitors (TKIs) and= monoclonal antibodies (mAbs)
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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The Need to Identify the Targetbull Appropriate use of newly approved and
expensive targeted therapies for cancer firstdepends on the pathologist identifying the targetfor treatment in the tumour sample
bull urren y e wo ma or c asses o arge etherapy are
= the small molecule tyrosine kinase
inhibitors (TKIs) and= monoclonal antibodies (mAbs)
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Six Essential Alterations
in Cell Physiology in Malignancy
Insensitivity to
anti-growth signals
Self-sufficiency in
growth signals
Evading
apoptosis
Targets for classical drugs
Hanahan amp WeinbergCell 10057 (2000)
Limitless replicativepotential
Tissue invasionamp metastasis
Sustained
angiogenesis
Targets for novel drugs
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Figure 1 Mechanisms of traditional chemotherapy These drugs act on rapidlydividing cells which include normal tissues (eg hair gastrointestinal epithelium
bone marrow) in addition to cancer cells Alkylating agents interfere with DNA basepairing leading to strand breaks and arresting DNA replication Topoisomeraseinhibitors prevent DNA uncoiling Taxanes and vinca alkaloids interfere withmicrotubule function required for cell mitosis Antimetabolites block the formationand use of nucleic acids essential for DNA replication
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Figure 2 Mechanisms of targeted therapies The molecular targets in this figure are notoverexpressed in a single cell type but rather on various malignant and normal tissues For
example CD20 is present on lymphoma and normal lymphoid cells HER2neu is presenton 25 percent of breast cancer cells and VEGFR is present on normal and tumor-associated vasculature Downstream intracellular signaling molecules some of which aretargeted by small molecule inhibitors are not depicted Some drugs (eg sorafenib[Nexavar] sunitinib [Sutent] imatinib [Gleevec] dasatinib [Sprycel]) have multiple targetsmost of which are not depicted (CD = cluster of differentiation BCR-ABL = breakpoint
cluster region-Abelson EGFR = epithelial growth factor receptor VEGFR = vascularendothelial growth factor receptor VEGF = vascular endothelial growth factor)
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
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Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
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Table 1 Glossary of Oncology Terms Angiogenesis The growth of new blood vessels from preexisting
vasculature
Epidermal growth factor receptor (EGFR also known as HER1)
A tyrosine kinase that when activated by binding of specific ligandstriggers intracellular signaling that ultimately leads to cellproliferation invasion and migration it is a target of treatment (withthe monoclonal antibodies cetuximab [Erbitux] and panitumumab[Vectibix] and the small molecule inhibitors erlotinib [Tarceva]
Fragment antigen binding (Fab) The region of an antibodyresponsible for recognizing and binding to antigens
Fragment crystallizable (Fc) The region of an antibody responsiblefor interacting with immune system components such as naturalkiller cells and the complement cascade in some instances it maybe conjugated to a lethal payload such as a radioisotope or toxin
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HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
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Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1451
HER2neu A tyrosine kinase related to epidermal growth
factor receptor it has a role in the pathogenesis of
breast cancer and is a target of treatment (with the
monoclonal antibody trastuzumab [Herceptin] and the
small molecule inhibitor lapatinib [Tykerb]) in the 25
percent of persons with breast cancer in which
HER2neu is associated with disease recurrence and
worse prognosis HER2 is named because it has
similar structure to human epidermal growth factor
receptor (HER1) neu is so named because it was
derived from a neuroglioblastoma cell line
7182019 Targeted Therapy in Cancer
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Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1651
What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1751
Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1851
The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
7182019 Targeted Therapy in Cancer
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2051
Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2151
mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2251
Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
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7182019 Targeted Therapy in Cancer
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7182019 Targeted Therapy in Cancer
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
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On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
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Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
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Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
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GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
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ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
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STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
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PET Before and after Glivec
for GIST
7120071200 91019101
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7182019 Targeted Therapy in Cancer
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Table 3 Small Molecule Inhibitors for Cancer Treatment
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Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
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Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
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Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
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Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1551
Ligand A molecule that binds to a specific receptor
Monoclonal antibodies Identical antibodies produced bya single type of immune cell in targeted cancer therapythey are directed against molecules unique tooverexpressed in or mutated in cancer cells
Small molecule inhibitors Drugs that interfere with thefunction of molecules involved in the development andprogression of cancer most commonly they interferewith tyrosine kinases
Tyrosine kinase Enzyme that transfers a phosphategroup from adenosine triphosphate to a tyrosine aminoacid residue in a protein which may then triggerdownstream molecular signaling
Vascular endothelial growth factor (VEGF) A signalingprotein involved in angiogenesis it binds to tyrosinekinases (VEGF receptors) to initiate and promoteangiogenesis It is a target of treatment with the
monoclonal antibody bevacizumab (Avastin)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1651
What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1751
Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1851
The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1951
The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2051
Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2151
mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2251
Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
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Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
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7182019 Targeted Therapy in Cancer
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The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
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Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
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note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
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carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
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Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
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Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
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Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
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What is antibodiesAn antibody is a protein used by the immune system to identify and neutralize foreign
objects like bacteria and viruses Each antibody recognizes a specific antigenunique to its target
Monoclonal antibodies (mAb) are antibodies that are identical because they were
produced by one type of immune cell all clones of a single parent cell
Polyclonal antibodies are antibodies that are derived from different cell lines
Isot es
According to differences in their heavy chain constant domains immunoglobulinsare grouped into five classes or isotypes IgG IgA IgM IgD and IgE
IgG IgG1 (66) IgG2 (23) IgG3 (7) and IgG4 (4) blood and tissue liquid
IgAIgA1 (90) and IgA2 (10) stomach and intestines
IgM normally pentamer ocassionally hexamer multiple immunoglobins linked withdisulfide bonds
IgD1 of proteins in the plasma membranes of B-lymphocytes function unknown
IgE on the surface of plasma membrane of mast cells play a role in immediatehypersensitive and denfensive for parasite
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1751
Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
7182019 Targeted Therapy in Cancer
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
7182019 Targeted Therapy in Cancer
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The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
7182019 Targeted Therapy in Cancer
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Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
7182019 Targeted Therapy in Cancer
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
7182019 Targeted Therapy in Cancer
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Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
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HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
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Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
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7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
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Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
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Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1751
Monoclonal Antibodies
bull Action of the mAbs rituximab
(Mabtherareg) for NHL andtrastuzumab (Herceptinreg) for
reas cancer epen on etargets CD20 expression anderbB2 gene being amplified andresponsible for growth
7182019 Targeted Therapy in Cancer
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The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1951
The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2051
Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
7182019 Targeted Therapy in Cancer
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mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2251
Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2451
Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1851
The structure of antibodies
bull httpwwwpathcamacuk~mrc7igsmikeimageshtml
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1951
The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2051
Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2151
mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2251
Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2451
Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 1951
The types of mAb designed
AMurin source mAbs rodent mAbs withexcellent affinities and specificities generatedusing conventional hydrioma technologyClinical efficacy compromised by HAMA(humananti murine antibody) response which lead toallergic or immune complex herpersensitivities
BChimeric mAbs chimers combine the humanconstant regions with the intact rodent variableregions Affinity and specificity unchangedAlso cause human antichimeric antibodyresponse (30 murine resource)
CHumanized mAbs contained only the CDRs ofthe rodent variable region grafted onto human
variable region framework
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2051
Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2151
mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2251
Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2451
Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2051
Monoclonal antibodies for cancer
treatment
Mechanisms that could be responsible for the
cancer treatmentA mAbs act directely when binding to a cancer
specific antigens and induce immunological
response to cancer cells Such as inducing cancercell apoptosis inhibiting growth or interfering witha key function
B mAbs was modified for delivery of a toxinradioisotope cytokine or other active conjugates
C it is also possible to design bispecific antibodies that canbind with their Fab regions both to target antigen and to aconjugate or effector cell
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2151
mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2251
Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2451
Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2151
mAbs treatment for cancer cells
ADEPT antibody directed enzyme prodrug therapy ADCC antibody
dependent cell-mediated cytotoxicity CDC complement dependentcytotoxicity MAb monoclonal antibody scFv single-chain Fv fragment
Carter P Improving the efficacy of antibody-based cancer therapies Nat Rev Cancer
20011118-129
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2251
Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2451
Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2251
Mabthera
bull Mabthera is an Anti-CD20 monoclonalantibody for lymphoma
bull CD20 is a protein on the surface of malignantlymphoma cells
bull CD20 expressed on 90 of B-cells in
Side effects includeInfusion related fever chills rigors
N + V urticaria pruritis headache fatiguebronchospasm hypersensitivityRare heart rhythm disturbanceLow blood counts for up to 30 days
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2451
Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2351
HER2
= HER2 gene (neu c-erb-2) ecodes atransmembrane gycoprotein receptor
= HER 2 is over expressed by 14 human breastcancer and correlates with poorer outcome
=overexpressing cells
As a single agent 15 chance of shrinking metastatic
breast cancer 4 chance of a complete shrinkage inheavily pretreated patientsDuration of response can be 9 months which is at least asgood as single chemotherapy agents
Can combine with chemotherapy
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2451
Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2451
Figure 3 Acneiform rash on (A) the face and (B) back of
patients treated with cetuximab (Erbitux) a monoclonalantibody targeting epidermal growth factor receptor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2551
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorsbullbull ErlotinibErlotinib
bullbull GefitinibGefitinib
bullbull ZD6474ZD6474
bullbull SunitinibSunitinibbullbull SorafenibSorafenib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
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Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2751
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2851
The Angiogenic Switchis Necessary for Tumor Growth and Metastasis
Tumor is dormant
Neovascularization
Angiogenic switch
Somaticmutation
Smallavascular
tumor
Tumor secretion ofangiogenic factors
stimulatesangiogenesis
Rapid tumor growth andmetastasis
Carmeliet and Jain Nature 2000 407249 Bergers and Benjamin Nat Rev Cancer 2003 3401
bull Allows rapid tumor
growth by providingoxygen nutrientsand waste removal
bull Facilitatesmetastasis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 2951
On
The Angiogenic Switch
The Angiogenic Switch
The Balance Hypothesis
Hanahan and Folkman Cell 1996 86353
= Activators (eg VEGF bFGF IL-8)
= Inhibitors (eg thrombospondin-1 angiostatin interferon ααααββββ)
Off
VEGF = Vascular endothelial growth factor
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3051
Agents targeting the
VEGF pathway
Agents targeting the
VEGF pathway
SolubleVEGF
receptors
VEGFAnti-VEGFantibodies
(bevacizumab)
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial cell
Small-molecule
VEGFR inhibitors
(PTKZK)
Ribozymes(angiozyme)
Anti-VEGFRantibodies(IMC-2C7)
(VEGF-Trap)
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3151
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
(EGFR)(EGFR)
bullbull EGFR has an essential role in tumorEGFR has an essential role in tumor
progressionprogressionbullbull Tyrosine Kinase inhibitors blockTyrosine Kinase inhibitors block
intracellular hos hor lation of EGFRintracellular hos hor lation of EGFR
bullbull Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptorsignaling impairedsignaling impaired
bullbull Inhibits production of VEGFInhibits production of VEGF
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3251
GefitinibGefitinib
bullbull Small Molecule Tyrosine Kinase inhibitorSmall Molecule Tyrosine Kinase inhibitorbullbull Iressa Survival Evaluation in advanced lungIressa Survival Evaluation in advanced lung
cancercancer
bullbull Gefitinib vs placeboGefitinib vs placebobullbull Conditional approval in 2003 on the basis ofConditional approval in 2003 on the basis of
10 response rate in clinical study10 response rate in clinical study
bullbull Use restricted to responders after ISEL studyUse restricted to responders after ISEL studyshowed no survival advantageshowed no survival advantage
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3351
ErlotinibErlotinibbullbull NCI CTC BR21NCI CTC BR21
bullbull 731 Patients731 Patientsbullbull NSCLCA with disease progression afterNSCLCA with disease progression after
chemotherapychemotherapy
bullbull r o n mg ay vs ace or o n mg ay vs ace o
bullbull Median survival 67 vs 47 months (plt001)Median survival 67 vs 47 months (plt001)
bullbull One year survival 297 vs 205One year survival 297 vs 205
bullbull Quality of life improvementQuality of life improvement
bullbullFDA indication for locally advancedFDA indication for locally advanced
bullbull or metastatic NSCLC after failure of oneor metastatic NSCLC after failure of one
bullbullor more chemotherapy regimensor more chemotherapy regimens
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3451
STI 571 (Glivec)bull Specific inhibitor for BCR-ABL PDGF receptor
and c-kit tyrosine kinases produced by thesegenes which are responsible for growth in CMLand GIST
bull Effective in chronic myeloid leukaemiabull Effective in GIST Gastrointestinal stroma
tumours which over express c-kit
bull Side effects ndash Nausea myalgia oedema diarrhoea
myelosuppression LFTrsquos early ldquostormrdquo
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3551
PET Before and after Glivec
for GIST
7120071200 91019101
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3651
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3751
Table 3 Small Molecule Inhibitors for Cancer Treatment
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3851
Table 3 Small Molecule Inhibitors for Cancer Treatment
Drug Target
FDA-approved
indications
Toxicities side
effects and
precautions Monitoring
Bortezom
ib
(Velcade)
26S
proteaso
me
Multiple
myeloma
mantle cell
lymphoma
(a subtype of
Peripheral
neuropathy
myelosuppression
rash constipation
diarrhea edema
Signs and
symptoms of
peripheral
neuropathy CBC
non- o g n s
lymphoma)
nausea an
vomiting
Dasatinib
(Sprycel)
BCR-
ABL
SRCfamily
c-KIT
PDGFR
Chronic
myeloid
leukemiaacute
lymphocytic
leukemia
Rash diarrhea
pleural effusion
fluid retentionmucositis
myelosuppression
QT interval
prolongation
CBC ECG liver
chemistries
weight signs andsymptoms of fluid
retention
Erlotinib EGFR Non-small cell Acneiform rash Liver chemistries
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 3951
Erlotinib
(Tarceva)
EGFR Non-small cell
lung cancer
pancreaticcancer
Acneiform rash
diarrhea loss of
appetite nausea andvomiting fatigue
conjunctivitis
elevated liver
chemistries
Liver chemistries
signs of
inflammatory orinfectious sequelae
in patients with
dermatologic
toxicity
Gefitinib
(Iressa)
EGFR Non-small cell
lung cancer
Acneiform rash
diarrhea loss of
appetite interstitial
lung disease (rare)
elevated liverchemistries
Liver chemistries
signs of
inflammatory or
infectious sequelae
in patients withdermatologic
toxicity
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4051
Imatinib
(Gleevec)
BCR-
ABLc-KIT
PDGFR
Acute
lymphocyticleukemia
chronic
myeloidleukemia
gastrointestin
Rash weight
gain edemapleural
effusion
cardiactoxicity
(depression of
CBC liver
chemistriesweight signs
and symptoms
of fluidretention
al stromaltumor
hypereosinop
hilicsyndrome
systemic
mastocytosis
LVEF)nausea and
vomiting
arthralgiasand myalgias
myelosuppres
sion
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4151
Lapatinib
(Tykerb)
HER2
neu
EGFR
Breast cancer
with HER2neu
overexpression
Cardiac toxicity
(depression of
LVEF QT
prolongation)
acneiform rash
palmar-plantar
LVEF ECG
electrolyte
levels liver
chemistries
ia (hand-foot
syndrome)
diarrhea nausea
and vomiting
elevated liver
chemistries
Sorafenib BRAF Renal cell Hypertension Blood
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4251
Sorafenib(Nexavar)
BRAFVEGFR
EGFRPDGFR
Renal cellcancer
hepatocellularcarcinoma
Hypertensionalopecia bleeding
rash palmar-plantarerythrodysesthesia(hand-footsyndrome)hypophosphatemia diarrhea nauseaand vomiting
Bloodpressure
dermatologictoxicity(includingpalmar-plantarerythrodysesthesia [hand-foot
e eva e amy ase
and lipase levelsmyelosuppressionwound-healingcomplications
Discontinuetreatmenttemporarily forsurgicalprocedures
syn rome
amylaselipase andphosphatelevels CBC
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4351
note
= All small molecule inhibitors are administeredorally except bortezomib which is administered
intravenously
= Most small molecule inhibitors undergometabolism by cytochrome P450 enzymes and are
=anticonvulsants azole antifungals dexamethasone
isoniazid [Nydrazid] macrolide antibiotics nefazodone
[Serzone brand no longer available in the UnitedStates] protease inhibitors rifampin [Rifadin] St
Johns wort verapamil [Calan] and warfarin
[Coumadin])
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4451
carcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983156983144983141 (983137) 983141983152983145983140983141983154983149983137983148 983143983154983151983159983156983144 983142983137983139983156983151983154 (983109983111983110)
983137983150983140 983109983111983110 983154983141983139983141983152983156983151983154 (983109983111983110983122) 983142983137983149983145983148983161 (983138) 983158983137983155983139983157983148983137983154 983141983150983140983151983156983144983141983148983145983137983148
983143983154983151983159983156983144 983142983137983139983156983151983154 (983126983109983111983110)
983137983150983140 983126983109983111983110 983154983141983139983141983152983156983151983154 (983126983109983111983110983122) 983142983137983149983145983148983161 983137983150983140 (983139) 983145983150983155983157983148983145983150983085983148983145983147983141 983143983154983151983159983156983144
983142983137983139983156983151983154 (983113983111983110) 983137983150983140 983113983111983110 983154983141983139983141983152983156983151983154 (983113983111983110983122) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141
983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155
Molecularly targeted therapy for hepatocellular
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4551
Molecularly targeted therapy for hepatocellularcarcinoma
983117983151983148983141983139983157983148983137983154 983156983137983154983143983141983156983155 983145983150 983149983145983156983151983143983141983150983085983137983139983156983145983158983137983156983141983140 983152983154983151983156983141983145983150 983147983145983150983137983155983141 (983117983105983120983115) 983137983150983140 983152983144983151983155983152983144983137983156983145983140983161983148983145983150983151983155983145983156983151983148983085983091
983147983145983150983137983155983141 (983120983113983091983115) 983155983145983143983150983137983148 983156983154983137983150983155983140983157983139983156983145983151983150 983152983137983156983144983159983137983161983155
983155983156983145983149983157983148983137983156983141983140 983138983161 983154983141983139983141983152983156983151983154 983156983161983154983151983155983145983150983141 983147983145983150983137983155983141983155 (983122983124983115) 983124983137983154983143983141983156983141983140 983137983143983141983150983156983155 983137983154983141 983145983150983140983145983139983137983156983141983140 983138983161 983137983154983154983151983159983155 983111983110
983143983154983151983159983156983144 983142983137983139983156983151983154983099 983123983119983123 983155983157983150 983151983142 983155983141983158983141983150983148983141983155983155983099 983117983109983115 983117983105983120983115
983141983160983156983154983137983139983141983148983148983157983148983137983154 983154983141983143983157983148983137983156983141983140 983147983145983150983137983155983141 983147983145983150983137983155983141983099 983120983124983109983118 983152983144983151983155983152983144983137983154983137983155983141 983137983150983140 983156983141983150983155983145983150 983144983151983149983151983148983151983143983157983141983099 983120983108983115
983152983144983151983155983152983144983151983145983150983151983155983145983156983145983140983141983085983140983141983152983141983150983140983141983150983156 983147983145983150983137983155983141983099 983113983115983115 983113κ983106 983147983145983150983137983155983141983099 983149983124983119983122
983149983137983149983149983137983148983145983137983150 983156983137983154983143983141983156 983151983142 983154983137983152983137983149983161983139983145983150
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4651
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4751
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Hepatocellular carcinoma (HCC) is the
most common primary liver tumorresponsible for about 90 of liver cancers
challenge to physicians
bull Many chemotherapeutic agents have been
tried but none had shown a significantresult of improved survival or quality of life
Sorafenib in the treatment of advanced
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4851
Sorafenib in the treatment of advancedhepatocellular carcinoma
bull Sorafenib reg is a multikinase inhibitor that has
recently obtained Food and Drug Administration(FDA) approval for the treatment of advancedrenal cell carcinoma (RCC)
bull It has been tried in several solid tumorsincluding HCC
bull A recent phase III trial has shown that sorafenib
significantly extends survival for patients withadvanced HCC
S f ib
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 4951
Sorafenib
bull Sorafenib is an inhibitor of several kinases involved inboth tumor cell proliferation (tumor growth) andangiogenesis (tumor blood supply) These include Raf
VEGFR and PDGFRbull Raf is serinetheonine kinase which when activated by
Ras membrane localized rotein stimulates ene
transcription in the nucleus leading to a variety of tumor-promoting cellular effects
bull VEGF is the primary mediator of both normal and tumor-associated angiogenesis It exerts this effect through
several mechanisms including induction of endothelialcell division and migration promotion of endothelial cellsurvival through protection from apoptosis and reversalof endothelial cell aging
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5051
Sorafenibbull VEGF interacts with receptors (VEGFR 1 2 3)
present on the endothelial cell surface whichleads to autophosphorylation of intracellularreceptor tyrosine kinase and a cascade ofdownstream proteins is activated
PDGF has its receptor on the surface of capillaryendothelial cells The binding of PDGF to the
receptors has several effects on endothelial cellmotility and apoptosis
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information
7182019 Targeted Therapy in Cancer
httpslidepdfcomreaderfulltargeted-therapy-in-cancer 5151
Conclusionsbull Targeted therapies which improve
the therapeutic index are the futureof anti-cancer therapy
provide the means to identify thetargets and will be used to subtypetumours and will provide predict
response to therapy and provideprognostic information