Strategies to improve anti tumor effectiveness of radiotherapy · – Control cell survival –...
Transcript of Strategies to improve anti tumor effectiveness of radiotherapy · – Control cell survival –...
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Strategies to improve anti tumor effectiveness of
radiotherapy
Eric Deutsch MD PhDInstitut Gustave Roussy
Villejuif, France
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RadiosensitizationRadiosensitization....
DNA damageDNA damagemodificationmodification
ApoptosisApoptosisinductioninduction
IncreaseIncrease in PA02in PA02NucleotideNucleotidedepletiondepletion
InhibitionInhibitionof DNA of DNA repairrepair
CellCell cycle cycle redistributionredistribution
Classical view : radiosensitization….
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Radiosensitization
Hypoxic targeting
Tyrosin kinaseinhibition
Tumor suppresor genesreplacement
COX-2 inhibition
Apoptosisinduction
Antiangiogenesis
Biological view..
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« Intrinsic »radiation response
Anti EGFr, mTOR, PI3K.. COX-2, Proteasome inhibitors, TNFr inducers
« extrinsic »micro environment
Anti VEGFr, FGFr
More than 60 new agents tested in phase I or II trials
*Source : www.clinicaltrials.gov
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MAPK
MEK
Gene transcriptionCell cycle progression
PI3-K
RAS RAF
SOSGRB2
PTEN AKTSTAT
R
KpY
R
pY
pY
K
proliferation/maturation
survival/anti-apoptosis angiogenesis
metastasis
DNAmyc
Myc
cyclin D1 Cyclin D1
Jun Fos
P P
chemotherapy/ radiotherapy resistance
EGFrEGFr
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R R
K K
Ligand
Tyrosine kinase inhibitors
ZD1839, Cp-358, PKI166
Monoclonal AB
C225..C225..
Signal transduction
SPECIFIC EGFr INHIBITORS :SPECIFIC EGFr INHIBITORS :
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C225 + irradiation
in vitro
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L. L. MilasMilas, T. , T. AkimotoAkimoto, , Int J Int J RadiatRadiat OncolOncol BiolBiol PhysPhys 5252 (2002), (2002),
EGFr expression : Dose EGFr expression : Dose effecteffect relationshiprelationship
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C225 & irradiation :
transfert from bench to clinic
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EGFR & radiotherapy :First clinical evidence of the value
of target agentscombined to radiotherapy
C225 + radiotherapie : Bonner NEJM 2006
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On the other side :the endothelial cell
Wachsberger, Clinical Cancer Research Vol. 9, 1957-1971, June 2003
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Tumor Neovasculature: Comparative Tortuosity and
Disorganization
From Konerding et al. In Molls and Vaupel, eds. Blood Perfusion and Microenvironment of Human Tumors, 2002.
Normal colorectal mucosa Nearby colorectal cancer
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Antivascular agents :a way to increase RT efficacy?
Wilett, Nature Medicine 05
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Toxicities of new agents
Budach W, New England Journal of Medicine, 2007
Anti EGFr + Radiotherapy : One (unusual) case of grade IV skin necrosis
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Modulation of lung injury
Abdollahi JEM 2005
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DEVELOPMENTS in RADIOTHERAPY
TECHNICAL BIOLOGY
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BALISITICS OPTIMIZATION : IMRT
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IMRTIn HNSCC
IMRT allows better accuracy
1) Normal tissues sparing
2) Dose escalation
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OPTIMIZED RADIOTHERAPY in GI TUMORS :Toward a bettertherapeutic index..
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The usefulness of functionnal imaging :the example of tyrapazamine
• Bioreductive agent whenhypoxic
• Radiosensitizer
Randomized phase III
RT + CDDP
RT + CDDP + Tyrapazamine
Overall results : 2 arms similar!!
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Tirapazamine : Hypoxia PET to select the patients?
Rischin, JCO 2006
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THE NEXT STEP :IMAGE GUIDED RADIOTHERAPY (PET as a tool for radiotherapy)
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DEVELOPMENTS in RADIOTHERAPY
TECHNICAL BIOLOGY
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Tumor stem cells :
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Stem cells radioresistance : G2/M arrest
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Induction polyploidy in p53-/-HCT116 cells by AZD1152
cycle HCT116 24h exposure to AZD1152
-10
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s - G1
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s - G1
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s - G1
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s - G1
G1
S
G2
>4N
p53-/- AZD1152
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Figure 6 HT29 cells IR and AZD1152 in vivo
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p53-/- and wt HCT116 tumour growth delay by IR and AZD1152 in vivo
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HCT116 cells xenograft
days IR alone
IR + AZD1152
Tao et al BJC 2008, Tao et al Oncogene 2008
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Cell death mecanims as targets for radiosensitizationMorphology of mitotic catastrophe (MC)
control
micronuclei
MC
Hoechst/β-tubulin
multinucleation
Morse et al, 2005
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Preferential mitotis entry for P53 deficient cells after irradiation
Different HCT116 cell lines mitosis index 24h after X and IR
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MPM
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cells
%
14-3-3-/-Mad2+/-wtp53-/-
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• Oncogenes– Activated from protooncogenes– Usually enhance cell proliferation
• Tumor suppressor genes– Inactivated by mutation or
deletion– Usually arrest cell proliferation
• Genes regulating apoptosis– Control cell survival– Overexpression,mutation or
deletion can enhance cell survival• Genes regulating metastasis
– Control cell motility and interaction with the environment
– Both activating and inactivating mutations
Hanahan and Weinberg 2000The hallmarks of cancer
Cell 100, 57-70.
Genes involved in cancer
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From the benchmark to the patients…
Oncogene2007
?++Aurora B
IJROBPCCR
Pfizer++++Statins
Can Res2003
??-++Roscovitine
AACR 2003-++Metastat
??-++Ritonavir
Oncogene2003Lancet Oncol
Ongoing-++Cidofovir
BJC, IJROBP <1995
OngoingSanofi
-++Tirapazamine
BJC 2003Abbott+++Omega-3
BJC 2003
??+/-++AG1024
J Urol 2003Ongoing+/-++NS398
PublicationXRTPhase I
Normal tissue
VivoVitroDrug
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Sorafenib, Chiron 265MélanomeB-RAF
AZD compoundsThyroïdeRET
DrogueCancerGène
Polyglogulies
LMCLAMLAM
Retinoblastome
GIST
Colon/Poumon
Li Fraumeni
Colon
Sein
Gllevec, Sutent, SorafenibC-Kit
Gleevec, DasatinibCEP701
Bcr-AblFLT-3PML-RAR
Brca1
AZD compoundsJAK
RB
Akt inhibitorsPTEN
p53
FTIPI3K inhibitors
K-RASPIKCAAPC
What mightmight What doesdoes cause cancerShift
Future challenges : Organ specific drug targeting
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« oncogene addiction »
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Weinstein Can Res 08
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Molecular pathology into radiation practice ?
TNM « ultra staging »• -GI tumors
• -Cervical cancer
• -Lung tumors
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Targeted therapies for RECTUM PRE OP RT?
HIGH EGFr
K-Ras 30%
PI3KCA mutations :20%
AKTAKT
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EGFR EGFR PDGFRPDGFRIGFIGF--1R1R
Tyrosine kinase receptorGrowthFactor
SH2SH2
Ras GTPRas GTP
P3P(3,4,5)
P
PP2
P(4,5)
PP
P
PTEN
P85PI3K
P
PDK1
AKT/PKB
P
P110PI3K
PI3K AKT the main pathwayfor radiation response
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Cell cycle
Apoptosis
Angiogenesis
PI3K/AKTPI3K/AKT
DNA repair
RAS Egfr
AKT the main AKTor
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The PI3K and mTOR inhibitor selectivelysensizites
« addicted tumor cells »
Cancer Res in press
Non tumor cells no/low PI3K activation Tumor cells with PI3K activation
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Virus related cancers (15% of cancers wordwide and 7% in western countries)…
Epstein-Barr virus (EBV) : Lymphoma, Nasopharynx…
Human papilloma virus (HPV) : Carcinoma of the cervix, HNSCC, anal cancer
Uterine cervix carcinoma : HPV 16 & 18 …
500 000 cases / year (3.700 in France)
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Cidofovir (HPMPC)
Phosphonates nucléoside acyclique Demi-vie de la drogue in vivo : 48 h
(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)Cytosine: [(S)-HPMPC]
Mécanisme d’actiondu Cidofovir
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ADNh
ADNh/V
Epithelila cell
+HPV16/18
DNA viral persistence
E6 E7
p53 pRb
In situ cancer
Cidofovir (10 ug/mL)+9GyAbdulkarim B et al 2001
/2002
Cervical cancer
p21 Cyclin E
(Abdulkarim et al 2001 oncogene)
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Abdulkarim et al. Oncogene, 2002
HPC positive : Me180 cell line
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HPV postivie tumors : restoration of p53 and pRB
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Oncogenes alterated inlung cancer :
NSCLC vs SCLC
RASC-MycEGFRHER2/neuIGF1
C-mycMybIGF-1BCL2
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Lung cancer :
0
500
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J15 J21 J28 J35 J42 J49 J56
T
RC
ASO
RC+RT
ASO+RT
BCL2 inhibition :
Loriot et al NCI EORTC 2007
Increase in radiation response in SCLC
NSCLC :
No moderate/zero effect
SCLC
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Looking toward the future..
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Personalised medicine : Challenges rely on tumor response
probability
Optimise radiotherapyDecrease late effects
Radiation sensitizer
Poor prognosis : Tumor « response » profile
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Toward molecular profiling?
• PreoperativeRadiotherapyin rectal cancer
responders
non responders
Watanade Can Res 2006
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Toward molecular profiling?
• PreoperativeRadiotherapyin rectal cancer
responders
non responders
Watanade Can Res 2006
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Fractionnation
Radiation sensitizers (EGFr…)
High Tech RT, IGRT
Drugs adaptedto
Molecularpathology
Increasing the antitumorefficacy of radiotherapywill require…
..integration of all aspects of radiation biology