Angiotherapy and gene therapy in cancer treatment
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Transcript of Angiotherapy and gene therapy in cancer treatment
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Angiotherapy and gene therapy in Angiotherapy and gene therapy in cancer treatmentcancer treatment
These slides provide an overview of angiotherapy and gene therapy in cancer
Dr. Momna Hejmadi, University of Bath
N.B. Some images used in these slides are from the textbooks listed and are not covered under the Creative Commons license as yet
This resource created by Dr. Momna Hejmadi, University of Bath, 2010, is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 2.0 UK: England & Wales License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/2.0/uk/
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Newer cancer therapiesNewer cancer therapies
AngiotherapyAngiotherapy
use of agents that inhibit angiogenesisuse of agents that inhibit angiogenesis
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Angiogenesis-overviewAngiogenesis-overview
Nature Reviews Drug Discovery 1, 415-426 (2002)
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EndostatinEndostatin Discovered in 1995 by Judah Folkman et alDiscovered in 1995 by Judah Folkman et al Phase I clinical trial in 1999Phase I clinical trial in 1999Dr. James Watson predicted that Dr. Folkman would cure all Dr. James Watson predicted that Dr. Folkman would cure all
cancer within 2 yearscancer within 2 years
Dr. Folkman’s responseDr. Folkman’s response““If you are a mouse and have cancer we can If you are a mouse and have cancer we can take good care of you. However, in our take good care of you. However, in our experiments we mostly sacrifice the mice. So, I experiments we mostly sacrifice the mice. So, I don't know if that qualifies as taking good don't know if that qualifies as taking good care”care”
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Angiogenesis: an organizing principle for drug discovery by Judah Folkman
Nature Reviews Drug Discovery 6, 273-286 (April 2007)
(Courtesy of L. Heuser and R. Ackland, University of Louisville, USA
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Categories of anti-angiogenicsCategories of anti-angiogenicsAnti-angiogenic molecules fall into 5 categories inhibitors of angiogenic growth factors:VEGF, bFGF, PDGF protease inhibitors: prevents the breakdown of the
surrounding matrix, which is needed for blood-vessel growth
Analogs of endogenous inhibitors of angiogenesis e.g. endostatin;
inhibitors of cellular adhesion molecules molecules with undefined mechanisms
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‘‘cryptic’ angiogenesis inhibitorscryptic’ angiogenesis inhibitors
AngiostatinAngiostatin 38kDa fragment of 38kDa fragment of
plasminogenplasminogen
EndostatinEndostatin 20kDa fragment of collagen 20kDa fragment of collagen
XVIIIXVIII Endothelial cell specificEndothelial cell specific Complete regression in miceComplete regression in mice No drug resistanceNo drug resistance
Inactive until released from the parent protein by enzymatic cleavage
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FDA approved drugsFDA approved drugs
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Anti-VEGFR2 Anti-VEGFR2 therapytherapy
(c,d) Anti-VEGFR2 prunes immature vessels, leading to a progressively 'normalized' vasculature(e) Further treatment leads to a vasculature that is inadequate to sustain tumour growth by day 5. (f) Perivascular cells expressing GFP (under the control of the VEGF promoter) envelope some vessels in the tumour interior. (g) A perivascular cell, presumably a fibroblast, leading the endothelial sprout (arrow).
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Before treatment after treatment
Efficacy of thalidomide as an anti-angiogenic agentEfficacy of thalidomide as an anti-angiogenic agent
Blood-flow maps a | before treatment and b | six months aftertreatment of a patient with metastatic renal-cell carcinoma with thalidomide.
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Haematological malignancies?Haematological malignancies?Neovasculature around bone marrow in certain
leukaemias. Anti-angiogenic drugs could therefore be useful in haematolgical malignancies
Bone marrow from a child with newly diagnosed acute lymphoblastic leukaemia reveals intense neovascularization, with microvessels of variable diameters.
normal bone marrow (from a child with a non-neoplastic
disease) shows normal microvasculature of uniform-
sized vessels.
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Timeline of anti-angiogenic drugsTimeline of anti-angiogenic drugs
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Combination with chemotherapyCombination with chemotherapyDosing schedule differences between conventional Dosing schedule differences between conventional chemotherapy (red) and anti-angiogenic chemotherapychemotherapy (red) and anti-angiogenic chemotherapy
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ReferencesReferences
1) Angiogenesis modulation in cancer research:Novel clinical 1) Angiogenesis modulation in cancer research:Novel clinical approaches by approaches by M Cristofanilli, C Charnsangavej‡ M Cristofanilli, C Charnsangavej‡ and GN.Hortobagyiand GN.Hortobagyi
Nature reviews drug discovery VOL 1 JUNE pp 415 (2002)Nature reviews drug discovery VOL 1 JUNE pp 415 (2002)
2) 2) Angiogenesis: an organizing principle for drug discovery by Judah Folkman
Nature Reviews Drug Discovery 6, 273-286 (April 2007)
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Newer cancer therapiesNewer cancer therapies
gene therapygene therapy
Direct genetic modification of cells in patients
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deliverydelivery
3 challenges in gene therapy3 challenges in gene therapy
deliverydelivery deliverydelivery
1)1) Package the genePackage the gene2)2) Protect the geneProtect the gene3)3) targeted delivery to the nucleus and targeted delivery to the nucleus and
release in an active formrelease in an active form
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Carrier molecules designed specifically Carrier molecules designed specifically
to enter cells & deposit therapeutic to enter cells & deposit therapeutic
genesgenes
Vectors ‘Trojan horses’ that sneak the gene into the cell
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METHODS OF VECTOR DELIVERYMETHODS OF VECTOR DELIVERY
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Viral vector strategyViral vector strategyReplication & virulence genes can be Replication & virulence genes can be
substituted with therapeutic genessubstituted with therapeutic genes
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designed to enter cell and deposit genesdesigned to enter cell and deposit genes
Specially constructed Specially constructed to prevent the generation to prevent the generation
of replication competent retroviruses (RCR)of replication competent retroviruses (RCR)
Retroviral vectorsRetroviral vectors
AdvantagesAdvantages• long-term expression long-term expression • low toxicity low toxicity • high capacity high capacity • low antivector low antivector
immunityimmunity
ProblemsProblems• Lack of cell specificityLack of cell specificity• Random splicing into Random splicing into
host DNAhost DNA
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Minimal HIV vector plasmid
All genes coding for enzymatic or structural HIV proteins have been removed.(1) consisting of the CMV/HIV LTR hybrid promoter followed by the packaging signal ( Ψ), the rev-binding element RRE for cytoplasmic export of the RNA, the transgene expression cassette consisting of internal promoter(s) and transgene(s), and the 3' self-inactivating (SIN) LTR. Together with the HIV vector plasmid (1), the HIV packaging plasmid (2), HIV rev (3), and an envelope expressing plasmid (4) are needed for HIV vector production.
Gene Therapy (2005) 12, 1089–1098
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Adenoviral vectorsAdenoviral vectors
do not insert into genome
temporary
lack of specificity
strong immune response
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Adeno-associated viral vectorsAdeno-associated viral vectors
Nature Reviews Genetics 1; 91-99 (2000);
Integrate into genome but small in size
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Non-toxicNon-toxic
no immune responseno immune response
reduced specificityreduced specificity
Non-viral VectorsNon-viral Vectors
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Non-viral VectorsNon-viral Vectors
liposomes (liposomes (lipoplexeslipoplexes)) Gene gun
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clinical trials by vector
27%
12%
11%
2% 7%6%
34%
retrovirusadenoviruslipofectionnaked DNApox virusAAVothers
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Germ line gene therapyGerm line gene therapy
Somatic cell gene therapySomatic cell gene therapy
Gene augmentationGene augmentation
Gene replacementGene replacement
Specific inhibition of gene expressionSpecific inhibition of gene expression
Targeted cell death Targeted cell death
Gene therapy targetsGene therapy targets
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Gene augmentationGene augmentationmost therapies simply add a useful gene into a selected cell type to most therapies simply add a useful gene into a selected cell type to
compensate for the missing or flawed version. compensate for the missing or flawed version.
Useful in treating loss of function mutations such as Tumour suppressor genesUseful in treating loss of function mutations such as Tumour suppressor genes
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Gene replacementGene replacement
This strategy replaces the mutant copy with a correctly This strategy replaces the mutant copy with a correctly functioning copy in situ. functioning copy in situ.
Useful for gain of function mutations such as oncogenesUseful for gain of function mutations such as oncogenes
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Specific inhibition of gene expressionSpecific inhibition of gene expressionInvolves silencing of specific genes like activated oncogenes, Involves silencing of specific genes like activated oncogenes,
by using molecules that degrade RNA transcripts. by using molecules that degrade RNA transcripts. Strategies includeStrategies include
Antisense therapyAntisense therapysiRNA (siRNA (small interfering RNA)small interfering RNA)Ribozymes etcRibozymes etc
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Targeted cell deathTargeted cell death
Tissue-specific delivery of drugs using vectors resulting in Tissue-specific delivery of drugs using vectors resulting in tissue specific toxicity. tissue specific toxicity.
Direct approachDirect approach
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Targeted cell deathTargeted cell deathIndirect approachIndirect approach
stimulating an immune response against selected stimulating an immune response against selected cells or eliminating the blood supply.cells or eliminating the blood supply.
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Gene therapy in cancerGene therapy in cancergene therapy clinical trials
12%
6%
8%10%
64%
cancer
monogenic disease
infectious disease
vascular disease
others
http://www.wiley.co.uk/genetherapy/clinical/
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Some examples Some examples
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Severe Combined Immunodeficiency
(SCID)
Rare condition caused by the lack or reduction in the immune system (‘bubble baby syndrome’)
Patients cannot make T lymphocytes and their B lymphocytes fail to make essential antibodies for fighting infections.
Gene therapy in X-SCID patients
X-SCID caused by mutations in the X-linked gene IL2RG, which encodes the common gamma chain (gc) of the lymphocyte receptors for interleukin-2 (IL-2) and many other cytokines
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Gene therapy by injection of retrovirally transduced autologous CD34+ hematopoietic stem cells (HSCs).
insertional mutagenesis near the proto-oncogene LMO2 promoter (Science, 302:415-419, October 17, 2003)
2/11 X-SCID patients developed 2/11 X-SCID patients developed leukemialeukemia
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ReferencesReferences
Chapter 16: Biology of Cancer by RA Chapter 16: Biology of Cancer by RA Weinberg Weinberg
Human gene therapy by Ioannou, Panos A(www.els.net)
Nature Reviews Cancer (2001) vol 1 pp 130-141 by Francis McCormick