angiogenesis presentation
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ANGIOGENESISDR. RAJKUMAR , R M.D.III YR POST GRADUATE
DEPT. OF MEDICAL ONCOLOGY
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Historical Highlights of the Anti-Angiogenesis Field
Historical Highlights of the Anti-Angiogenesis Field
• 1787 - British surgeon Dr. John Hunter first uses the term 'angiogenesis' (new blood vessel growth) to
describe blood vessels growing in the reindeer antler
• 1971 - Surgeon Dr. Judah Folkman hypothesizes that tumor growth is dependent upon angiogenesis. His theory, published in the New England Journal of Medicine, and is initially regarded as heresy by leading physician and scientists.
• 1975 - The first angiogenesis inhibitor is discovered in cartilage by Dr. Henry Brem and Dr. Judah Folkman.
• 1984 - The first angiogenic factor (basic fibroblast growth factor, bFGF) is purified by Yuen Shing and Michael
Klagsbrun at Harvard Medical School. • 1989 - One of the most important angiogenic factors, vascular
endothelial growth factor (VEGF), is discovered by Dr. Napoleone Ferrara and by Dr. Jean Plouet. It turns out to be identical to a molecule called Vascular Permeability Factor (VPF) discovered in 1983 by Dr. Harold Dvorak.
• 1787 - British surgeon Dr. John Hunter first uses the term 'angiogenesis' (new blood vessel growth) to
describe blood vessels growing in the reindeer antler
• 1971 - Surgeon Dr. Judah Folkman hypothesizes that tumor growth is dependent upon angiogenesis. His theory, published in the New England Journal of Medicine, and is initially regarded as heresy by leading physician and scientists.
• 1975 - The first angiogenesis inhibitor is discovered in cartilage by Dr. Henry Brem and Dr. Judah Folkman.
• 1984 - The first angiogenic factor (basic fibroblast growth factor, bFGF) is purified by Yuen Shing and Michael
Klagsbrun at Harvard Medical School. • 1989 - One of the most important angiogenic factors, vascular
endothelial growth factor (VEGF), is discovered by Dr. Napoleone Ferrara and by Dr. Jean Plouet. It turns out to be identical to a molecule called Vascular Permeability Factor (VPF) discovered in 1983 by Dr. Harold Dvorak.
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Historical Highlights of the Anti-Angiogenesis Field
Historical Highlights of the Anti-Angiogenesis Field
• 1997 - Dr. Michael O'Reilly publishes research finding in the journal Nature showing complete regression of
cancerous tumors following repeated cycles of anti-angiogenic therapy using angiostatin and endostatin
• 1999 - Massive wave of anti-angiogenic drugs in clinical trials: 46 anti- angiogenic drugs for cancer patients; 5 drugs for macular degeneration; 1 drug for diabetic retinopathy; 4 drugs for psoriasis.
• 1999 - Dr. Richard Klausner, Director of the U.S. National Cancer Institute designates the development of anti-
angiogenic therapies for cancer as a national priority. • 2003 - The monoclonal antibody drug Avastin (Bevacizumab)
becomes the first anti-angiogenic drug shown in large-scale clinical trials inhibiting tumor blood vessel growth can prolong survival in cancer patients.
• 1997 - Dr. Michael O'Reilly publishes research finding in the journal Nature showing complete regression of
cancerous tumors following repeated cycles of anti-angiogenic therapy using angiostatin and endostatin
• 1999 - Massive wave of anti-angiogenic drugs in clinical trials: 46 anti- angiogenic drugs for cancer patients; 5 drugs for macular degeneration; 1 drug for diabetic retinopathy; 4 drugs for psoriasis.
• 1999 - Dr. Richard Klausner, Director of the U.S. National Cancer Institute designates the development of anti-
angiogenic therapies for cancer as a national priority. • 2003 - The monoclonal antibody drug Avastin (Bevacizumab)
becomes the first anti-angiogenic drug shown in large-scale clinical trials inhibiting tumor blood vessel growth can prolong survival in cancer patients.
JUDAH FOLKMAN: Father of Angiogenesis
First person to observe angiogenesis as having pathological Implications in cancer in 1971
Born in Cleveland in 1933
Began his surgical residency at the Massachusetts General Hospital and served as chief resident in surgery from 1964-1965
Folkman Facts
While serving as a lieutenant in the U.S. Navy from 1960-1962, Folkman and a colleague first reported the use of silicone rubber implantable polymers for the sustained release of drugs
Formed basis of development of Norplant
INTRODUCTION
Angiogenesis : A fundamental biological process
Regulated by a fine balance Deranged in various diseases Historically, implicated in few diseases In recent years, it has been increasingly
evident that excessive, insufficient or abnormal angiogenesis contributes to the pathogenesis of many more disorders. 6
DEFINITION
The formation of new blood vessels out of pre-existing capillaries.
INVOLVES : Sprouting
Splitting
Remodeling of the existing vessels
WHY IT IS IMPORTANT? Supply of oxygen and nutrients Removal of waste products
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VASCULOGENESIS : the generation of blood vessels from hemangioblasts (endothelial cell precursors).
New blood vessels mainly emerge from pre-existing ones.
Can be seen in adult life also.
Physiologic stimuli during wound healing and the reproductive cycle in women lead to angiogenesis.
New endothelial cells differentiate from stem cells.
Seen during embryonic development( for primary vasculature).
Vasculogenesis is absent even in presence of physiologic stimuli.
ANGIOGENESIS VASCULOGENESIS
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Definitions
Vasculogenesis Formation of new vessels from EC precursors (angioblasts)
Angiogenesis Formation of new vessels from pre-existing BV by sprouting
Arteriogenesis Subsequent stabilisation and maturation
Collateralisation Enlarging existing vessels as bridges between networks
(Myogenesis)
What Is Tumor Angiogenesis?
Blood vessel
Tumor that can grow and spreadSmall localized tumor
Signaling molecule
Angiogenesis
Normal Angiogenesis in Children
Normal Angiogenesis in Adults
Angiogenesis in tissue during wound healing
Angiogenesis in uterine lining
Angiogenesis andVascular Endothelial Cells
Vascular endothelial cells
Blood vessel
Angiogenesis and Regulatory Proteins
Rare cell division
Concentration of Angiogenesis Inhibitors
Blood vessel
Inhibitors low
Activators high
Inhibitors high
Activators low
Frequent cell division
Angiogenesis and Cancer
AngiogenesisVessel dilation
New TheoryOld Theory
Without Angiogenesis,Tumor Growth Stops
Injected cancer cells stop growing as mass reaches 1–2 mm in diameter
Isolated organ (e.g., thyroid gland)
Infuse nutrient solution
With Angiogenesis,Tumor Growth Proceeds
Tumor suspended in anterior chamber
Tum
or s
ize
Days
Iris
Lens
Tumor growing on the iris
Tumor suspended in anterior chamber
CorneaTumor growing on the iris
2 4 6 8 10
What Prompts Angiogenesis?
Angiogenesis
Chamber
Cancer cell Signaling molecule
Place chamber beneath an animal's skin
Tumor Angiogenesis: A Balancing Act
Folkman J, Nature Drug Discovery 6:274, 2007
Activators of Angiogenesis
Vascular Endothelial Growth Factor
• Glycoproteins consisting of A-, B-, C-, D-, E- forms and Placenta Growth Factor (PLGF)
• Within the six subtypes multiple isoforms exist
• Loss of even a single VEGF-A allele results in embryonic lethality due to cardiac complications
VEGF Receptors• 3 types of receptors- VEGFR-1, VEGFR-2 (KDR, Flk-1), VEGFR-3
• Tyrosine kinases
• 316 residues
• 35% helical
• 15% beta sheet
Figure 1 VEGF family ligands and receptors
Biochemical Society Transactions www.biochemsoctrans.org Biochem. Soc. Trans. (2003) 31, 1171-1177
Figure 2 VEGF signaling pathways
Biochemical Society Transactions www.biochemsoctrans.org Biochem. Soc. Trans. (2003) 31, 1171-1177
Platelet-derived growth factor
• The platelet-derived growth factor (PDGF) regulates the recruitment of pericytes and smooth muscle cells
required for further stabilization of the new capillaries
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Fibroblast growth factor
• Fibroblast growth factor (FGF) family are also potent inducers of angiogenesis. The effects of FGFs are mediated via high-affinity tyrosine kinase receptors.
• Cellular responses mediated by FGFs include cell migration proliferation differentiation
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The Angiogenesis Signaling Cascade
Genes are activated in cell nucleus
Cancer cell
VEGF (or bFGF)
Endothelial cell surfaceRelay
proteins
Receptor protein
Proteins stimulate new endothelial cell
growth
Endothelial Cell Activation
SecretesMMPs that
digest surrounding
matrix
Cell migrates and divides
Matrix
Activated endothelial cell
Inhibitors of Angiogenesis
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Angiogenesis InhibitorsAngiogenesis Inhibitors• Other angiogenesis inhibitors have been found
in nature - in green tea, soy products, fungi, mushrooms, Chinese cabbage, tree bark, shark tissues, snake venom, red wine, and many other substances.
• Still other angiogenesis inhibitors have been manufactured synthetically in the laboratory.
• Some FDA-approved medicines have also been "re-discovered" to have anti-angiogenic properties.
• Other angiogenesis inhibitors have been found in nature - in green tea, soy products, fungi, mushrooms, Chinese cabbage, tree bark, shark tissues, snake venom, red wine, and many other substances.
• Still other angiogenesis inhibitors have been manufactured synthetically in the laboratory.
• Some FDA-approved medicines have also been "re-discovered" to have anti-angiogenic properties.
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ENDOSTATINENDOSTATIN• It was first discovered
in 1995 in Dr. Folkman’s lab
• Phase I clinical studies began at M.D. Anderson November 1999
• A naturally-occurring 20-kDa C-terminal fragment derived from type XVIII collagen.
• Interfere with the pro-angiogenic action of growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and vascular endothelial growth factor (VEGF)
• It was first discovered in 1995 in Dr. Folkman’s lab
• Phase I clinical studies began at M.D. Anderson November 1999
• A naturally-occurring 20-kDa C-terminal fragment derived from type XVIII collagen.
• Interfere with the pro-angiogenic action of growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and vascular endothelial growth factor (VEGF)
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ANGIOSTATINANGIOSTATIN• Naturally occurring
protein found in several animal species, including humans.
• It is an endogenous angiogenesis inhibitor
• Angiostatin is produced by autoproteolytic cleavage of plasminogen,
• Can be cleaved from plasminogen by different metalloproteinases (MMPs), elastase, prostata-specific antigen (PSA), 13 KD serine protease, or 24KD endopeptidase.
• Naturally occurring protein found in several animal species, including humans.
• It is an endogenous angiogenesis inhibitor
• Angiostatin is produced by autoproteolytic cleavage of plasminogen,
• Can be cleaved from plasminogen by different metalloproteinases (MMPs), elastase, prostata-specific antigen (PSA), 13 KD serine protease, or 24KD endopeptidase.
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ANGIOSTATINANGIOSTATIN
• It is a 57 kDa fragment of a larger protein, Plasmin (itself a fragment of plasminogen)
• Encloses three to five contiguous Kringle modules.
• Each Kringle module contains two small beta sheets and three disulfide bonds.
• Considerable uncertainty on its mechanism of action, but it seems to involve the inhibition of endothelial cell migration, proliferation and induction of apoptosis.
• It is a 57 kDa fragment of a larger protein, Plasmin (itself a fragment of plasminogen)
• Encloses three to five contiguous Kringle modules.
• Each Kringle module contains two small beta sheets and three disulfide bonds.
• Considerable uncertainty on its mechanism of action, but it seems to involve the inhibition of endothelial cell migration, proliferation and induction of apoptosis.
Angiogenesis Inhibitors andPrimary Tumors
Stop
Tumor size
in mice
Endostatin Treatment
0 40 80 120 160 200 240Days
Start Start
Stop
Angiogenesis Inhibitors and Metastasis
Injectcancer cells
Angiostatin injections
No treatment
Allow time for metastases to appear
Many metastasesFew metastases
Removeinitial tumor
Let initial tumor grow for
several weeks
Angiogenesis and Tumor Dormancy
Large primary tumor
Angiostatin inhibits
Tiny dormant tumor masses
Cancer in Angiogenesis-Deficient Mice
Normal mouse
No cancerCancer
Inject breast cancer cells
Angiogenesis-deficient mutant mouse
Angiogenesis Inhibitors in theTreatment of Human Cancer
Matrix
Cancer cell
VEGF (or bFGF)
Angiogenesis Inhibitors
MMPs
Receptor protein
Endothelial cell
Drugs That Inhibit Angiogenesis Directly
Integrin
Combretastatin A4
Apoptosis
Endostatin EMD121974 TNP-470 Squalamine
Cancer cell
VEGF(or bFGF)
MMPs
Receptor protein
Matrix
Endothelial cell
Integrin interacts with drugs to destroy proliferating endothelial cells
Drugmolecule
Old Drug With a New Use
Matrix
Cancer cell
VEGF (or bFGF)
MMPs
Receptor protein
Endothelial cell Thalidomide
Drugs That Block theAngiogenesis Signaling Cascade
Matrix
Cancer cell
VEGF (or bFGF)
MMPs
Receptor protein
Endothelial cell
Interferon-alpha
Anti-VEGF antibodySU5416 SU6668 PTK787/ZK 22584
No endothelialcell growth
Drugs That BlockExtracellular Matrix Breakdown
MarimistatAG3340COL-3NeovastatBMS-275291
Matrix
Cancer cell
VEGF (or bFGF)
MMPs
Receptor protein
Endothelial cell
No endothelialcell migration
Potential Mechanism of Efficacy Folkman Hypothesis – Glioblastomas are
angiogenesis- dependent – Growth advantage Jain Hypothesis – Normalization of vessels →
Reduction of hypoxia, interstitial pressure, and increased drug delivery
Stem Cell Hypothesis – Glioma stem cells promote angiogenesis via VEGF – Vascular niche protects stem cells (Bao et al., Cancer Res, 2006; 66:7843-8)
NORMAL BODY BLOOD VESSEL FORMATION
• Stages
A: Vasculogenesis
B: Angiogenic remodeling
C: Stabilization and maturation
D: Destabilization
E: Regression
F: Sprouting
STAGE A: VASCULOGENESIS
• Undifferentiated
vascular bedding
during embryonic
development• Vascular
Endothelial Growth
Factor (VEGF) triggers this process
STAGE B: ANGIOGENESIS• Pruning of primitive tubular network to form
blood vessels • Vascular Endothelial Growth Factor (VEGF)
is required
STAGE C: STABILIZATION AND MATURATION
Endothelial cells integrate
tightly with supporting cells
such as smooth muscle cells
and pericytes
Cell walls mature
STAGE D: DESTABILIZATION
• Angiogenic sprouting into previously avascular tissue occurs
• Distinct angiogenesis
from previous type • Only possible if pre-existing
vessels are first destabilized
TUMOR ANGIOGENIC DEPENDENCY
• Tumor- undesired growth of cells
• Once a tumor grows beyond 100-200 μM in size, the development of new vasculature becomes essential to maintain adequate tumor oxygenation and sustained tumor growth
Structure of vessels and capillaries
Monocellular layer of endothelial cellsSmall artery:
Capillary: endothelial cell, basal lamina, pericytes
Angiogenesis:Sprouting of cells from mature endothelial cells of the vessel wall
Mouse cornea:wounding induces angiogenesis,chemotactic response toangiogenic factors
(secretion of proteases, resolution ofBasal lamina, migration towards Chemotactic gradient, proliferation,Tube formation)
VEGF is factor largely specific for endothelial cells,bFGF can also induce, not specific for EC)
Sprouting towards chemotactic gradient: VEGF
Hypoxia - HIF - VEGFevery cell must be within 50 to 100 mm of a capillary
HIF: hypoxia inducible factorVEGF: vascular endothelial growth factor
VEGF-gene:Regulated by HIF,HIF is continously produced,ubiquitinylated, degraded in proteasome,therefore low concentration;
Ubiquitinylation dependent onHippel-Lindau tumor suppressor(part of an E3 ubiquitin-ligase complex)
HIF1ais modified by a prolyl hydroxylase,then better interaction with vHL protein, high turnover;Hydroxylase is regulated by O2
Von Hippel-Lindau Tumor Suppressor, HIF and VEGF
capillaries sprouting in the retina of an embryonic mouse
capillary lumen opening up behind the tip cell(red dye injected)
ROLE OF VEGF
• VEGF production is under control of :
hypoxia inducible factor (HIF) • VEGF receptor expression is up-regulated under :
hypoxic or ischemic conditions. So, early involvement of VEGF in this process.
• VEGF is a major player in angiogenesis initiation
because: i) it induces vasodilatation
via endothelial NO production
ii)it increases endothelial cell
permeability
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So it cause:
1. vasodilatation
2. increased vascular permeability
3. can induce the expression of proteases and receptors important in cellular invasion and tissue remodeling
4. prevent endothelial cell apoptosis
But angiogenesis is not completely dependent on VEGF production. Recently shown by : Hansen-Algenstaedt et al.
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VASCULOGENESIS
Formation of vessels by differentiation of cells from angioblasts in the yolk sac of the embryo:
Is differentiation and proliferation of endothelial cells in a non-vascularized tissue
Leads to formation of a primitive tubular network
Has to undergo angiogenic remodeling to stable vascular system
Hemangioblast Angioblast EC
POSTNATAL VASCULOGENESIS
TUMOR ANGIOGENESIS
Three major steps
(A) Initiation of the angiogenic response,
(B) Endothelial cell(EC) migration, proliferation
and tube formation,
(C) Finally the maturation of the neovasculature.62
Proteases
matrix metalloproteases plasminogen activator(PA) /
(MMPs) plasmin system
PAs activate the plasminogen
degrade different into plasmin, which degrades
protein types several components of
extracellular matrix (ECM)
• Both PAs and MMPs are secreted together with their inhibitors: PAI &TIMP• It ensures a stringent control of local proteolytic activity.
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TUMOR ANGIOGENESIS
So, the extracellular matrix is degraded
An increased concentration of various
growth factors
So, EC(‘leader EC’) migration and
proliferation.
Result : small sprouts
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(b) Endothelial cell migration, proliferation, and tube formation
• The ‘leader EC’ starts migrating and proliferating • More EC starts to migrate through the degraded
matrix• So, forms small sprouts.
• After the initial period of migration, rapid EC proliferation begins, thus increasing the rate of sprout elongation.
• These processes are also mediated by cell adhesion molecules(CAM).
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cell adhesion molecules(CAM)
• Integrin, cadherin, vascular cell adhesion molecule-1, P-
selectin and E-selectin are implicated in angiogenesis.
• Integrin αvβ3 plays a critical role in angiogenesis.
• It is expressed at high levels in : tumor vasculature and wound-healing tissues , but at extremely low levels in normal blood vessels.
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(C) Maturation of the neovasculature
• THE FINAL PHASE• Establishment of polarity of the endothelial cells :
by CAM Finally, when sufficient neovascularization has
occurred, the angiogenic factors are down regulated
or
the local concentration of the inhibitors increases.
“A FINELY BALANCED EQUILIBRIUM”
As a result, the endothelial cells become quiescent. 67
Cellular mechanisms of tumour angiogenesis
(1) host vascular network expands by budding of endothelial sprouts or formation of bridges (angiogenesis);
(2) tumour vessels remodel and expand by the insertion of interstitial tissue columns into the lumen of pre-existing vessels (intussusception); and
(3) endothelial cell precursors (angioblasts) home from the bone marrow or peripheral blood into tumours and contribute to the endothelial lining of tumour vessels (vasculogenesis)
(4) Lymphatic vessels around tumours drain the interstitial fluid and provide a gateway for metastasizing tumour cells.
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3
4
1
2
3
4
Cellular angiogenesis-overview
Nature Reviews Drug Discovery 1, 415-426 (2002)
Steps in network formation and maturation during tumour angiogenesis
Key differences in tumour vasculature
Different flow characteristics or blood volume
Microvasculature permeability
Increased fractional volume of extravascular, extracellular space
AngiogenesisDysregulation in disease states
INSUFFICIENT ANGIOGENESIS :
1. Ischemic tissue injury e.g. critical limb ischemia in diabetes
2. Cardiac failure
3. Delayed healing of gastric ulcers
4. Recurrent aphthous ulcerations
5. Organ dysfunction occurring in pre-eclampsia
6. Age-related diseases e.g. nephropathy and osteoporosis
7. Purpura, Telangiectasia
8. Pulmonary fibrosis & Emphysema
9. Amyotrophic Lateral Sclerosis
10. Alzheimer's disease So PROMOTING ANGIOGENESIS is helpful here
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EXCESS ANGIOGENESIS :
• Cancer• Arthritis• Psoriasis• Blinding retinopathy • Atherosclerosis• Restenosis• Transplant
arteriopathy• Warts• Scar keloids • Synovitis • Osteomyelitis
• Asthma• Nasal polyps• Choroideal and
intraocular disorders• Retinopathy of
prematurity• Diabetic retinopathy• AIDS• Endometriosis
So HALTING ANGIOGENESIS is helpful here
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THERAPEUTIC ANGIOGENESIS
Stimulation :
Approved indication• Chronic wound – diabetic
ulcer
Experimental indication
• Myocardial infarction• Peripheral ischemia• Cerebral ischemia• Reconstructive surgery• Gastoduodenal ulcer
Inhibition : Approved indication• Advanced cancer• Ocular neovascularization• Kaposi sarcoma
Experimental indication • Hemangioma• Psoriasis• Rheumatoid arthritis• Endometriosis• Atherosclerosis
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CHALLENGES OF ANGIOGENIC THERAPY
• VEGF forms leaky and tortuous vessels• Adverse Effects of increased levels of
angiogenic factors such as triggering of dormant tumors and acceleration of atherosclerosis.
77
development of angiogenesis inhibitors
Usually follows any the following :
1. inhibition of tumor cell synthesis of angiogenic proteins
2. the neutralization of angiogenic proteins by antibodies or traps
3. inhibition of endothelial cell binding to angiogenic proteins
4. direct induction of endothelial cell apoptosis.78
Strategies for inhibition of tumor growth by anti-
angiogenic drugs
79
ANTIANGIOGENIC THERAPY
• A large number of agents that target angiogenesis are in clinical development. They can be broadly classified as :
I. agents that have been developed primarily for their antiangiogenic activity
II. those that have been developed or used for other biologic effects but also have anti-angiogenic activity e.g. celecoxib, rosiglitazone, zolendronic acid, interferon alpha, everolimus,vorinostat etc.
80
HOW TO MAKE THESE AGENT MORE ATTRACTIVE FOR USE
• One possible approach to improve the therapeutic efficacy and selective toxicity of anticancer drugs is by targeting anticancer drugs through
I. monoclonal antibodies (MAbs) or
II. peptide ligands that bind to molecules that are over expressed on the plasma membrane of cancer cells or tumor-associated endothelial cells. 81
DRUGS THAT BLOCK THE ANGIOGENESIS SIGNALING CASCADE Anti-VEGF antibodies that block the VEGF receptor from
binding growth factor. Bevacizumab, is the first of these anti-VEGF antibodies.
Interferon-alpha, is a naturally occurring protein that inhibits the production of bFGF and VEGF, preventing these growth factors from starting the signaling cascade
DRUGS THAT INHIBIT ANGIOGENESIS DIRECTLY
Endostatin, the naturally occurring protein known to inhibit tumor growth in animals.
Combretastatin A4, causes growing endothelial cells to commit suicide (apoptosis).
DRUGS THAT BLOCK EXTRACELLULAR MATRIX BREAKDOWN
Marimistat Neovastat
DRUGS WITH OTHER MECHANISMS OF ACTION
Involves mechanisms that are either nonspecific or are not clearly understood.
A drug called CAI, exerts its effects by inhibiting the influx of calcium ions into cells.
While this inhibition of calcium uptake suppresses the growth of endothelial cells, such a general mechanism may affect many other cellular processes.
Current Angiogenic Inhibitors in Clinical Use and Clinical Trials
Bevacizumab (Avastin™) Sunitinib (Sutent™) Sorafenib (Nexavar™) Cederanib (Recentin™ - AZD- 2171) Cilengitide VEGF-Trap
Many others in development
“AVASTIN BEVACIZUMAB- REACH BEYOND CONVENTION”
Recombinant, humanized monoclonal antibody that binds to all isoforms of VEGF-A such that KDR signaling is inhibited
Developed by Genentech BioOncology
Not a chemotherapy drug: “Targeted Therapy”
BEVACIZUMAB CONTINUED
FDA-approved for first and second-line treatment of colorectal and rectum cancer in combination with oxaliplatin, leucovorin and fluorouracil (FOLFOX4) in 2004
Approved for first-line treatment of Non-Small Cell Lung Cancer in combination with Carboplatin and Paclitaxel
Previously investigated in combination with Fluorouracil in phase II and III trials in a wide variety of tumors
Study results initially presented at the 2003 Annual Meeting of the American Society of Clinical Oncology (ASCO)
EFFICACY Adding Bevacizumab to chemotherapy
results in increased median Progression Free Survival by 33%
Median survival was 15.1 and 18.3 months in the Leucovorin (IFL)/placebo, and 5-FU/LV/Bevacizumab trial groups respectively
Overall Response Rate and duration of response were also increased in the Bevacizumab-containing group
DOSAGE
Colorectal and rectum cancer AVASTIN in combination with
intravenous 5-FU-based chemotherapy- 5 mg/kg or 10 mg/kg every 14 days AVASTIN in combination with bolus-IFL- 5 mg/kg AVASTIN in combination with FOLFOX4- 10 mg/kgNon-Squamous, Non-Small Cell Lung
Cancer 15 mg/kg, as an IV infusion every 3 weeks
BENEFITS
Non chemotherapeutic- biological agent that is less invasive to the body than chemotherapeutic agents
Half life of 20 days- good drug retention
CONCERNS Since Bevacizumab is expected to inhibit new
angiogenic growth, concerns have been raised regarding postoperative wound-healing and bleeding complications in patients who undergo surgery within 1 to 2 months of Bevacizumab therapy
BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION
Gastrointestinal (GI) perforation
Wound healing complication
Hemorrhage
Neutropenia
FUTURE DIRECTIONS-VEGF-TRAP
Composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to a human Fc segment of IgG1 that binds VEGF
Decreases free VEGF to bind to receptors and prevent vessel growth
FDA approved for macular degeneration
Bevacizumab- Efficacy in Clinical Trials – Metastatic Colorectal Cancer
From Ferrara N, Nat Rev Drug Discovery, 2004; Hurwitz et al, NEJM, 2004
Bevacizumab + Irinotecan
Patient 2 before and after (2 mos apart)
Courtesy Dr. Sajeel Chowdhary, Moffitt Cancer Center
Response Rates 6-month PFS of 43% and median PFS of 24 weeks
compares favorably to historical controls (Wong et al., J. Clin.
Oncol., 1999) of 15% and 9 weeks, using 8 previous chemotherapy regimens
Overall 1-year survival of 37% compares favorably to historical control of 21% (Wong et al., 1999)
Temozolomide, in combination with other agents
(e.g., irinotecan, erlotinib, etoposide) produced modest improvements in R.R. or O.S., but not as dramatic as bevacizumab + irinotecan
THE TOXICITIES INDUCED BY ANTI-ANGIOGENIC THERAPY
CONCLUSION
The study of angiogenesis is making a profound impact on the biological and medical world.
The hope of being able to build new, functional, and durable blood vessels in ischemic tissues, or conversely, to prevent their further growth in malignant and inflamed tissues is becoming more realistic every day.
However, efforts to therapeutically stimulate new blood vessels have significantly lagged behind those to inhibit angiogenesis.
Better understanding of the underlying process will enable the scientist to develop new drugs and therapies that will significantly enhance our ability to treat intractable diseases, such as, cancer, diabetes, and heart disease.
Modulation of angiogenesis may have an impact on diseases in the
twenty-first century similar to that which the discovery of
antibiotics had in the twentieth century….
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