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.

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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

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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.

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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….