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Angiogenesis presentation

  2. 2. 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. 2
  3. 3. Historical Highlights of the Anti-Angiogenesis Field• 1997 - Dr. Michael OReilly 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. 3
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. DEFINITIONThe formation of new blood vessels out of pre-existing capillaries.INVOLVES : Sprouting Splitting Remodeling of the existing vesselsWHY IT IS IMPORTANT? Supply of oxygen and nutrients 7 Removal of waste products
  8. 8. VASCULOGENESIS : the generationof blood vessels from hemangioblasts (endothelial cell precursors). ANGIOGENESIS VASCULOGENESIS New blood vessels mainly  New endothelial cells emerge from pre-existing differentiate from stem cells. ones.  Seen during embryonic Can be seen in adult life development( for primary also. vasculature). Physiologic stimuli during  Vasculogenesis is absent even wound healing and the in presence of physiologic reproductive cycle in stimuli. 8 women lead to angiogenesis.
  9. 9. DefinitionsVasculogenesis Formation of new vessels from EC precursors (angioblasts)Angiogenesis Formation of new vessels from pre- existing BV by sproutingArteriogenesis Subsequent stabilisation and maturationCollateralisation Enlarging existing vessels as bridges between networks(Myogenesis)
  10. 10. What Is Tumor Angiogenesis? Small localized tumor Tumor that can grow and spread AngiogenesisBlood vessel Signaling molecule
  11. 11. Normal Angiogenesis in Children
  12. 12. Normal Angiogenesis in Adults Angiogenesis in uterine lining Angiogenesis in tissue during wound healing
  13. 13. Angiogenesis andVascular Endothelial CellsBlood vessel Vascular endothelial cells
  14. 14. Angiogenesis and Regulatory Proteins Concentration of Angiogenesis Inhibitors Inhibitors high Inhibitors low Activators low Activators high Blood vessel Rare cell division Frequent cell division
  15. 15. Angiogenesis and Cancer Old Theory New TheoryVessel dilation Angiogenesis
  16. 16. Without Angiogenesis, Tumor Growth StopsInfuse nutrient solution Isolated organ (e.g., thyroid gland) Injected cancer cells stop growing as mass reaches 1–2 mm in diameter
  17. 17. With Angiogenesis, Tumor Growth Proceeds Tumor suspended in anterior chamber Tumor growing on the iris TumorCornea growing Tumor size on the iris Tumor suspended in anterior Iris chamber Lens 2 4 6 8 10 Days
  18. 18. What Prompts Angiogenesis? Chamber Cancer cell Signaling molecule Place chamber beneath an animals skin Angiogenesis
  19. 19. Tumor Angiogenesis: A Balancing ActFolkman J, Nature Drug Discovery 6:274, 2007
  20. 20. Activators of Angiogenesis
  21. 21. 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
  22. 22. VEGF Receptors• 3 types of receptors- VEGFR-1, VEGFR-2 (KDR, Flk-1), VEGFR-3• Tyrosine kinases• 316 residues• 35% helical• 15% beta sheet
  23. 23. Figure 1 VEGF family ligands and receptorsBiochemical Society Transactions Biochem. Soc. Trans. (2003) 31, 1171-1177
  24. 24. Figure 2 VEGF signaling pathwaysBiochemical Society Transactions Biochem. Soc. Trans. (2003) 31, 1171-1177
  25. 25. 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 26
  26. 26. 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 27
  27. 27. The Angiogenesis Signaling Cascade Cancer cell VEGF (or bFGF) Receptor protein Endothelial Relay cell surface proteins Genes are activated in cell nucleus Proteins stimulate new endothelial cell growth
  28. 28. Endothelial Cell Activation Secretes MMPs that Activated digest endothelial surrounding cell matrix Matrix Cell migrates and divides
  29. 29. Inhibitors of Angiogenesis
  30. 30. Angiogenesis 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. 31
  31. 31. ENDOSTATIN • 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) 32
  32. 32. ANGIOSTATIN • 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. 33
  33. 33. ANGIOSTATIN• 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. 34
  34. 34. Angiogenesis Inhibitors and Primary TumorsTumor size in mice 0 40 80 120 160 200 240 Days Start Start Stop Stop Endostatin Treatment
  35. 35. Angiogenesis Inhibitors and Metastasis Inject cancer cells Let initial tumor grow for several weeks Remove initial tumor Allow time for metastases to appear Angiostatin No injections treatment Few metastases Many metastases
  36. 36. Angiogenesis and Tumor Dormancy Angiostatin inhibits Large primary tumor Tiny dormant tumor masses
  37. 37. Cancer in Angiogenesis-Deficient Mice Normal mouse Angiogenesis-deficient mutant mouse Inject breast cancer cells Cancer No cancer
  38. 38. Angiogenesis Inhibitors in the Treatment of Human Cancer Cancer cell VEGF (or bFGF) Receptor protein Endothelial Angiogenesis cell Inhibitors MMPs Matrix
  39. 39. Drugs That Inhibit Angiogenesis Directly Cancer cell Endostatin VEGF EMD121974 (or bFGF) TNP-470 Squalamine Receptor protein Apoptosis Endothelial cell Combretastatin A4 MMPs Matrix Integrin Drug molecule Integrin interacts with drugs to destroy proliferating endothelial cells
  40. 40. Old Drug With a New Use Cancer cell VEGF (or bFGF) Receptor protein Endothelial cell Thalidomide MMPs Matrix
  41. 41. Drugs That Block theAngiogenesis Signaling Cascade Cancer cell Interferon-alpha VEGF (or bFGF) Receptor protein Anti-VEGF antibody SU5416 SU6668 Endothelial PTK787/ZK 22584 cell MMPs No endothelial cell growth Matrix
  42. 42. Drugs That BlockExtracellular Matrix Breakdown Cancer cell VEGF (or bFGF) Receptor protein Marimistat AG3340 COL-3 Neovastat Endothelial BMS-275291 cell No MMPs endothelial cell migration Matrix
  43. 43. 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)
  44. 44. NORMAL BODY BLOOD VESSEL FORMATION• StagesA: VasculogenesisB: Angiogenic remodelingC: Stabilization and maturationD: DestabilizationE: RegressionF: Sprouting
  45. 45. STAGE A: VASCULOGENESIS • Undifferentiated vascular bedding during embryonic development • Vascular Endothelial Growth Factor (VEGF) triggers this process
  46. 46. STAGE B: ANGIOGENESIS• Pruning of primitive tubular network to form blood vessels• Vascular Endothelial Growth Factor (VEGF) is required
  47. 47. STAGE C: STABILIZATION AND MATURATION Endothelial cells integrate tightly with supporting cells such as smooth muscle cells and pericytes Cell walls mature
  48. 48. STAGE D: DESTABILIZATION• Angiogenic sprouting into previously avascular tissue occurs• Distinct angiogenesis from previous type• Only possible if pre-existing vessels are first destabilized
  49. 49. 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
  50. 50. Structure of vessels and capillariesSmall artery: Monocellular layer of endothelial cells Capillary: endothelial cell, basal lamina, pericytes
  51. 51. Angiogenesis:Sprouting of cells from mature endothelial cells of the vessel wall (secretion of proteases, resolution of Basal lamina, migration towards Chemotactic gradient, proliferation, Tube formation) VEGF is factor largely specific for endothelial cells, bFGF can also induce, not specific for EC) Mouse cornea: wounding induces angiogenesis, chemotactic response to angiogenic factors
  52. 52. Sprouting towards chemotactic gradient: VEGF
  53. 53. Hypoxia - HIF - VEGFevery cell must be within 50 to 100 m of a capillary HIF: hypoxia inducible factor VEGF: vascular endothelial growth factor
  54. 54. Von Hippel-Lindau Tumor Suppressor, HIF and VEGF VEGF-gene: Regulated by HIF, HIF is continously produced, ubiquitinylated, degraded in proteasome, therefore low concentration; Ubiquitinylation dependent on Hippel-Lindau tumor suppressor (part of an E3 ubiquitin-ligase complex) HIF1 is modified by a prolyl hydroxylase, then better interaction with vHL protein, high turnover; Hydroxylase is regulated by O2
  55. 55. 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 58 permeability
  56. 56. So it cause:1. vasodilatation2. increased vascular permeability3. can induce the expression of proteases and receptors important in cellular invasion and tissue remodeling4. prevent endothelial cell apoptosis But angiogenesis is not completely dependent on VEGF production. Recently shown by : Hansen-Algenstaedt et al. 59
  57. 57. VASCULOGENESISFormation of vessels bydifferentiation of cells fromangioblasts in the yolk sacof the embryo:Is differentiation and proliferationof endothelial cellsin a non-vascularized tissueLeads to formation of a primitivetubular networkHas to undergo angiogenicremodeling to stable vascularsystem
  58. 58. POSTNATAL VASCULOGENESISHemangioblast Angioblast EC
  59. 59. TUMOR ANGIOGENESISThree major steps (A) Initiation of the angiogenic response, (B) Endothelial cell(EC) migration, proliferation and tube formation, (C) Finally the maturation of the 62 neovasculature.
  60. 60. Proteasesmatrix 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. 63
  61. 61. TUMOR ANGIOGENESIS So, the extracellular matrix isdegraded An increased concentration ofvarious growth factors 64 So, EC(„leader EC‟) migrationand
  62. 62. (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. 65• These processes are also mediated by cell adhesion molecules(CAM).
  63. 63. 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. 66
  64. 64. (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
  65. 65. Cellular mechanisms of tumour angiogenesis(1) host vascular network 1 expands by budding of endothelial sprouts or 3 formation of bridges (angiogenesis);(2) tumour vessels remodel 2 2 1 and expand by the insertion of interstitial tissue columns into the lumen of pre- existing vessels (intussusception); and 3(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(4) tumours drain the interstitial 4 fluid and provide a gateway for metastasizing tumour cells.
  66. 66. Cellular angiogenesis-overviewNature Reviews Drug Discovery 1, 415-426 (2002)
  67. 67. Steps in network formation and maturation during tumour angiogenesis
  68. 68. Key differences in tumour vasculatureDifferent flow characteristics or blood volumeMicrovasculature permeabilityIncreased fractional volume of extravascular, extracellular space
  69. 69. AngiogenesisDysregulation in disease states
  70. 70. INSUFFICIENT ANGIOGENESIS :1. Ischemic tissue injury e.g. critical limb ischemia in diabetes2. Cardiac failure3. Delayed healing of gastric ulcers4. Recurrent aphthous ulcerations5. Organ dysfunction occurring in pre-eclampsia6. Age-related diseases e.g. nephropathy and osteoporosis7. Purpura, Telangiectasia8. Pulmonary fibrosis & Emphysema9. Amyotrophic Lateral Sclerosis10.Alzheimers disease So PROMOTING ANGIOGENESIS is helpful 73 here
  71. 71. EXCESS ANGIOGENESIS :• Cancer • Nasal polyps• Arthritis • Choroideal and• Psoriasis intraocular disorders• Blinding retinopathy • Retinopathy of• Atherosclerosis prematurity• Restenosis • Diabetic retinopathy• Transplant • AIDS arteriopathy • Endometriosis• Warts• Scar keloids So HALTING• Synovitis ANGIOGENESIS is helpful here• Osteomyelitis 74• Asthma
  72. 72. 75
  73. 73. THERAPEUTIC ANGIOGENESISStimulation : Inhibition :  Approved indication Approved indication • Advanced cancer• Chronic wound – • Ocular diabetic ulcer neovascularization • Kaposi sarcoma Experimental indication  Experimental• Myocardial infarction indication• Peripheral ischemia • Hemangioma• Cerebral ischemia • Psoriasis• Reconstructive surgery • Rheumatoid arthritis• Gastoduodenal ulcer • Endometriosis • Atherosclerosis 76
  74. 74. 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
  75. 75. development of angiogenesis inhibitorsUsually follows any the following :1. inhibition of tumor cell synthesis of angiogenic proteins2. the neutralization of angiogenic proteins by antibodies or traps3. inhibition of endothelial cell binding to angiogenic proteins 784. direct induction of endothelial cell
  76. 76. Strategies for inhibition of tumorgrowth by anti-angiogenic drugs 79
  77. 77. 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 activityII. those that have been developed or used for other biologic effects but also have anti-angiogenic activity e.g. 80 celecoxib, rosiglitazone, zolendronic acid, interferon alpha, everolimus,vorinostat
  78. 78. 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 throughI. monoclonal antibodies (MAbs) orII. peptide ligands that bind to molecules that are over expressed on the plasma membrane of cancer cells or tumor- associated endothelial cells. 81
  79. 79. DRUGS THAT BLOCK THE ANGIOGENESISSIGNALING 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 82
  80. 80. DRUGS THAT INHIBIT ANGIOGENESISDIRECTLY  Endostatin, the naturally occurring protein known to inhibit tumor growth in animals.  Combretastatin A4, causes growing endothelial cells to commit suicide (apoptosis). 83
  82. 82. DRUGS WITH OTHER MECHANISMS OFACTION  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. 85
  83. 83. Current Angiogenic Inhibitors in Clinical Use and Clinical Trials Bevacizumab (Avastin™) Sunitinib (Sutent™) Sorafenib (Nexavar™) Cederanib (Recentin™ - AZD- 2171) Cilengitide VEGF-TrapMany others in development
  84. 84. “AVASTIN BEVACIZUMAB- REACH BEYONDCONVENTION”  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”
  85. 85. 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)
  86. 86. 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
  87. 87. DOSAGEColorectal 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
  88. 88. BENEFITS Non chemotherapeutic- biological agent that is less invasive to the body than chemotherapeutic agents Half life of 20 days- good drug retention
  89. 89. 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
  90. 90. BOXED WARNINGS AND ADDITIONALIMPORTANT SAFETY INFORMATION  Gastrointestinal (GI) perforation  Wound healing complication  Hemorrhage  Neutropenia
  91. 91. 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
  92. 92. Bevacizumab- Efficacy in Clinical Trials –Metastatic Colorectal CancerFrom Ferrara N, Nat Rev Drug Discovery, 2004; Hurwitz et al, NEJM, 2004
  93. 93. Bevacizumab + Irinotecan
  94. 94. Patient 2 before and after (2 mos apart)Courtesy Dr. Sajeel Chowdhary, Moffitt Cancer Center
  95. 95. 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
  97. 97. 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. 100
  98. 98.  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. 101
  99. 99. Modulation of angiogenesis may have an impact on diseases in the twenty-first centurysimilar to that which the discovery of antibiotics had in the twentieth century…. 102