Anti-Angiogenic Cancer Therapies

1. Anti-Angiogenic Cancer Therapies Tangela S. Feemster Tuesday, March 27, 2007 Dr. Buynak Medicinal Chemistry

2. Definition of Angiogenic Therapy • A new form of cancer treatment using drugs called 'angiogenesis inhibitors' that specifically halt new blood vessel growth and starve a tumor by cutting off its blood supply. • A substance in the body called Vascular Endothelial Growth Factor (VEGF) is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues. • Anti-Angiogenic drugs prevent the VEGF from binding with the receptors on the surface of the endothelial cells.

3. Three Major Types of Anti-angiogenic Therapies for Cancer • Drugs that stop new blood vessels from sprouting (true angiogenesis inhibitors) • Drugs that attack a tumor's established blood supply (vascular targeting agents) • Drugs that attack both the cancer cells as well as blood vessel cells (the double-barreled approach).

4. To date more than 300 angiogenesis inhibitor molecules have been discovered:Some angiogenesis inhibitors are naturally present in the human body because healthy tissues appear to resist cancer growth by containing these anti-angiogenic compounds.

5. 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.

6. Angiogenic Inhibitors • Currently, a number of clinical trials in progress are combining anti-angiogenic therapy with cytotoxic chemotherapy or radiation, as a way to maximize the anti-tumor treatment in human cancer patients sponsored by biotechnology and pharmaceutical companies, medical centers and by the U.S. National Cancer Institute. These clinical trials are taking place in the United States, Canada, Australia, and throughout Europe.

7. Anti-Angiogenic Drugs in Clinical Trial for Cancer

8. Understanding Angiogenesis • Angiogenesis is defined as the growth of blood vessels and is an important natural process used by the body for reproduction and for healing injured tissues • Blood vessels bring oxygen and nutrients via the circulation to nourish all tissues in the body • The cells comprising blood vessels are called endothelial cells • The endothelial cells of a blood vessel also produce molecules that support the growth of tissues • Cancer cells take over the body's control of angiogenesis in order to recruit their own private blood supply

9. 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.

10. 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.

11. Specific Angiogenic Inhibitors • Angiostatin • Avastin (Bevacizumab) • Celebrex (Celecoxib) • Endostatin • Metaret (Suramin) • Thalidomide

12. 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.

13. 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.

14. Avastin • Avastin is a humanized monoclonal antibody (MAb) that targets vascular endothelial growth factor (VEGF) • Causes regression of tumor vasculature • Reduces intra-tumor pressure, thereby improving the delivery of cytotoxic agents to the tumor • Also inhibits new tumor blood vessel formation, restricting tumor growth. • The first anti-angiogenic agent with demonstrated anticancer benefit in phase III trials. • Avastin-VEGF Animation

15. Celecoxib • Is one of the “rediscovered” drugs • It is better known as Celebrex, a non-steroidal, anti-inflammatory drug • Celecoxib is a COX-2 inhibitor • Overexpression of COX-2 in cancer cells induces the production of VEGF, PDGF, bFGF and TGF-beta. • Through these angiogenesis mediators and their receptors on the endothelial cells, COX-2 increased vascular permeability and induced endothelial cell proliferation and migration. • COX-2 overexpression led to the production of matrix metalloproteinase (MMPs), which have been implicated in extracellular matrix invasion • COX enzymes are essential for maintenance of the migration and attachment of endothelial cells through integrin pathways • Therefore a COX-2 inhibitor will block new vessel formation

16. Celecoxib

17. 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)

18. Suramin • Developed by Oskar Dressel and Richard Kothe of Bayer, Germany in 1916 • A polysulfonated naphthylurea • Is a prototype of a pharmacological antagonist of growth factors,including basic fibroblast growth factor (bFGF) • It is usually used for treatment of human sleeping sickness, onchocerciasis and other diseases caused by trypanosomes and worms

19. Thalidomide • One of the most perplexing drugs in medical history. • It is a hypnotic, causes peripheral nerve damage and severe birth defects, is anti-inflammatory, enhances the immune system, inhibits HIV replication, and inhibits some cancers • Thalidomide decreases TNF-a, tumor necrosis factor alpha levels, • TNF causes apoptotic cell death, • cellular proliferation, • differentiation, • inflammation, and • tumorigenesis

20. Thalidomide

21. Thalidomide

22. Summary • Angiogenesis inhibitors specifically halt new blood vessel growth and starve a tumor by cutting off its blood supply. • VEGF is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues. • Angiogenesis inhibitors prevent the VEGF from binding with the receptors on the surface of the endothelial cells. • There are 3 major types of anti-angiogenic therapies • Angiogenesis is the growth of blood vessels and is an important natural process used by the body for reproduction and for healing injured tissues

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