The Use of Anti-angiogenic Factors in the Treatment of Oncologic Disease Kyle Treesh, PA-S Bob Hadley, Ph.D., PA-C, Advisor University of Kentucky

Learning Objectives Why do we need new cancer treatments? Why do we need new cancer treatments? What is angiogenesis? What is angiogenesis? What are the anti-angiogenesis agents? What are the anti-angiogenesis agents? What agents are FDA-approved? What agents are FDA-approved? What combinations of treatment are best? What combinations of treatment are best? What does the future hold for these therapies? What does the future hold for these therapies?

U.S. Cancer Statistics Cancer is a major public health problem! Cancer is a major public health problem! One in four deaths is due to cancer (570,280 deaths in 2005) One in four deaths is due to cancer (570,280 deaths in 2005) 1,372,910 new cancer cases in ,372,910 new cancer cases in 2005 Lung and bronchus, and colon and rectum equal 25% of total cancer deaths Lung and bronchus, and colon and rectum equal 25% of total cancer deaths Breast and Prostate cancers are prevalent in their respective sexes Breast and Prostate cancers are prevalent in their respective sexes

What is angiogenesis? Think way back to pathophysiology… Think way back to pathophysiology… Angiogenesis is the formation of blood vessels in a tissue initiated by VEGF and bfGF Angiogenesis is the formation of blood vessels in a tissue initiated by VEGF and bfGF Angiogenesis aids in the healing of wounds, proliferates the endometrium, and is a vital part of pregnancy Angiogenesis aids in the healing of wounds, proliferates the endometrium, and is a vital part of pregnancy Tumors can also cause angiogenesis to occur in order to bring oxygen and nutrients to the tumor for growth Tumors can also cause angiogenesis to occur in order to bring oxygen and nutrients to the tumor for growth These new blood vessels are the vehicle for metastasis These new blood vessels are the vehicle for metastasis

Anti-angiogenesis factors Protein anti-angiogenic agents Protein anti-angiogenic agents Monoclonal antibody anti-angiogenic agents Monoclonal antibody anti-angiogenic agents Metronomic chemotherapy Metronomic chemotherapy

Bevacizumab/Avastin 1 st FDA-approved Angiogenesis Inhibitor 1 st FDA-approved Angiogenesis Inhibitor Approved for use with chemotherapy in the treatment of colorectal cancer Approved for use with chemotherapy in the treatment of colorectal cancer Prolonged lives 5 months compared to standard treatment Prolonged lives 5 months compared to standard treatment No additional side effects! No additional side effects! Not expected to be a cure, but provides hope for a longer life Not expected to be a cure, but provides hope for a longer life

Combination Therapies with Anti- angiogenesis agents: With Chemotherapy With Chemotherapy With Radiation With Radiation With other anti-angiogenesis agents With other anti-angiogenesis agents With Vascular Disrupting Agents With Vascular Disrupting Agents Metronomic Chemotherapy Metronomic Chemotherapy Trimodal Therapy Trimodal Therapy

Into the Future… What are the limitations of these therapies? What are the limitations of these therapies? Can these agents work in all cancer sites? Can these agents work in all cancer sites? Could these agents be used for prevention of a recurrent cancer (e.g. Breast CA)? Could these agents be used for prevention of a recurrent cancer (e.g. Breast CA)? Will clinicians use these therapies? Will clinicians use these therapies? Over 50 angiogenesis inhibitors in ongoing clinical trials Over 50 angiogenesis inhibitors in ongoing clinical trials

The bottom line… Angiogenesis inhibitors have the potential to prolong cancer patients’ quantity of life without diminishing their quality of life Angiogenesis inhibitors have the potential to prolong cancer patients’ quantity of life without diminishing their quality of life

For more information: The American Cancer Society The American Cancer Society The National Cancer Institute The National Cancer Institute

Questions?

References: 1. Jemal A, Murray T, Ward E, Samuels A, Tiwari R, Ghafoor A, et al. Cancer Statistics, ; CA: A Cancer Journal for Clinicians 55: Wittekind C, and Neid N. Cancer Invasion and Metastasis. 2005; Oncology 69: ACS, What is antiangiogenesis therapy? 2 April 2005, available at: Accessed 3 Nov Isayeva T, Kumar S, and Ponnazhagan S. Anti-angiogenic gene therapy for cancer (review). 2004: International Journal of Oncology 25: ACS, Why do tumors need their own blood supply? 2 April 2005, available at: Accessed 3 Nov ACS, How different antiangiogenesis drugs work. 2 April 2005, available at: Accessed 3 Nov NCI, Understanding cancer series: angiogenesis. 28 Jan 2005, available at: Accessed 3 Nov ACS, Possible pros and cons of antiangiogenesis drugs. 2 April 2005, available at: Accessed 3 Nov Ma L, Giulio F, Viloria-Petit A, Hicklin DJ, du Manior J, Rak J, et al. In vitro procoagulant activity induced in endotelial calls by chemotherapy and antiangiogenic drug combinations: modulation by lower-dose chemotherapy. 2005; Cancer Research 65: Hurwitz H, and Kabbinavar F. Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer. 2005; Oncology 69: ACS, Recent research in antiangiogenesis therapy. 2 April 2005, available at: Accessed 3 Nov ACS, The future of antiangiogenesis. 2 April 2005, available at: Accessed 3 Nov Huber PE, Bischof M, Jenne J, Heiland S, Peschke P, Saffrich R, et al. Trimodal cancer treatment: beneficial effects of combined antiangiogenesis, radiation, and chemotherapy. 2005; Cancer Research 65: Siemann DW and Shi W. Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors International Journal of Radiation Oncology*Biology*Physics 60: Klement G, Huang P, Mayer B, Green SK, Man S, Bohlen P, et al. Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. 2002; Clinical Cancer Research 8: NCI, Angiogenesis inhibitors in the treatment of cancer. 20 May 2002, available at: Accessed 3 Nov