Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer: Characterizing a New Therapy and Investigating Potential Mechanisms of Resistance
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Angiogenesis is the development of blood vessels from a pre-existing vascular network. This process is essential during growth, development and wound healing and plays a critical role in the growth and progression of cancer. Initial tumor size is restricted by the diffusion capacity of oxygen and nutrients from surrounding blood vessels. Therefore, to progress beyond a volume of several millimeters, a tumor must stimulate angiogenesis to generate a vascular network that will supply the tumor with the necessary blood, oxygen and nutrients that will allow for continued growth, invasion and metastasis. Over forty years ago, Judah Folkman hypothesized that targeting tumor angiogenesis would be beneficial for cancer patients. One of the first targets for this new class of drugs was vascular endothelial growth factor (VEGF) a predominant mediator of physiological and pathological angiogenesis. Bevacizumab (Avastin®, Genentech/Roche), a humanized monoclonal antibody that recognizes human VEGF and blocks VEGF from binding to VEGF receptor (VEGFR) 1 and 2, was the first anti-angiogenic drug approved by the United States Food and Drug Administration for the treatment of cancer and remains the gold standard for this class of therapeutics. The Brekken laboratory, in collaborations with Peregrine Pharmaceuticals and Affitech A/S has generated a fully human monoclonal antibody, r84 that recognizes mouse and human VEGF and blocks VEGF binding only to VEGFR2. The data presented in the first half of this dissertation demonstrate the specificity of r84 for VEGF in vitro and in vivo, the efficacy of r84 to control tumor growth and the superior safety profile of r84 as compared to bevacizumab. Although anti-angiogenic therapy was highly anticipated to have great success in patients, overall results have been somewhat disappointing with modest improvements in patient progression free survival and few improvements to overall survival. In addition, with the expanding use of anti-angiogenic drugs such as bevacizumab and a host of receptor tyrosine kinase inhibitors in the clinic, it is becoming increasingly apparent that not all tumors respond or maintain sensitivity to treatment. Therefore, it is increasingly important to identify mechanisms of resistance to anti-angiogenic therapy so that new drug targets can be identified and/or patients can be appropriately screened for markers that can predict for resistance or sensitivity to anti-angiogenic therapy de novo. Non-small cell lung cancer (NSCLC), the most common form of lung cancer, claims the most new diagnoses and cancer-related deaths than any other cancer worldwide and the therapeutic options currently available for this disease, including bevacizumab have done little to change this statistic. The latter half of this thesis focuses on the in vivo screening of human NSCLC cell lines to identify mechanisms of resistance to the anti-angiogenic monoclonal antibodies bevacizumab and r84 in non-small cell lung cancer.