Symposium 3-1:

-Prediction of response and tolerance of cacer drugs-

Targeting VEGF-A to treat cancer and other disorders

Napoleone Ferrara, MD

Genentech, Inc, South San Francisco, CA, 94080, USA

Vascular endothelial growth factor (VEGF)-A is a well-characterized angiogenic factor involved in physiological and pathological growth of blood vessels. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are the main VEGF-A receptors. The importance of VEGF-A in vascular development is underscored by defective vascularization and embryonic lethality following inactivation of a single VEGF-A allele in mice. High expression of VEGF-A mRNA has been reported in many human tumors, including kidney, colorectal, lung, breast and several brain tumors, including the highly vascularized glioblastoma multiforme. Anti-VEGF-A monoclonal antibodies or other VEGF inhibitors block growth and neovascularization in tumor models. We developed a humanized anti-VEGF-A monoclonal antibody (bevacizumab). Bevacizumab has demonstrated clinical effi cacy, including a survival advantage, in multiple tumor types. Bevacizumab has been approved by the USA Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer, non-small-cell lung cancer, metastatic breast cancer, renal cell carcinoma and glioblastoma multiforme. Numerous clinical trials testing bevacizumab in combination with the standard of therapy are underway in additional indications. Currently, efforts are ongoing to elucidate mechanisms of refractoriness/resistance to anti-VEGF therapies. Recent work from our laboratory identifi ed myeloid cells and fi broblasts as sources of angiogenic factors potentially mediating tumor resistance to anti-VEGF. Furthermore, VEGF-A is implicated in intraocular neovascularization associated with active proliferative retinopathies and the wet form of age-related macular degeneration (AMD). A humanized anti –VEGF-A Fab (ranibizumab) has been developed for the treatment of the neovascular form of AMD. Ranibizumab administration maintained and even improved visual acuity.

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