Physical Mechanisms of VEGF receptor activation and novel models of inhibition

In order for lung cancer tumors to grow, they need new blood vessels to grow into the tumor. This process, known as tumor angiogenesis, provides vital nutrients for the tumor and iscritical for the growth and progression of non-small cell lung cancer (NSCLC). Indeed, >90% of NSCLC tumors have been shown to use the key pro-angiogenic cytokine vascular endothelial growth factor (VEGF) to recruit new blood vessels. The angiogenesis inhibitor Avastin, which targets VEGF, was approved for use in 2006 in combination with carboplatin and paclitaxel as a first-line treatment for NSCLC patients. This therapy provides significant benefit, improving both time to regression and overall survival. However, the duration of effectiveness is limited and recent studies suggest that use of Avastin may actually increase tumor aggressiveness over the long term. For this reason, new targeted therapies are needed. However, there are ten known proteins involved in VEGF signaling and the details of how they function is unknown. Knowing which protein to target and how to target it is a major focus of current research. For this reason, we propose studies to first determine how the VEGF secreted by the tumor activates the two families of cell surface receptors on existing blood vessels. We then propose development and initial testing of ligand blocking peptides and activation blocking antibodies for the two families of receptors. We hypothesize that defining the common activation mechanisms coupled with design of effective inhibitors will provide unique opportunities to develop agents which compliment or replace existing angiogenesis inhibitors.