A new model for discovering genetic determinants of angiogenesis and the effect o

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DESCRIPTION (provided by applicant): A majority of cancer patients are often unresponsive to a given drug. It is a significant challenge to identify patients who would gain more benefit fro one therapy over another. Genetic markers have shown to be useful in predicting patient drug responses but for many drugs, for example the VEGF-pathway inhibitors, no validated markers to guide drug selection presently exist. VEGF-pathway inhibitors target and suppress the growth of tumor vasculature and the associated endothelium. The VEGF-pathway plays a central role in angiogenesis and has been shown to relate to cancer disease progression. Indeed, heritable genetic markers in the VEGF-pathway have been found to associate with patient outcomes in many cancers, including lung cancer. Lung cancer is a case model for a cancer which is affected by the angiogenic potential of a tumor and for which VEGF inhibitors are being used in the clinic and experimentally evaluated. The overall aim of this research is to find VEGF-pathway genetic markers which could be used to predict cancer patient prognosis or responses to VEGF-pathway inhibitor drugs. A major problem is that studies that examine associations between VEGF-pathway genetic markers and patient outcomes are often inconclusive. This is, in part, a consequence of a lack of knowledge about the angiogenic function of these markers. Thus, genetic markers of the VEGF-pathway cannot be used to individualize therapy in cancer patients at this time. The proposed research will analyze candidate genetic markers from the VEGF-pathway to determine whether they have function which would impact tumor angiogenesis and responses to VEGF-pathway inhibitors. Human endothelial cells will be genetically engineered so that isogenic cell lines are created, differing solely at the position of genetic markers selected from prior VEGF-pathway studies of lung cancer. This model system will allow the effects of VEGF-pathway genetic markers to be isolated in cellular assays that examine endothelial cellular properties relevant to angiogenesis. Genetic markers that show effects in these assays will be analyzed in experiments in which isogenic endothelial cells are treated with VEGF-pathway inhibitors. The anti-angiogenic effects of these drugs will be examined in the same cellular angiogenesis assays as before, in addition to cell viability assays, to determine whether the cellular responses are dependent on the VEGF- pathway genetic marker present. The information gained from this research could significantly advance and inform the development of VEGF- pathway genetic markers as predictors of cancer outcomes and responses to VEGF-pathway inhibitors. These markers could be tested in clinical trials to determine if they could be used to identify cancer patients at risk of early disease progression who might benefit from more aggressive therapy or patients who would receive benefit from a specific VEGF-pathway inhibitor over other drugs.