(grant originally made to Hyun Jin Choi, MD)
Inhibition of vessel production is a promising therapeutic approach to fighting advanced cancer. But, resistance emerges quickly and new approaches are needed. Using sophisticated genomic approaches with endothelial cells isolated from tumors with adaptive resistance to anti-VEGF therapy, we identified substantially elevated CD5L levels. When we silence gene activity of CD5L, vessel production was remarkably reduced in a mouse ovarian cancer model, even in tumors that were resistant to anti-VEGF therapy. We found that CD5L silencing resulted in increased cell death in the tumor-associated endothelial cells. Preliminary mechanistic studies suggest that CD5L is increased by hypoxia and protects endothelial cells from apoptotic effects. Our overall hypothesis is that resistance to anti-angiogenic therapy can be overcome by targeting CD5L. This hypothesis will be tested under the following two specific aims: Aim 1: To determine the mechanisms by which CD5L supports endothelial cell survival during anti-VEGF therapy. Aim 2: To investigate the biological effects of CD5L inhibition using orthotopic mouse models of adaptive resistance to anti-VEGF therapy. We expect that results from this study will not only provide a new understanding of the mechanisms underlying resistance to anti-angiogenic therapy, but will have translational implications by identifying innovative therapeutic strategies for overcoming such resistance.