Targeting adaptive changes to anti-VEGF therapy in ovarian cancer

• Applicant: Dr. Anca Chelariu-Raicu
• Subject Area: Gynaecology and Obstetrics
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 324931830

Anti-angiogenic therapy holds tremendous promise as a therapeutic strategy for advanced ovarian cancer. Unfortunately, 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 have observed substantially elevated CD5L levels. Mouse-specific CD5L silencing in orthotopic ovarian tumors resulted in robust reduction of tumor burden and a marked reduction in vascular density, even in tumors that were resistant to anti-VEGF therapy. We found that CD5L silencing resulted in increased apoptosis in the tumor-associated endothelial cells. Preliminary mechanistic studies suggest that CD5L levels increased in response to hypoxia and that CD5L 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 also have translational implications by identifying innovative therapeutic strategies for overcoming such resistance.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Anil K. Sood