Immunotherapy Targeting Stromal CD5L in Ovarian Cancer

Although the FDA approved anti-angiogenesis therapies, such as bevacizumab, for treatment in upfront and relapsed ovarian cancers, development of adaptive resistance to such therapy remains a major clinical barrier. To date, only a portion of the molecular mechanisms underlying drug resistance to anti-VEGF antibody therapy like bevacizumab have been studied. The proposed work aims to investigate the therapeutic potential for a novel monoclonal antibody, rAb-anti-CD5L to overcome adaptive resistance in ovarian cancer during application of anti-VEGF drugs. We also aim to characterize the roles for CD5L and its endothelial-specific receptors in mediating development of resistance to anti-VEGF antibody therapeutics in endothelial cells, and the mechanisms of rAb-anti-CD5L in interfering with such activities. The short-term goal of this proposal is to understand mechanisms of action of rAb-anti-CD5L in targeting stromal CD5L in ovarian tumors with anti-VEGF-therapy resistance. We expect this work will lead to a new therapeutic approach for ovarian cancer patients. Overall, our proposal is highly translational and has profound implications for developing a novel, antibody-based therapy for ovarian cancer. Thus, this proposal is directly responsive to the Program Announcement for the Investigator-Initiated Research Award from DOD-OCRP, in that we will identify novel approaches for overcoming adaptive resistance to anti-VEGF therapy in ovarian cancer. Further clinical development of rAb-anti-CD5L will require formal safety studies (GLP regulations); we are well poised to carry out such work and have extensive experience in drug development. Moreover, the Moon Shot Program for Ovarian Cancer at MD Anderson will provide clinical resources for us to formally test the utility of novel drugs following induction with bevacizumab based therapy.