Treatment of recurrent ovarian cancer is complex and can vary based on patient and tumor specific characteristics. One important treatment option for the advanced ovarian cancer is the use of bevacizumab (Avastin®, an anti-vascular endothelial growth factor (VEGF) antibody) in combination with chemotherapy. Despite the initial response, most patients unfortunately still relapse after approximately 7-13 months of bevacizumab treatment. Our laboratory is dedicated to investigating the mechanisms leading to adaptive resistance to anti-VEGF antibody (AVA) therapy. We established an array of mouse models carrying tumors from human ovarian cancer, which have developed adaptive resistance to the anti-VEGF antibody B20, a pharmaceutical alternative to bevacizumab. By comparing genomic profiles of tumors collected at pre-treatment, at maximal response, and at tumor progression, we found substantially elevated CD5 antigen-like precursor (CD5L) in tumor endothelial cells at the time of progression. This finding was particularly intriguing as the formation and migration of these CD5L-overexpressing tumor endothelial cells are integral to angiogenesis, an essential function in tumor growth and metastasis.
Our clinical analysis suggested that overexpression of CD5L is associated with worse overall survival of patients with high-grade serous ovarian cancer (HGSC), the most commonly diagnosed ovarian cancer. We further discovered that: 1) CD5L plays a central role in mediating endothelial cells to develop adaptive resistance to AVA therapy; 2) CD5L silencing with siRNA (a short interfering RNA interfering expression of CD5L gene) results in robust reduction in tumor growth and tumor angiogenesis. Therefore, our preliminary results suggested a strong therapeutic potential for developing a CD5L-targeted therapy.
Based on our preliminary data, we generated rAb-anti-CD5L, a monoclonal, function-blocking antibody. Our central hypothesis is that blocking CD5L protein via rAb-anti-CD5L overcomes adaptive resistance to AVA therapy in ovarian cancer. The goal of this proposal is to revolutionize the anti-angiogenic therapeutics for ovarian cancer by replacing current interventions with a low-toxicity, highly effective, antibody-based regimen. To test our hypothesis, we proposed these specific aims: #1: Evaluate the therapeutic efficacy of rAb-anti-CD5L in overcoming adaptive resistance to anti-VEGF therapy using cell-based and patient-derived xenograft orthotopic ovarian cancer models; #2: Determine the mechanisms by which rAb-anti-CD5L reduces resistance to anti-VEGF therapy in endothelial cells. Our team includes leading experts in ovarian cancer biology, angiogenesis pathways, developmental therapeutics, and the care of women with ovarian cancer, which places us in an excellent position to carry out the proposed study. We believe the outcomes from this proposal will help to produce an effective, neoadjuvant therapy, which can significantly improve the clinical outcomes for patients with advanced-stage ovarian cancer, particularly for those who have developed the adaptive resistance