Immunotherapy Targeting Stromal CD5L in Ovarian Cancer
Abstract
Ovarian cancer is the most deadly gynecologic malignancy with 5-year survival rates ranging from 45% for all stages combined to 27% for those with advanced stage, recurrent disease. Treatment of recurrent ovarian cancer is complex and can vary based on patient and tumor specific characteristics. One important treatment option for 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 rates using bevacizumab in recurrent ovarian cancer, most patients unfortunately still relapse after approximately 7-13 months of bev-treatment, depending on their platinum sensitivity status. Our laboratory is dedicated to investigating the mechanisms leading to adaptive resistance to anti-VEGF therapy and exploring the novel targeted therapeutic approaches. To emulate the response (or lack thereof) seen in humans, we established an array of mouse models carrying tumors from human ovarian cancer that 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. Next, we investigated the expression of CD5L in a large cohort of ovarian cancer patients, and 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 next explored the mechanism of action for targeting CD5L in mouse models carrying human ovarian tumor and discovered that: 1. CD5L plays a central role in mediating endothelial cells to develop adaptive resistance to anti-VEGF 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. On this purpose, we have 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 anti-VEGF 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: Aim 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. Aim 2. Determine the mechanisms by which rAb-anti-CD5L reduces resistance to anti-VEGF therapy in endothelial cells. The work proposed in our application will significantly improve the current knowledge on understanding the roles for CD5L and its receptors during the development of adaptive resistance to anti-VEGF therapy and offers a new therapeutic modality for treatment of ovarian cancer through targeting angiogenesis. 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 that can significantly improve the clinical outcomes for patients with advanced-stage ovarian cancer, particularly those who have d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010335
Entities
People
- Yunfei Wen
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army