Blocking Adaptive Resistance to Anti-Angiogenesis Drugs
Abstract
While therapy that reduces new blood vessel formation (anti-angiogenic therapy) is efficacious in patients with ovarian cancer, most patients eventually develop cancer resistant to this treatment. The precise molecular mechanisms underlying this drug resistance are not well understood. We need to develop methods to enhance the efficacy of a particular anti-angiogenesis treatment (anti-VEGF) and block growth-promoting changes in the tumors. We identified elevated MSMP protein in resistant tumors and demonstrated that reducing MSMP in ovarian tumors results in robust reduction of tumors and reduced blood vessel formation. But the mechanisms by which this occurs are unknown, and a highly specific inhibitor of MSMP is urgently needed. Our team has been at the forefront of addressing these issues and made key discoveries related to adaptive resistance. Aptamers, also known as chemical antibodies, can bind to their targets with high specificity and affinity and might represent an excellent alternative to replace or supplement the current anti-angiogenic molecules, protein antibodies. We have already screened and identified highly selective aptamers for targeting MSMP that can be rapidly scaled up for therapeutic applications. In this project, we propose to explore the mechanisms by which MSMP promotes resistance to anti-angiogenic therapy. We will make chemically modified versions of the aptamers with high counts to find derivatives with even better binding and cancer silencing properties using our well-established screening methods, and we will further investigate the biological effects of MSMP/thioaptamer using mouse models of resistance to anti-VEGF therapy. Our team, coupled with world-renowned physician-scientists, is well-positioned for conducting the proposed project. If successful, it could have an exceptionally high impact on overcoming the resistance to anti-VEGF therapy for ovarian cancer patients and lead to truly substantial advances in cancer treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910171
Entities
People
- Wei Hu
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army