Identifying Therapeutics for Platinum-Resistant Ovarian Cancer by Next-Generation Mechanotyping
Abstract
Ovarian cancer is a devastating disease: even though chemotherapy treatments can initially be effective, this cancer recurs in over 80% of cases, so the majority of patients do not live beyond 5 years past their initial diagnosis. A primary reason for disease recurrence is that cancer cells develop resistance to common chemotherapy drugs, such as platinum-based chemotherapies, so treatments become ineffective. If we could identify a combination of drugs that could arrest the growth of cancer cells, including the drug-resistant cells, this would prevent the death of thousands ovarian cancer patients each year. The goal of this proposed work is to identify novel compounds that target platinum-resistant ovarian cancer cells. To achieve this goal, we have assembled a multidisciplinary team that consists of physicists, engineers, pathologists, and translational cancer biologists. Our approach is based on our recent discovery that platinum-resistant cancer cells are softer, or more deformable, than their drug-sensitive counterparts. We will use a novel technology that we recently invented to measure cell stiffness across large numbers of cell samples. In the proposed research, we will probe the stiffness of platinum-resistant cells that are treated with over 30,000 small molecules and identify the compounds that restore the stiffness of the drug-resistant cells to levels of the drug-sensitive cells. We will then verify the effects of the identified molecules in detailed follow-up studies to characterize cell survival, invasion, and proliferation. Following these proposed preclinical studies, future experiments would test our new identified compounds in mice and a clinical trial would validate the drug(s) in patients. Our proposed research is well aligned with the vision of the Ovarian Cancer Research Program (OCRP). Our innovative approach provides a radically different way to search for effective new drugs for ovarian cancer treatment and offers a new paradigm for drug discovery in cancer; this could thus lead us to identify a new compound that would target chemoresistant cells, make treatments more effective, result in less recurrence, and ultimately increase patient survival. This high-risk/high-reward project addresses the major challenge of chemoresistance in ovarian cancer, which is an OCRP Fiscal Year 2015 Area of Encouragement. Our work will also impact the health and welfare of the military. Ovarian cancer is a deadly malignancy that affects "one out of every 70 female Service members, military wives, and adult daughters of Service members over their lifetime" (Colorectal Cancer Coalition, 2014). Ovarian cancer is a devastating disease for military families, for troop readiness and efficacy, and for additional TRICARE treatment costs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610092
Entities
People
- Amy Rowat
Organizations
- United States Army
- University of California, Los Angeles