Determine the Impact of Novel BRCA1 Translation Start Sites on Therapy Resistance in Ovarian Cancer
Abstract
Rationale and Objective: Hereditary mutations in the BRCA1 gene predispose carriers to early onset ovarian cancer. The BRCA1 protein is involved in repairing DNA damage induced by DNA damaging chemotherapies such as platinum and PARP inhibitors. BRCA1 mutations often render the protein product dysfunctional, consequently tumors cannot repair DNA damage caused by chemotherapy, and so these types of tumors are highly sensitive to DNA damaging agents. Our current work has uncovered a novel mechanism of resistance to therapy in BRCA1-mutant cancer cell lines, warranting further investigation in additional model systems. Our preliminary data suggest that cancer cell lines harboring BRCA1 mutations utilize new DNA sequences that are downstream of the original mutation to restore BRCA1 protein levels under PARP inhibitor or cisplatin selection pressure. The novel proteins retain more than 90% of the normal BRCA1 product but lack the initial region of protein. We hypothesize that ovarian cancer in patients with germline BRCA1 mutations that are close to the start of the gene restore protein function by utilizing new protein start sites that are downstream of the original deleterious mutation. In turn, restoration of protein function restores DNA repair and provides resistance to DNA damaging chemotherapies. Although the new BRCA1 proteins provide cellular PARP inhibitor and cisplatin resistance, they lack a region of the protein that normally interacts with another important DNA repair protein, BARD1, and do not form BRCA1-BARD1 complexes. We will characterize the role of BRCA1 proteins that do not interact with BARD1 in the DNA damage response. Furthermore, we predict that under particular conditions of stress or forms of DNA damage, cells may require BRCA1-BARD1 activity for survival; our strategy will uncover small molecules that elicit a cellular dependency on BRCA1-BARD1 activity. Our ultimate objective is to generate strategies for targeting DNA damaging agent chemotherapy-resistant ovarian cancer that can be developed for clinical application. Central Problem Addressed: Platinum-based chemotherapy has been the mainstay of ovarian cancer therapy for the past three decades. More recently, poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as promising agents for the treatment of ovarian cancer. However, similar to platinum, all patients eventually demonstrate tumor progression while being treated with PARP inhibitor therapy, and drug resistance is a major clinical hurdle. This proposal addresses the central problem of tumor response to therapy, survival, and drug resistance in ovarian cancer. Relevance to Mission of the Ovarian Cancer Research Program (OCRP): The current proposal directly addresses the OCRP mission to investigate tumor response to therapy and will enhance the pool of ovarian cancer scientists through the Teal Scholar application for Dr. Yifan Wang. Impact: Our work will have immediate therapeutic implications for military members and their families that have or will develop ovarian cancer. Platinum therapy resistance continues to present itself as a major hurdle in the pursuit of curative treatments for ovarian cancer. Data described in this proposal indicate that patients with certain types of BRCA1 mutant tumors will develop identical mechanisms of resistance to PARP inhibitors and platinum-based therapies, suggesting drug cross-resistance. When either platinum or PARP inhibitor resistance develops, patients with BRCA1 allelic mutations may benefit from alternative therapies with different mechanisms of action. In this proposal, we will identify such drugs, and in long-term outcomes, drugs will be developed for clinical treatment of BRCA1 mutant ovarian cancer patients with drug-resistant disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510197
Entities
People
- Neil F. Johnson
Organizations
- United States Army