Elucidating Polymerase Theta Functions and Genetic Determinants of Synthetic Lethality in Breast Cancer
Abstract
Hereditary breast cancer is frequently caused by inherited mutations in genes involved in a specific type of DNA repair called homologous recombination (e.g., BRCA1, BRCA2, and PALB2). Alterations in the homologous recombination (HR) pathway have also been described in an aggressive subset of non-familial breast cancer referred to as triple-negative breast cancer (TNBC) -- defined by absent expression of ER (estrogen receptor), PR (progesterone receptor), and HER2 (Human EGF Receptor 2). Patients with these types of breast cancer are often treated with highly toxic chemotherapy, which can result in long-term adverse effects on quality of life and patient survival. Recently, a newly described DNA repair pathway -- Polymerase Theta Mediated End Joining (TMEJ) -- was discovered to be essential in BRCA1/2-deficient breast cancer, whereas inactivating this pathway in normal cells has minimal effect. This finding has generated immense enthusiasm, and considerable efforts are being directed towards identifying inhibitors of Polymerase Theta (Pol-theta) as a novel therapeutic strategy in this subset of breast cancer. However, a more complete understanding of how this pathway functions in normal cells and in HR-deficient breast cancer cells will be necessary to optimally translate Pol-theta inhibitors into clinical use when they become available. The goal of this proposal is to identify the functions of Pol-theta that are dispensable in normal cells but become vital for the survival of breast cancer cells with HR deficiency. We anticipate that inhibitors that target these Pol-theta functional domains will be most clinically effective against HR-deficient breast cancer, while also minimizing normal tissue toxicity. This will both improve cancer-free survival and reduce treatment-associated morbidity. We will also evaluate the relationship between Pol-theta and another class of targeted therapy for BRCA1/2 mutant breast cancer -- Poly ADP-Ribose Polymerase inhibitors (PARPi). We will determine if Pol-theta is an important way for breast cancer patients with BRCA mutations to acquire resistance to PARPi therapy. Finally, we will perform a genetic screen to identify additional deficiencies -- beyond BRCA1/2 -- that also sensitize cancer cells to Pol-theta inactivation. This may broaden the applicability of Pol-theta inhibitors to more breast cancer patients who are found to have specific gene mutations using modern cancer genome sequencing assays. Thus, the goal of this 3-year research plan is to provide preclinical data in support of identifying new, safer, and more effective therapy for breast cancer and determine the full spectrum of cancer patients that could benefit from this new therapy. Given intensive ongoing efforts by several research groups, we are optimistic that clinical-grade Pol-theta inhibitors will be identified within 3 years, thus making the research described herein imminently relevant to patients with hereditary or triple-negative breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810047
Entities
People
- Gaorav P Gupta
Organizations
- United States Army
- University of North Carolina at Chapel Hill