Exploiting SIRT2 for Breast Cancer Therapy
Abstract
Breast cancer is the most commonly diagnosed non-skin cancer in women and the second leading cause of cancer death in women in the United States. Despite recent advances in improving treatment outcomes, the overall impact of breast cancer remains devastating due to its prevalence. A major challenge for the eradication of breast cancer is the need to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. This is especially important for patients with triple-negative breast cancer (TNBC) who do not respond to more tumor-specific treatments such as tamoxifen or herceptin and thus are treated with less tumor-specific treatments such as chemotherapy and radiation therapy and have poor clinical outcomes. Chemotherapy and radiation therapy primarily cause cell death by inducing DNA damage; however, the effectiveness of these treatments is often limited by lack of response and/or resistance. Thus, determining the mechanisms governing resistance to DNA damaging agents in breast cancer may lead to more effective treatment approaches. We have been studying a protein called Sirtuin 2 (SIRT2), which functions as a deacetylase that removes acetyl modifications from proteins to regulate their function. Significantly, mice deficient in Sirt2 develop breast and liver cancers, suggesting that SIRT2 is a tumor suppressor protein. Paradoxically, SIRT2 is also overexpressed in many human cancers, including 50% of TNBCs, and, furthermore, our data suggest that high levels of SIRT2 expression contribute to resistance to many types of cancer treatments, including radiation therapy, poly ADP-ribose polymerase (PARP) inhibitor, and chemotherapy, and are associated with poor survival in breast cancer patients treated with post-operative radiation therapy, suggesting that SIRT2 may be a promising therapeutic target to overcome breast cancer treatment resistance. We have found a novel role for SIRT2 in promoting the repair of DNA double-strand breaks (DSB) by facilitating the resection of the ends of DSBs. Our preliminary data indicate that SIRT2 interacts with and deacetylates MRE11, which is a critical regulatory protein involved in DNA end resection. We plan to test the hypothesis that SIRT2 governs breast cancer treatment resistance, at least in part, by directing DSB repair through deacetylation of MRE11 and that this may be exploited to improve breast cancer control. We propose to determine the role of SIRT2 in directing MRE11 in DSB repair and establish SIRT2 as a new molecular target for breast cancer resistant to DNA damaging agents. Importantly, we will test if SIRT2 inhibitor sensitizes resistant breast cancer cells and tumors derived from patients who failed breast cancer therapy to radiation therapy and other clinically relevant agents that induce DSBs. Successful completion of these studies will establish proof of concept for the use of SIRT2 inhibitor as a novel therapeutic approach for overcoming resistance to DNA damaging agents in TNBC patients that may have a transformative impact on clinical outcome. Our goal will be to move our work forward with a Phase I/II clinical trial and ultimately to a randomized clinical trial. We hope that within 2 to 3 years, the use of SIRT2 inhibitor as novel therapeutic approach for sensitizing resistant breast cancer to DSB-inducing agents can come to fruition.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910069
Entities
People
- David Yu
Organizations
- Emory University
- United States Army