Understanding and Exploiting SIRT2-BRCA1 Interplay for Ovarian Cancer Therapy
Abstract
Ovarian cancer is the leading cause of death among gynecologic cancers, with poor outcomes with current therapies. Therefore, novel approaches for treating patients with ovarian cancer are urgently needed. Mutations in BRCA1 lead to a 40% lifetime risk of ovarian cancer, and moreover, about half of all ovarian cancers exhibit "BRCAness" or traits shared with ovarian cancers with inherited BRCA1/BRCA2 mutations. BRCA1 functions to respond to DNA damage and thus plays an important role in the response of ovarian cancer to many types of chemotherapeutic agents. Work in our lab recently found that BRCA1 is regulated by a protein called sirtuin 2 (SIRT2), which removes acetyl modifications from proteins to regulate their activity. Significantly, SIRT2 is dysregulated in 13% of ovarian cancers, and this dysregulation is associated with worse clinical outcome. Our preliminary data indicate that depletion of SIRT2 in ovarian cancer cells causes increased sensitivity to cisplatin and gemcitabine, two ovarian cancer chemotherapeutic agents, suggesting that SIRT2 may a promising therapeutic target in ovarian cancer. We further found that SIRT2 interacts in a complex with and removes acetyl modifications from BRCA1. The goal of this project is to determine the significance of the regulation of BRCA1 by SIRT2 and to determine whether SIRT2 inhibitors can be an effective therapeutic strategy in ovarian cancers with dysregulation of BRCA1/BRCA2. Completion of this research is expected to provide new insights into how BRCA1 is regulated by SIRT2 deacetylation and whether SIRT2 inhibitors can be a promising therapeutic strategy for ovarian cancer patients with BRCA1/BRCA2 dysregulation. Thus, this research is innovative in defining a novel mechanism for regulation of BRCA1 function by acetylation and in pioneering a novel approach for treating patients with BRCA1/BRCA2 dysregulation by SIRT2 inhibition that may have transformative effects on accelerating progress towards eliminating ovarian cancer. In addition, since about half of all ovarian cancers exhibit BRCAness, we anticipate that SIRT2 inhibitors will likely be of benefit even for many ovarian cancer patients without inherited BRCA1/BRCA2 mutations. Therefore, this research ultimately is expected to have a substantial impact on improving clinical outcomes and quality of life for military members, their families, and their beneficiaries suffering from ovarian cancer. We anticipate that following completion of this work, which will provide preclinical proof of concept for the efficacy of SIRT2 inhibitors in the treatment of ovarian cancer, a Phase I/II clinical trial incorporating the use of SIRT2 inhibitors will be rapidly initiated within the following year.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710104
Entities
People
- David Yu
Organizations
- Emory University
- United States Army