Abstract A003: Identification of a potential chemoprevention agent for BRCA1- mutated cancers

Abstract

Abstract BRCA1 mutation carriers are predisposed to developing aggressive breast, ovarian, and other cancers at a relatively early age. Unfortunately, these cancers lack an effective chemoprevention option. We have found that cells containing mutant BRCA1 harbor defective repair of oxidative DNA damage, an early trigger to tumorigenesis. Therefore, we sought to target this defect and discover a novel chemoprevention agent for these cancers. High-throughput screening of a chemical library identified a novel class of small-molecules that enhance repair of oxidative DNA damage, which we termed DNA repair-activating agents. One of these agents, benserazide, increased base-excision repair of oxidative DNA damage utilizing a cell-based DNA repair assay, decreased levels of 8-oxo-g (i.e. most common oxidized lesion in human genome) using flow cytometric analysis, and decreased levels of oxidative DNA damage as determined by alkaline comet assay modified for detection of oxidized DNA lesions. These results were observed in mutant but not wild-type BRCA1 breast cancer cells. Benserazide, but not tamoxifen (current FDA-approved breast cancer chemoprevention agent), also decreased in vitro tumorigenesis of mutant BRCA1 or BRCA1-depleted breast cancer cells according to the soft-agar colony formation assay, and delayed tumor formation in vivo using a xenograft mouse model. Lastly, benserazide led to elevated levels of 8-oxo-dG (a by-product of base-excision repair) in conditioned media of mutant BRCA1 breast cancer cells, and concurrently increased serum levels of 8oxodG and decreased tumor burden in mice. Taken together, benserazide is a DNA-repair activating agent that enhances repair of oxidative DNA damage and decreases tumorigenesis in vitro and in vivo, and thus may serve as a potential chemoprevention agent for BRCA1-mutated cancers. Further, circulating levels of 8oxoG/8oxodG may function as a predictive biomarker for the efficacy of benserazide, which would prove useful in the clinical evaluation of benserazide for cancer chemoprevention. Citation Format: Sujeeth Shanmugam, Eboni Hosch, Dipasri Konar, James M. Ford, Elizabeth Alli. Identification of a potential chemoprevention agent for BRCA1- mutated cancers [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A003.