Elizabeth Alli, PhD
Our main focus is on triple-negative breast cancers which are named for their lack of expression of estrogen receptor, progesterone receptor, and HER2/NEU. They often encompass hereditary breast cancers due to germline mutations in the Breast Cancer Susceptibility Gene 1 (BRCA1). Collectively, triple-negative breast cancers associate with an aggressive clinical course and are relatively insensitive to existing drugs available via precision medicine, and thus, are in need of more effective anti-cancer strategies.
Triple-negative breast cancer cells have been shown to exhibit a defective BER phenotype that results in elevated levels of oxidative DNA damage. We are working to specify the molecular defects that produce this phenotype as well as identifying other malignancies that display it. The purpose of this project is to gain a better understanding of tumorigenic mechanisms and to identify potential targets for new anti-cancer drugs.
BRCA1 is gaining attention for its role in repair of oxidative DNA damage by BER, and when mutated or deficient, produces a defective-BER phenotype. Given that mutations in BRCA1 significantly lead to the development of breast, ovarian, and other cancers, it seems feasible to circumvent defective BER to prevent tumorigenesis. We are currently developing a new class of drugs termed “DNA-repair activating agents” that reduce levels of oxidative DNA damage and impede tumorigenesis by enhancing base-excision repair. These drugs are anticipated to be the first chemoprevention agents that target BRCA1-mutated cancers.
Agents that lend to excessive amounts of DNA damage may overwhelm defective DNA repair systems in cancer cells and force death pathways. We are in the process of discovering novel therapeutic agents that inhibit the BER pathway or that increase levels of oxidative DNA damage beyond a viable threshold for selective targeting of cancers with a defective-BER phenotype. Our current efforts focus on treatment regimens that are better-targeted for triple-negative breast cancers.