Elizabeth Alli Lab
Oxidative DNA damage,
which is generated endogenously by normal biological
processes, is typically repaired by the DNA base-excision repair (BER)
pathway. Cells with defective BER tend
to accumulate excessive oxidative DNA damage, which leads to
mutagenesis, genetic instability, and ultimately, tumorigenesis. My lab investigates
and manipulates such tumorigenic mechanisms for purposes of cancer
chemoprevention and targeted therapy.
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.
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.
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
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.