Emma Maudal

Clear cell ovarian carcinoma (CCOC) expresses high levels of APOBEC3B (A3B), a protein that catalyzes mutations in single-stranded DNA. The standard-of-care treatment for patients with CCOC involves surgery and platinum-based chemotherapy, but tumors often develop resistance to treatment. Therefore, it is necessary to explore and improve cancer therapeutics. Research from the Harris Lab suggests that tumors with high A3B expression respond better to platinum-based therapy: The combination of genotoxic stress from A3B expression and chemotherapy leads to increased cancer cell death. This phenomenon is known as synthetic lethality. Based on these data, I hypothesize that an elevated state of genotoxicity from A3B overexpression renders CCOC tumors dependent upon DNA repair and thus sensitizes them to DNA repair inhibition. To test my hypothesis, I chose the CCOC cell line JHOC5 that has high levels of A3B expression and no DNA repair pathway alterations. It is engineered with CRISPR technology to establish clonal cell lines with A3B present (control clones) or absent (A3B knock-out clones). Each cell line is treated with either ATM or ATR inhibitors at various concentrations. The goal is to determine the cell viability by two different assays: quantifying colony formation capabilities and measuring metabolic activity (MTS tetrazolium assay). Due to greater genotoxic stress, I anticipate that CCOC JHOC5 cells with high A3B expression will be more sensitive to ATM and ATR inhibition, compared to their isogenic counterparts lacking A3B. Positive results from my studies would encourage further in vivo investigations and possible future clinical trials in CCOC patients.