Epithelial ovarian cancer (EOC) is the fifth most common cancer in women in the United States and the leading cause of death among gynecologic cancers. Combination of platinum-based therapy and taxane is now the standard of chemotherapy for EOC patients. Although many patients initially respond, the majority of patients relapse with resistant disease. Recent data suggest that one mechanism for chemotherapy resistance is the presence of a population of cells with stem cell-like characteristics termed cancer stem cells (CSCs). Indeed, emerging data indicate that patients with high levels of CSCs have a poor prognosis. Aldehyde dehydrogenase (ALDH) activity has been shown to be an attractive CSCs marker in ovarian cancer. A subpopulation of ovarian cancer cells with high expression level of ALDH1A1, one of the ALDH families, possesses CSCs characteristics. Significantly, ALDH1A1 is functionally important for CSCs in ovarian cancer, as genetic knockdown of ALDH1A1 is sufficient to sensitize platinum resistant EOC cells to chemotherapy. Thus, ALDH1A1 represents a target for developing CSCs-eradicating EOC therapeutics.
Epigenetic aberrations are common in cancer and epigenetic regulators play a major role in stem cell differentiation. The reversibility of epigenetic changes makes them ideal targets for developing novel cancer therapeutics. Indeed, DNA methyltransferase inhibitors reduce the stem-like properties of ALDH1A1 positive cells in EOC. In my preliminary studies, I screened a library of small molecule inhibitors of epigenetic regulators to identify compounds that suppress ALDH1A1 activity in multiple EOC cell lines. The screen identified a class of bromodomain and extraterminal (BET) inhibitors (such as JQ1 and I-BET-762) that suppress ALDH1A1 expression and activity. Additional characterization revealed that BRD4 is the target of the BET inhibitors in suppressing ALDH1A1 and knockdown of BRD4 is sufficient to decrease ALDH1A1 expression and activity. Therefore, I hypothesize that targeting BRD4 using clinically applicable small molecule BET inhibitors is sufficient to overcome platinum resistance of EOC by eradicating CSCs. The ultimate goal of this proposal is to develop novel EOC therapeutic strategies to overcome chemotherapy resistance using clinically applicable BET inhibitors.
This proposal aims to elucidate the molecular events underlying EOC chemotherapy resistance by understanding the role of BRD4 in regulating ALDH1A1 expression and CSCs properties. It will lay a critical foundation to establish the use of BET inhibitors to target EOC CSCs to overcome chemotherapy resistance, a major challenge in clinical management of EOC. Clinically applicable BET inhibitors are already in trials for other diseases. If successful, these findings will have immediate impact on EOC patients.
This grant is made possible by a generous donation from Phil and Judy Messing, in memory of Carol S. Messing.