Recent clinical trials showed that PARP inhibitors and platinum are effective in treating ovarian cancer patients with mutations BRCA1, BRCA2, and other genes encoding proteins involved in Homologous Recombination (HR), a form of DNA repair. Proteins involved in HR promote repair of DNA lesions caused by PARP inhibitors and platinum, and this repair contributes to chemotherapy resistance. How to treat ovarian cancers with intact HR repair is a very important unanswered question. Our preliminary data suggest that a chromatin remodeling protein, BRD9, regulates HR. In addition, inhibition of BRD9 makes ovarian cancer cells sensitive to cisplatin. We hypothesize that combined treatment using the BRD9 inhibitor I-BRD9 and platinum or PARP inhibitor might be a novel treatment strategy to effectively treat ovarian cancers with higher expression of BRD9 and intact HR capacity, which are otherwise resistant to platinum. Taken together, this combined treatment may expand the efficacy of PARP inhibitors and platinum in treating ovarian cancers and benefiting ovarian cancer patients.
The short-term impact is to clarify how BRD9-RAD51 axis regulates HR and validate BRD9 as a potential drug target in ovarian cancer. If our results are consistent with the hypothesis, the project will potentially impact clinical practice. In collaboration with clinician investigators, we will try to move the platinum/BRD9 inhibitor combination into clinical trials to help improve treatment for ovarian cancer patients. The TCGA database suggests that BRD9 is upregulated in ovarian cancers. I hope the platinum/BRD9 inhibitor combination will help overcome chemoresistance in these patients and eventually contribute to improved health of women affected by ovarian cancer.
Dr. Yuan is currently an Assistant Professor in the Department of Molecular Pharmacology and Experimental Therapeutics at Mayo Clinic. He received his Ph.D. from Fudan University at China. Dr. Yuan pursued postdoctoral training in the laboratory of Dr. Zhenkun Lou at Mayo Clinic, where he studied the DNA damage response signaling pathway. Dr. Yuan’s current research interests focus on the molecular mechanism of chemoresistance in ovarian cancer. In addition to the Ovarian Cancer Research Alliance Liz Tilberis Early Career Award, Dr. Yuan’s work has been supported by NCI RO1 grant.