Mutations in subunits of the SWI/SNF chromatin remodeling complex occur in 20% of all human cancers, and generally function as tumor suppressor genes. Remarkably, certain cancer types have frequent mutation of particular subunits, which is especially true for many subtypes of ovarian cancer. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is defined by its biallelic inactivation of SMARCA4 and coincident SMARCA2 epigenetic silencing, resulting in the loss of both ATPases of the SWI/SNF complex in this cancer type. ARID1A is also lost in 50% of ovarian clear cell carcinomas (OCCC), and various SWI/SNF subunits are loss in 25% of high grade serous ovarian carcinomas (HGSC). We are interested in how SWI/SNF loss in ovarian cancer leads to alterations in the epigenetic landscape, tumorigenic processes, and therapeutic vulnerabilities.
Super-enhancers are large blocks of enhancer regulatory regions that are commonly associated with genes defining cell lineage in normal cells. In cancer, these regions are found in close proximity to known oncogenes, further supporting cancer growth. Many mechanisms can lead to super-enhancer gains in cancer, but we are interested in how SWI/SNF loss, a frequent event in many cancers, can change the super-enhancer landscape, which may lead to the identification of new therapeutic targets not revealed simply by genetic variant analysis.
Our research program is designed to bring translational findings in our lab for clinical benefit for ovarian cancer patients who need new and better options for therapy. Currently, most ovarian cancers are treated with platinum-based chemotherapy. While effective for many patients, most patients will relapse or have treatment refractory cancers. PARP inhibitors have also been beneficial for the subset of ovarian cancer patients who display homologous recombination defects. We aim to identify therapies benefiting SWI/SNF-mutant ovarian cancer patients. Additionally, we hope to better understand how current standard-of-care chemotherapies change the super-enhancer landscape in ovarian cancer.