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 looking at copy number altered regions, as well as functionally testing the super-enhancers using CRISPR interference to determine necessity for cancer phenotypes.
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 use epigenetic therapies in novel ways to target ovarian cancers. This includes combination with current standard of care, identifying sequential treatments that maximally alter epigenetic targets, and identify key alterations in cancer that lead to particular epigenetic vulnerability, such as SWI/SNF mutations.
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.