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.
Because residual SWI/SNF in ATPase-deficient SCCOHT is essential for growth, we are building a research program on the basic molecular mechanisms of the residual SWI/SNF complex. SWI/SNF assembles through modular assembly with the ATPase module loading last. This means that ALL eukaryotic cells contain residual SWI/SNF. We are beginning to decipher the function of ATPase module-deficient complex in the absence of catalytic activity.
Nearly all ovarian cancer patients are treated with platinum-based chemotherapy. While most will respond favorably in the initial round of treatment, tumors recur in most patients, ultimately with platinum-resistant disease. Currently, the clinical measure of platinum resistance is through measurement of the interval of time between last treatment and recurrence (platinum-free interval).
Through the development of patient-derived organoids, we are coupling multiomic (DNA, RNA, histone post-translational modifications) features with both clinical and lab-measured chemotherapy response to better predict resistance in a tumor before it is observed clinically.