EZH2 inhibition in mutated clear cell and endometrioid ovarian and endometrioid endometrial cancers.

Clear cell carcinoma and endometrioid adenocarcinoma are histologic subtypes of ovarian and uterine cancer that demonstrate unique clinical behavior but share common underlying genomic aberrations and oncogenic pathways. mutations are more frequently identified in these tumors, in comparison to other gynecologic histologies, and loss of tumor suppressor function is thought to be an essential component of carcinogenic transformation. Several therapeutic targets in mutated cancers are in development, including EZH2 inhibitors. EZH2 facilitates epigenetic methylation to modulate gene expression, and both uterine and ovarian cancers show evidence of EZH2 over expression. EZH2 inhibition in mutated tumors acts in a synthetically lethal manner to suppress cell growth and promote apoptosis, revealing a unique new therapeutic opportunity. Several phase 1 and 2 clinical trials of EZH2 inhibitors are ongoing currently and there is considerable promise in translational trials for utilization of this new targeted therapy, both to capitalize on loss of function and to increase sensitivity to platinum-based adjuvant chemotherapies. This review will synthesize the molecular carcinogenesis of these malignancies and their unique clinical behavior, as a foundation for an emerging frontier of targeted therapeutics - the synergistic inhibition of EZH2 in mutated cancers.