Department of Pathology, Harvard Medical School,
A great challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors. We are particularly interested in identifying key genomic and global epigenetic signatures of chemoresistant tumor cells, including cancer stem cells, as an important step to increase the efficacy of current therapeutic regimens. Our current work shows the potential of using global epigenetic changes as sensitive diagnostic and prognostic biomarkers in the clinical setting to predict response to chemotherapy and clinical outcome. We further propose the use of combinatorial therapies involving epigenetic adjuvants to increase the efficacy of chemotherapy and immunotherapy regimens, especially in recurrent patients and platinum resistant disease. The vast majority of high-grade serous ovarian cancer (HGSOC) patients are diagnosed late with widely disseminated disease and, despite having an initially robust clinical response to platinum-based chemotherapy, relapse within 2 years or less following diagnosis. There are no good therapeutic options for the 30% of HGSOC patients who present with intrinsic platinum resistant disease and the remainder of relapsed patients who develop acquired platinum resistance as a result of repeated treatments. Furthermore, newly diagnosed patients are not even screened for resistance to platinum nor are they stratified by different regimens since no other therapeutic option currently available will likely increase their overall survival or quality of life. We present evidence that epigenetic markers can serve as a sensitive predictor of decreased tumor response, shorter time to relapse following platinum-based chemotherapy, and an overall poor clinical outcome in HGSOC. Most importantly, we describe targetable pathways to reverse these epigenetic changes, both genetically and pharmacologically, and restore sensitivity to platinum therapy in vitro and in vivo in chemoresistant HGSOC models.
Keywords: Ovarian cancer, epigenetic, cancer biomakers, platinum chemoresistance.