High grade serous ovarian cancer (HGSOC) is the deadliest gynecological malignancy, primarily due to late detection, very high rates of recurrence, and acquired chemotherapy resistance. Greater than 80% of HGSOC cases recur and ultimately become unresponsive to all available therapies, including targeted poly ADP- ribose polymerase inhibitors (PARPi). PARPi are rapidly being integrated into the standard of care for HGSOC patients. PARPi are now approved as first-line maintenance for nearly all HGSOC cases, and the number of patients receiving PARPi treatment is expanding. The long-term objectives of the proposed studies are to elucidate an epigenetic mechanism of PARPi resistance, and to provide the necessary preclinical data to support the development of combinatorial therapeutic strategies to defeat resistance. PARP enzymes recognize DNA single strand breaks (SSB) and recruit repair factors. PARPi prevent repair, causing subsequent double strand breaks (DSB) and cell death. Histone methyltransferases EHMT1 and EHMT2 are epigenetic ?writers? that function in a complex to catalyze dimethylation of histone H3 lysine 9 (H3K9me2), and also have direct roles in DNA repair, which is a mechanism of PARPi resistance. High EHMT1/2 expression and H3K9me2 correlate with poorer survival of ovarian cancer patients, and our prior studies show that EHMT1/2 are upregulated in both in vitro and in vivo models of PARPi-resistant HGSOC. We have published that disruption of EHMT1/2 sharply reduces H3K9me2 and the DNA repair capacity of PARPi-resistant HGSOC cells in vitro, causes striking changes in gene expression, and also sensitizes these cells to PARPi treatment. EHMT1/2 inhibition in combination with PARPi represents a novel therapeutic strategy against PARPi-resistant ovarian cancer. We propose to advance these promising results by identifying epigenetically-regulated factors promoting resistance, and by expanding into innovative in vivo models of PARPi-resistant disease. The proposed studies will examine two critical aspects of PARPi-resistant HGSOC. Our first hypothesis is that EHMT1/2 epigenetically regulate gene expression of important resistance factors in PARPi-resistant HGSOC cells. Using ChIP-Seq, we will reveal genes and pathways differentially regulated in PARPi-resistant cells. Our second hypothesis, supported by strong in vitro data, is that inhibition of EHMT1/2 will effectively reverse PARPi resistance in vivo. We will combine PARPi treatment with EHMT1/2 inhibition in patient-derived xenograft (PDX) and syngeneic, immunocompetent mouse models of PARPi-resistant HGSOC. These studies will address the significant clinical problem of PARPi resistance in ovarian cancer, and will aid in the development of urgently-needed targeted combinatorial therapies.
Resistance to chemotherapy, including PARP inhibitors, is a major cause of mortality in ovarian cancers. Histone methyltransferases EHMT1 and EHMT2 are epigenetic ?writers? that contribute to PARPi resistance, but the mechanisms are unexplored. Inhibiting EHMT1/2 may re-sensitize therapy-resistant ovarian cancers and greatly improve patient outcomes.
