Ovarian cancer is one of the leading causes of death for women. Approximately 15% of ovarian cancer harbors the inherited mutations in BRCA1 and BRCA2. The mutation carriers of BRCA1 and BRCA2 have up to 50% lifetime risk to develop ovarian cancer. Currently, PARP inhibitors (e.g. Olaparib, Rucaparib) have been approved by FDA to treat advanced ovarian cancer with BRCA mutations. However, long term treatment with PARP inhibitors causes drug resistance in cancer patients. In addition, recent clinical trials show that not all the BRCA tumor patients responded well to PARP inhibitors. Thus, developing novel therapeutic strategies is an urgent and important issue for the mutation carriers of BRCA1 and BRCA2. Interestingly, our recent study suggests that PARylation and dePARylation are not antagonistic processes during DNA damage repair. Instead, transient PARylation and quick dePARylation are sequential events that mediate the recruitment of DNA damage machineries to the sites of DNA damage. PARylation has to be removed by the dePARylation enzymes quickly so that DNA damage machineries are able to recognize DNA lesions and repair them. Therefore, dePARylation also plays an important role in DNA damage repair. And, targeting the major dePARylation enzyme PARG is an alternative approach to abolish PARP-dependent DNA damage repair. Here, we have identified a potent and cell-permeant PARG inhibitor (IC50= 3.77 nM). The PARG inhibitor treatment selectively kills BRCA1-deficient breast cancer cells (HCC1937). In the proposed research plan, we will investigate the role of this PARG inhibitor in DNA damage repair pathways and utilize this small molecule to treat the BRCA-mutant ovarian cancer cells in vivo. This study will not only reveal the mechanism of PARG inhibition in DNA damage response, but also facilitate developing novel therapeutic strategies for ovarian cancer patients.
This grant is made possible in part by a generous donation from Rock ‘N Run.