Abstract 4675: Novel combination therapy of DNA methyltransferase inhibitor guadecitabine (SGI-110) and PARP inhibitor talazoparib (BMN-673) for BRCA-proficient high-grade serous ovarian cancer
Authors: Pulliam Nicholas , Taverna Pietro , Lyons John , Nephew Kenneth P. 
Published: July 2017

Abstract
Ovarian cancer recurrence has been shown to be associated with increased DNA damage response (DDR) mediated by poly-(ADP)-ribose polymerase 1/2 (PARP1/2), which can be therapeutically targeted by PARP inhibitors (PARPi). PARPi are indicated for platinum-responsive, BRCA-mutated high-grade serous ovarian cancer, but most ovarian cancer patients have BRCA-proficient disease. Our previous studies support a role for DNA methylation in chemoresistant ovarian cancer mediated by the enzyme DNA methyltransferase 1 (DNMT1), and report on a functional role for DNMT1 in DNA damage repair. We therefore hypothesized that combining a DNMTi and PARPi will impair BRCA-mediated DDR, resulting in cytotoxicity in ovarian cancer cells. A panel of ovarian cancer cell lines (A2780, platinum sensitive, BRCA1/2-wild type; A2780-cp and HeyC2, platinum resistant, BRCA1/2-wild type; high-grade serous Kuramochi, platinum resistant, BRCA2 mutant) was examined for cell growth using colony formation assays after treatment with DNMTi guadecitabine (low dose, 20-100nm) and PARPi talazoparib (1-10nm), alone or in combination. While talazoparib alone only marginally reduced colony formation in all cell lines (dose-dependent effect), combining guadecitabine with talazoparib further decreased (P&lt;0.05) survival at all doses examined. To focus more specifically on BRCA status, we utilized two high-grade serous ovarian cancer cell lines (“PEO”) derived from the same patient but harboring a mutant (PEO1) or wild type (PEO4) BRCA2 gene (Langdon et al, 1988; Sakai et al, 2009). Treatment with low-dose guadecitabine (20 nm, 3 days) increased (P&lt;0.05) PARP levels (western blot analysis) as well as enzymatic activity (P&lt;0.05; ELISA analysis), while talazoparib treatment alone increased (P&lt;0.05) DNMT1 levels and decreased (P&lt;0.05) PARP enzymatic activity. Treatment with guadecitabine or talazoparib alone had no effect on cell proliferation; however, combining the two drugs inhibited (&gt;80%; P&lt;0.05) PEO1 and PEO4 proliferation and increased (3-fold; P&lt;0.05) apoptosis (caspase 3 cleavage) in both cell lines. Furthermore, co-administration guadecitabine (0.5mg/kg) and talazoparib (0.25mg/kg) to mice harboring BRCA2-wild type ovarian tumor xenografts decreased (p&lt;0.05) tumor volume (&gt;60%) and tumor weight (~70%) compared to control, respectively. In summary, combining a hypomethylating agent with a PARP inhibitor results in enhanced cytotoxicity in high-grade serous ovarian cancer cell lines harboring either wild type- or mutant-BRCA, indicating that the talazoparib-guadecitabine drug combination is effective regardless of BRCA-mediated DDR and may represent an effective treatment regimen for BRCA-related cancers.
Citation Format: Nicholas Pulliam, Pietro Taverna, John Lyons, Kenneth P. Nephew. Novel combination therapy of DNA methyltransferase inhibitor guadecitabine (SGI-110) and PARP inhibitor talazoparib (BMN-673) for BRCA-proficient high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4675. doi:10.1158/1538-7445.AM2017-4675