Abstract 3323: E7449, a potent inhibitor of PARP 1 and 2, is active in acute myeloid leukemia.

Abstract

Abstract Leukemic cells, like many other cancer cells, are often deficient in DNA repair capacity. PARP inhibitors have demonstrated synthetic lethality in cancer cells with defective DNA repair. E7449 is an orally bioavailable, potent, small molecule inhibitor of poly(ADP-ribose) polymerase (PARP)1 and PARP2. In this study we describe the therapeutic potential of the PARP inhibitor E7449 in acute myeloid leukemia (AML). E7449 inhibited proliferation of leukemia cells in a long term in vitro growth inhibition assay in a panel of leukemic cell lines. The MV-4-11 AML cell line was identified as particularly sensitive to E7449 PARP inhibition, and induction of apoptosis was observed in these cells. An in vivo survival model of acute myeloid leukemia (AML) was established in NSG mice using MV-4-11-luc2/AcGFP human AML cells. Daily dosing of E7449 at 100 mg/kg resulted in statistically significant anticancer activity in this model. Reduced disease burden as measured by luciferase signal was observed. This decrease in leukemic load also translated into a statistically significant survival benefit in E7449 treated mice. In AML cells, high P-glycoprotein (P-gp) expression is often observed, particularly in older patients, and this often leads to resistance to typical therapies. E7449 anti-proliferative activity was assessed in paired murine leukemia cells with basal (P388/S) and overexpressed P-gp protein (P388/VMDRC.04). E7449 effectively inhibited growth of the high P-gp expressing cells as well as the parent P388/S cells, with no significant difference in the presence or absence of verapamil, in contrast to data obtained for the P-gp substrate doxorubicin. These data demonstrate that E7449 is not a substrate for P-gp transport. Importantly, E7449 also significantly inhibited proliferation of primary patient AML cells ex vivo. In addition, E7449 proved highly potent at inhibiting colony formation in the majority of primary patient AML specimens assessed in long term (14 day) clonogenic survival assays. Studies to discern the mechanism underlying sensitivity to E7449 in AML cells are underway. Conclusion: In this study, E7449 possessed potent anti-cancer activity against AML cell lines and primary patient AML cells in vitro and ex vivo, it was not a substrate for P-gp transport, and it reduced disease burden and increased survival in an AML in vivo model. These data support the assessment of E7449 as a therapy for AML in the clinic. Citation Format: Sharon McGonigle, Zhihong Chen, Jiayi Wu, Donna Kolber-Simonds, Shannon McGrath, Karen TenDyke, Zichun Wang, Kenichi Nomoto. E7449, a potent inhibitor of PARP 1 and 2, is active in acute myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3323. doi:10.1158/1538-7445.AM2013-3323