Abstract 1930: Evaluating the effect of PARP inhibitors in combination with nicotinamide phosphoribosyltransferase inhibitors in Ewing sarcoma

Abstract

Abstract Previous research has shown that Ewing sarcoma cells are sensitive to PARP inhibition, but in vivo studies and early phase clinical trials have failed to demonstrate meaningful responses to PARP inhibitors when used as single agents. For this reason, studies combining PARP inhibitors with other agents to enhance their effects in Ewing sarcoma are of particular interest. PARP, an enzyme involved in DNA damage repair, relies on NAD to function. In tumor cells, NAD production occurs primarily through the salvage pathway, in which nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme. Hence, the combination of PARP and NAMPT inhibition would be expected to enhance the activity of PARP inhibition through depletion of cellular NAD. The aim of this study was to assess the synergistic potential of PARP inhibition in combination with NAMPT inhibition in Ewing sarcoma cell lines and xenograft models. Synergistic drug combinations in Ewing sarcoma cells were initially identified using a high-throughput matrix drug screen. In vitro activity was further assessed using proliferation assays of multiple Ewing sarcoma cell lines treated with the PARP inhibitor niraparib and the NAMPT inhibitor GNE-618. In vitro measurement of PAR activity was performed to further understand the mechanism of action of the combination. For in vivo studies, female SCID-biege mice were orthotopically injected with Ewing sarcoma cells and randomized into treatment groups of vehicle, niraparib, GNE-618, or the combination. The initial screen revealed synergy between NAMPT inhibitors and PARP inhibitors using multiple combinations of different agents in each drug class. In vitro assays of the combination of niraparib with GNE-618 confirmed the results of the screen. Assays measuring PAR activity yielded results supporting the hypothesis that dual inhibition of NAMPT and PARP depletes PARP more than PARP inhibitors alone. In vivo studies with short term (5 day) dosing showed no activity of single agent nirapirib and only temporary disease stabilization with single agent GNE-618. However, mice treated with the combination underwent tumor regressions resulting in prolonged survival. When treatments were extended to 2 cycles (5 days each), the effect persisted for longer. Mice tolerated the agents well, with no signs of toxicity. Preclinical data suggest that PARP inhibition in combination with NAMPT inhibition may be a promising therapeutic strategy for Ewing sarcoma patients. Citation Format: Joshua T. Baumgart, Christine Heske, Mindy I. Davis, Kelli Wilson, Xiaoha Zhang, Rajarshi Guha, Marc Ferrer, Arnulfo Mendoza, Craig J. Thomas, Lee J. Helman. Evaluating the effect of PARP inhibitors in combination with nicotinamide phosphoribosyltransferase inhibitors in Ewing sarcoma [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 1930. doi:10.1158/1538-7445.AM2017-1930