Abstract 1760: Tumor-specific targeting of the NAD metabolome with β-lapachone and NamPT inhibition

Abstract

Abstract Cancer cells require increased NAD+ synthesis to support anabolic metabolism, to sustain signaling processes such as sirtuin activity and ADP-ribosylation, and to maintain redox balance. Inhibitors of Nicotinamide phosphoribosyltransferase (NamPT), the rate-limiting step in NAD+ biosynthesis, have modest anti-tumor activity in monotherapy in vitro and in vivo, but failed clinical trials due to a lack of tumor specificity attributed to the necessity of NAD+ synthesis in normal proliferating cells. We found that the tumor specificity and efficacy of NamPT inhibition can be greatly increased when small molecule NamPT inhibitors, such as FK866, are used in combination with the NQO1 bioactivated therapeutic ß-lapachone (ß-lap). Most solid tumor cells overexpress NQO1, which catalyzes a futile redox cycle with ß-lap, resulting in the formation of a burst of reactive oxygen species (ROS). This results in substantial DNA single strand breaks and base damage in a tumor-specific manner, which hyperactivates poly(ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme that utilizes NAD+ to generate poly(ADP-ribose) (PAR)-protein moieties. Rapid NAD+ and ATP loss occurs and tumor cells die through programmed necrosis. PARP-1-mediated NAD+ depletion caused by ß-lap treatment synergizes with reduced NAD+ synthesis as a result of FK866-mediated NamPT inhibition. Enhanced cancer cell death in terms of loss of viability and clonogenicity at lower ß-lap doses was noted, while tumor specificity for NQO1 overexpressing cells was maintained. With combination treatment, cells are primed for ROS-mediated damage due to reduced glutathione and NAD(P)+ levels, they are unable to recover ATP, NAD+, and NADP+ synthesis even after only a 2 hour treatment, and they rapidly die through a caspase-independent mechanism. This therapeutic approach is highly effective against a variety of tumor cell lines from pancreatic, breast, and non-small cell lung, and is expected to improve the efficacy and tumor specificity of both of these drugs by allowing their use at lower doses in vivo. These studies were supported by an AACR/PanCan Innovator Award and NIH R01 CA102972 to DAB. Citation Format: Zachary Moore, David A. Boothman. Tumor-specific targeting of the NAD metabolome with β-lapachone and NamPT inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1760. doi:10.1158/1538-7445.AM2014-1760