Abstract B154: Co-administration of nicotinic acid with NAMPT small molecule inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models.
Authors: Sampath Deepak , Oeh Jason , Xiao Yang , Liang Xiaorong , Vanderbilt Alexander , Qin Ann , Yang LuLu , Lee Leslie , Ly Justin , Cosino Ely , LaCap Jennifer , Ogasawara Annie , Williams Simon , Nannini Michelle , Liederer Bianca , Jackson Peter , Dragovich Peter , O'Brien Thomas 
Published: August 2014

Abstract
Nicotinamide adenine dinucleotide (NAD) is a metabolite essential for cell survival and is generated de novo from tryptophan or recycled from nicotinamide (NAM) through the nicotinamide phosphoribosyl transferase (NAMPT)-dependent salvage pathway. Alternatively, tumors can convert nicotinic acid (NA) [also referred in the literature as vitamin B3 or niacin] to NAD through the nicotinic acid phosphoribosyltransferase 1 (NAPRT1)-dependent pathway. Tumor cells do not efficiently utilize the de novo synthesis pathway, rendering them more reliant on NAMPT and, therefore, making this enzyme an attractive therapeutic target. Moreover, it has been proposed that the therapeutic index of NAMPT inhibitors may be increased in tumors that lack NAPRT1 upon co-administration of NA as normal tissues can generate NAD through NAPRT1. Using novel and potent orally bioavailable NAMPT small molecule inhibitors, GNE-617 and GNE-618, we evaluated the feasibility of the latter approach in vivo using xenograft models (n=5) derived from tumor cells lines (n=3) and primary patient samples (n=2) that lacked NAPRT1. All xenograft models tested were sensitive to GNE-617 or GNE-618 demonstrated by rapid induction of tumor regressions upon treatment with NAMPT inhibitors. While NA did not protect NAPRT1-deficient tumor models in vitro or ex vivo from GNE-617 and GNE-618, it rescued the anti-tumor effects of these inhibitors in the same tumor models grown as xenografts in vivo. Co-administration of NA with GMX-1778, a previously reported NAMPT small molecule inhibitor, also resulted in complete loss of efficacy suggesting that rescuability with NA in vivo is not an inhibitor-specific phenomenon. Importantly, tumor xenografts remained NAPRT1-deficient upon NA co-treatment, indicating that tumors were not reactivating the NAPRT1-dependent salvage pathway to compensate for NAMPT inhibition. However, NA co-treatment increased NAD and NAM levels in NAPRT1-deficient tumor xenografts to levels that were sufficient to support robust tumor growth even in the presence of GNE-617. Furthermore, NAM co-administration with GNE-617 led to increased tumor NAD levels in vivo and afforded the same degree of protection as NA. Given that NAMPT inhibitors compete biochemically with NAM, a modest increase in tumor NAM levels may be sufficient to reduce NAMPT inhibition to adequately sustain NAD production. Thus, it appears that the tumor models tested in this study maybe utilizing exogenously supplied metabolites in vivo to circumvent the effects of NAMPT inhibition. The unexpected protection of NAPRT1-deficient tumors in vivo may be due to enhanced circulating levels of metabolites generated by normal tissue, such as liver, in response to NA. Our results have important implications for the development of NAMPT inhibitors when considering NA co-treatment as an antidote and strategy for increasing the therapeutic index.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B154.
Citation Format: Deepak Sampath, Jason Oeh, Yang Xiao, Xiaorong Liang, Alexander Vanderbilt, Ann Qin, LuLu Yang, Leslie Lee, Justin Ly, Ely Cosino, Jennifer LaCap, Annie Ogasawara, Simon Williams, Michelle Nannini, Bianca Liederer, Peter Jackson, Peter Dragovich, Thomas O'Brien. Co-administration of nicotinic acid with NAMPT small molecule inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B154.