Novel NAPRT specific antibody identifies small cell lung cancer and neuronal cancers as promising clinical indications for a NAMPT inhibitor/niacin co-administration strategy.

Jonathan Cole,Anne Roulston,Cynthia Bernier,Michel Gravel,Gordon C Shore,Marie-Christine Guiot

doi:10.18632/oncotarget.20840

Abstract

Tumor cells are particularly dependent on NAD+ due to higher rates of metabolism, DNA synthesis and repair. Nicotinamide phosphoribosyltransferase inhibitors (NAMPTis) inhibit NAD+ biosynthesis and represent promising new anti-cancer agents. However, clinical efficacy has been limited by toxicities demonstrating the need for drug combinations to broaden the therapeutic index. One potential combination involves niacin/NAMPTi co-administration. Niacin can rescue NAD+ biosynthesis through a parallel pathway that depends on nicotinic acid phosphoribosyltransferase (NAPRT) expression. Most normal tissues express NAPRT while a significant proportion of malignant cells do not, providing a possible selection marker for patients to achieve NAMPTi efficacy while minimizing toxicities.Here we identify and validate a novel highly NAPRT-specific monoclonal antibody (3C6D2) that detects functional NAPRT in paraffin embedded tissue sections by immunohistochemistry (IHC). NAPRT detection by 3C6D2 coincides with the ability of niacin to rescue cells from NAMPTi induced cytotoxicity in cell lines and animal xenograft models. 3C6D2 binds to an epitope that is unique to NAPRT among phosphoribosyltransferases. In a series of primary tumor samples from lung and brain cancer patients, we demonstrate that >70 % of human small cell lung carcinomas, glioblastomas and oligodendrogliomas lack NAPRT identifying them as potentially suitable indications for the NAMPT/niacin combination.

Highlights

Nicotinamide adenine dinucleotide (NAD+) plays a crucial role in cancer cell metabolism and is the substrate for important cancer related enzymes such as ADP-ribose transferases, including poly-ADP-ribose polymerases (PARPs), sirtuins and cyclic ADP ribose synthases
NAD+ is synthesized by two parallel routes: the primary pathway is via nicotinamide phosphoribosyltransferase (NAMPT) that derives NAD+ from the pre-cursor, nicotinamide [2, 7]; the secondary Preiss-Handler pathway, that operates in parallel, derives NAD+ from nicotinic acid, via nicotinic acid www.impactjournals.com/oncotarget phosphoribosyltransferase (NAPRT) [8, 9]
Successful implementation of the strategy to widen the therapeutic index of NAMPT inhibitors by coadministration with niacin, will depend on the ability to correctly detect functional nicotinic acid phosphoribosyltransferase (NAPRT) in tumor tissue and on the ability of normal tissue to be protected by niacin administration

Summary

Introduction

Nicotinamide adenine dinucleotide (NAD+) plays a crucial role in cancer cell metabolism and is the substrate for important cancer related enzymes such as ADP-ribose transferases, including poly-ADP-ribose polymerases (PARPs), sirtuins and cyclic ADP (cADP) ribose synthases. These enzymes are important in DNA repair, G-protein coupled receptor signaling, calcium homeostasis, transcriptional regulation, and cancer cell survival [1, 2]. NAMPT is the key biosynthetic enzyme involved in NAD+ generation and recycling in cells and is a compelling anti-cancer drug target

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