LAUSR

Since the discovery of nicotinamide phosphoribosyltransferase (NAMPT) as a pre-B cell-enhancing factor in 1994 by Samal et al. [1], many papers have described the pleiotropic function of this enzyme. A vital role of NAMPT in mammalian cells was attributed to its activity as a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide, and was supported by its widespread tissue distribution and by the embryonic lethality of total NAMPT knock-out mice [2]. It has been shown that tumours require increased levels of energetic molecules. Metabolic rewiring is now considered one of the hallmarks of tumours, sustaining the production of cellular energy [ie, adenosine triphosphate (ATP)], and their growth and invasive capacities [3]. The redox co-factor NAD, is fundamental in several metabolic reactions, and as a substrate for different NAD-consuming enzymes [eg, poly-ADP-ribose polymerases (PARPs) and sirtuins], involved in many cellular processes, including DNA repair and epigenetic regulation of gene expression [4]. A common strategy that several tumour types adopt to sustain NAD production is to overexpress NAMPT, regulated at the transcriptional level [5]. This finding has led to the design of numerous NAMPT inhibitors (NAMPTi) in the context of cancer therapy. Despite significant results in vitro and in vivo, phase I clinical trials with the first NAMPTi (ie, FK866 and GMX1778) in haematological or solid malignancies, showed no objective tumour remission, and toxicity. Besides the pharmacological properties of these drugs and their potential toxicity, one of the main aspects leading to the partial failure of NAMPTi treatment was due to the concomitant expression of others NAD-biosynthetic enzymes that can overcome NAMPT inhibition. It is now clear in the field that it is necessary to select tumours uniquely addicted to NAMPT activity in the generation of NAD. Novel NAMPTi are currently in pre-clinical and phase I-II clinical trials, highlighting an intense pharmacological effort to target this enzyme [6].