Abstract 1871: Targeting nicotinamide phosphoribosyltransferase (NAMPT) in cancer therapy.
Authors: Cristina Travelli, Sara Morlacchi, Antonio Caldarelli, Antonio Sica, Armando A. Genazzani
Journal: Cancer Research (2013)

Abstract Nicotinamide adenine dinucleotide (NAD) metabolism has been emerged as a new target pathway in developing new cancer therapies. NAD has principal two functions in cells: (i) cofactor in redox reactions and (ii) substrate of several classes of NAD-dependent enzymes (i.e. PARPs, sirtuins). When NAD is a redox carrier, its not consumed by cells, however NAD-utilizing enzymes degrade NAD, inducing a decrease of the intracellular NAD pool. Therefore, to re-establish NAD levels in cells, the so called “NAD salvage pathway” exists. In this pathway, nicotinamide phosphoribosyltransferase (NAMPT) plays a crucial role; this enzyme is able to convert nicotinamide (Nam), released by NAD-dependent enzymes, into nicotinamide mononucleotide (NMN), which is finally converted to NAD by NMNAT. Different expression and activity of NAMPT have been correlated with a number of pathologies, and cancer is not an exception. For example, NAMPT has been found up-regulated in several types of cancer. To date, two potent NAMPT inhibitors (FK866 and CHS828) have been discovered and are now in phase I and II of trials in different types of solid and non-solid cancers. However, the results of the trials are still unpublished. Moreover, NAMPT has been also described as a cytokine, also called visfatin, released by adipocytes and several types of activated immune cells. However the function of visfatin and the possible release of this cytokine by cancer cells are still unknown. We have investigated (i) the action of NAMPT inhibitors in two different types of cancer (neuroblastoma and melanoma) that differ in NAMPT expression and (ii) the contribution of extracellular form of NAMPT (visfatin) in tumour. We found a positive correlation between NAMPT expression and responsiveness to NAMPT inhibitors. In particular neuroblastoma cells, which express normal levels of NAMPT, are sensitive to FK866, contrary melanoma cells, which over-expressed NAMPT are refractory to FK866 treatment. Therefore, these data may suggest that in melanoma cells NAMPT may have not only an enzymatic activity but may have another function. We found that these cells are able to release NAMPT in a time-dependent manner, suggesting that NAMPT could act also as a cytokine in melanoma cell culture. Since cytokines are involved in inflammation, and that inflammation is a critical component of tumour progression, we decided to investigate the possible role of NAMPT and visfatin in tumour-related inflammation. Our preliminary results show that NAMPT altered the activity of myeloid-derived suppressor cells (MDSC), a heterogeneous population of early myeloid progenitors that facilitate tumour progression. Our results could be a starting point for future direction in targeting NAMPT to interfere with tumour-related inflammation. Citation Format: Cristina Travelli, Sara Morlacchi, Antonio Caldarelli, Antonio Sica, Armando A. Genazzani. Targeting nicotinamide phosphoribosyltransferase (NAMPT) in cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1871. doi:10.1158/1538-7445.AM2013-1871 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.