Utilization of 18F-fluorodeoxyglucose–positron emission tomography to understand the mechanism of nicotinamide phosphoribosyltransferase inhibitors in vivo

Abstract

Cancer cells are highly dependent on NAD1/NADH produced via the nicotinamide salvage pathway. The rate-limiting enzyme in this pathway is the nicotinamide phosphoribosyltransferase (NAMPT), which we have targeted with novel NAMPT inhibitors. NAMPT inhibition elicits depletion of total cellular NAD1 levels and ultimately cytotoxicity via depletion of cellular ATP levels. 18F-fluorodeoxyglucose– positron emission tomography (FDG-PET) is a translational imaging tool to assess glucose utilization in tumors and normal tissue. We used FDG-PET to understand the timing of ATP depletion in vivo and better understand the pharmacology of NAMPT inhibitors. Because of the intimate relationship between cellular ATP levels and cell viability, we developed an in-depth understanding of our NAMPT inhibitor pharmacology and the relationship with changes in tumor FDG uptake. Taken together, we show that FDG-PET could be used as a biomarker in clinical studies to understand dose and provide proof of mechanism for NAMPT inhibitors.