Targeting nicotinamide adenine dinucleotide metabolism for the treatment of chronic lymphocytic leukemia
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Date
2014-09
Authors
Bouchard, Eric
Journal Title
Journal ISSN
Volume Title
Publisher
American Association for Cancer Research, Inc.
Abstract
The nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising new target for the treatment of multiple malignancies, including chronic lymphocytic leukemia (CLL). However, results of early phase clinical trials suggest that effective use of NAMPT inhibitors will require the dose reduction and improved treatment efficacy afforded by combination therapy. In this study, we assessed the downstream effects of NAMPT inhibition on NAD-dependent pathways in primary CLL cells in vitro in order to identify promising targets for novel combinations therapies. We then investigated drug-drug interactions between the NAMPT inhibitors FK866 and GMX-1778, and chemotherapeutics and targeted agents in current clinical use, as well as agents targeting mitochondrial metabolism, glycolysis and oxidative stress. We identified several promising novel drug combinations for further investigation and development for CLL treatment.
Description
Keywords
Nicotinamide adenine dinucleotide (NAD), Chronic lymphocytic leukemia (CLL), Metabolism, Nicotinamide phosphoribosyltransferase (NAMPT), Synergy
Citation
Gehrke, I. et al. On-Target Effect of FK866, a Nicotinamide Phosphoribosyl Transferase Inhibitor, by Apoptosis-Mediated Death in Chronic Lymphocytic Leukemia Cells. Clin. Cancer Res. 20, 4861–72 (2014).