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Philip Michael Tedeschi
M.S., The Johns Hopkins University - 2011
Thesis Advisor: .Joseph R. Bertino, M.D.
Graduate Program in Cellular & Molecular Pharmacology
RWJMS Research Tower
Friday, April 24, 2015
The enzyme NAD+ kinase (NADK) catalyzes the phosphorylation of nicotinamide adenine dinucleotide (NAD+) to nicotinamide adenine dinucleotide phosphate (NADP+), using ATP as the phosphate donor. The pyridine nucleotides NAD+ and NADP+ can be reduced by a number of dehydrogenases to NADH and NADPH. Together, NAD/H and NADP/H function as important cofactors in a variety of metabolic and biosynthetic pathways as both hydrogen donors and acceptors through their ability to be oxidized and reduced.
The demand for NADPH in transformed cells is elevated as reducing equivalents are required for the elevated levels of nucleotide, protein and fatty acid synthesis found in proliferating cells, as well as for neutralizing high levels of reactive oxygen species (ROS). Growing evidence suggests that cancer cells exhibit increased intrinsic ROS stress due to this increased metabolic activity, causing DNA damage and oxidation of cellular components. The importance of NADPH to both ROS detoxification and as a cofactor in metabolic pathways is crucial to a transformed cells ability to proliferate; several therapeutic strategies aimed at NADPH metabolism are under study.
The aim of this study was to determine whether inhibition of NADK activity is a valid anti-cancer strategy. In vitro and in vivo inhibition of NADK activity with either shRNA or the NADK inhibitor prodrug thionicotinamide inhibited cell proliferation. Thionicotinamide enhanced ROS levels produced by several chemotherapeutic drugs in combination and demonstrated synergistic cell kill. NADK inhibitors alone or in combination with drugs that increase ROS-mediated stress may represent an efficacious antitumor combination. A novel NADK mutant was observed in pancreatic cancer patients, and was found to be a driver mutation, inducing transformation in normal pancreatic ductal cells. This data led us to develop a high throughput screen in an effort to identify a new generation of potent and specific NADK inhibitors. This study of the effect of NADK inhibition, as well as its new found clinical importance, support future drug discovery efforts focused on NADK as a potential therapeutic target in cancer.