Targeting NAD Catabolism in Pancreatic Cancer Cells: Role of Small Molecule SIRT

It has been known since the seminal discoveries of Otto Warburg in the early 1900's that cancer cells have unique metabolic features. However, it was not until recently that cancer cell metabolism became the focus of intense investigation. In particular, tumor cells undergo metabolic adaptations and have highly active glycolytic, pentose and fatty acid synthesis pathways. All of these metabolic changes contribute to increased tumor cell survival, proliferation and metastasis. Nicotinamide adenine dinucleotide (NAD) is central for these metabolic changes and cellular levels of NAD must be balanced to modulate these processes. A systematic analysis of the metabolism of NAD has not been performed in pancreatic cancer cells. NAD metabolism is regulated at the level of synthesis and degradation, and a decrease in cellular NAD levels leads to metabolic collapse and cell death. Recently, unique features of NAD metabolism have been described in cancer cells, opening the possibility that targeting NAD synthesis and/or degradation may lead to cancer specific metabolic collapse and serve as new therapy for a variety of human tumors including pancraeric cancer. Hence, we propose that activation of NAD degradation or inhibition of its synthesis will lead to a decrease in pancreatic cancer cell NAD levels and metabolic collapse, with subsequent tumor cell growth arrest and cell death. Our central hypothesis is that increasing NAD degradation (by activation of the enzyme SIRT1 with small molecules) or inhibiting its synthesis (using inhibitors of the enzyme Nampt) will cause metabolic collapse resulting in antitumor activity by itself and may also increase the antitumor activity of other chemotherapeutic agents. We will perform studies to elucidate the role of NAD metabolism in pancreatic cancer, characterize the major enzymes in pancreatic tumor tissue and test the combination of SRT3025 (a SIRT1 activator) with gemcitabine in a clinical trial of patients with metastatic pancreatic cancer. Our proposal is extremelly novel and of major relevance for the development of novel therapies for pancreatic cancer.