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.

Public Health Relevance

Pancreatic cancer is one of the top five causes of cancer-related deaths around the globe, with an extremely poor prognosis. New and effective therapies are urgently needed for this disease. Our studies will lead to pre-clinical and clinical studies with novel strategies aim at causing pancreatic cancer specific metabolic collapse and cell death, and may lead to novel and effective therapies for this deadly disease .

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Liou, Geou-Yarh; Döppler, Heike; Necela, Brian et al. (2015) Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov 5:52-63
Zhen, David B; Rabe, Kari G; Gallinger, Steven et al. (2015) BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 17:569-77
Delgiorno, Kathleen E; Hall, Jason C; Takeuchi, Kenneth K et al. (2014) Identification and manipulation of biliary metaplasia in pancreatic tumors. Gastroenterology 146:233-44.e5
Li, Liang; Fridley, Brooke L; Kalari, Krishna et al. (2014) Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell lines. BMC Genomics 15:93
Halfdanarson, Thorvardur R; Bamlet, William R; McWilliams, Robert R et al. (2014) Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study. Pancreas 43:1219-22
Mills, Lisa D; Zhang, Lizhi; Marler, Ronald et al. (2014) Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression. J Biol Chem 289:16516-25
Chini, Claudia C S; Guerrico, Anatilde M Gonzalez; Nin, Veronica et al. (2014) Targeting of NAD metabolism in pancreatic cancer cells: potential novel therapy for pancreatic tumors. Clin Cancer Res 20:120-30
Wu, Lang; Goldstein, Alisa M; Yu, Kai et al. (2014) Variants associated with susceptibility to pancreatic cancer and melanoma do not reciprocally affect risk. Cancer Epidemiol Biomarkers Prev 23:1121-4
Calvo, Ezequiel; Grzenda, Adrienne; Lomberk, Gwen et al. (2014) Single and combinatorial chromatin coupling events underlies the function of transcript factor Krüppel-like factor 11 in the regulation of gene networks. BMC Mol Biol 15:10
Urrutia, Raul; Velez, Gabriel; Lin, Marisa et al. (2014) Evidence supporting the existence of a NUPR1-like family of helix-loop-helix chromatin proteins related to, yet distinct from, AT hook-containing HMG proteins. J Mol Model 20:2357

Showing the most recent 10 out of 152 publications