Despite recent progress in the treatment of advanced stage pancreatic ductal adenocarcinoma (PDAC) through the use of toxic combination chemotherapy, the median survival remains under one year. Further therapeutic advances for this deadly disease will likely require a detailed understanding of the underlying pathophysiologic mechanisms driving this cancer and how these pathways can be specifically targeted. One such mechanism is the reliance of pancreatic ductal adenocarcinoma (PDAC) cells on aerobic glycolytic metabolism, broadly known as the Warburg effect. Although this key metabolic adaptation has been exploited diagnostically for decades (PET scan), little is known about how this process is regulated in pancreatic tumors. In recent studies, our laboratory showed that the histone deacetylase SIRT6 functions as a central regulator of glycolytic metabolism and is downregulated in human PDAC cancers. Strikingly, our preliminary data shows that loss of SIRT6 dramatically accelerates the development of PDAC in genetically engineered mouse models (GEMMs), leading to metastatic disease, a phenotype rarely observed in these models of PDAC. Further, restoration of SIRT6 expression in established PDAC cells reduces both aerobic glycolysis and proliferative capacity. In the experiments outlined in this proposal, we will address: 1-how SIRT6 may use its histone deacetylase activity to regulate glycolysis and 2- test whether pathways rendered hyperactive in SIRT6-deficient PDAC tumors may be therapeutically targeted. Thus, the proposed studies will allow us to understand the fundamental metabolic alterations mediated by SIRT6 in PDAC cells and whether SIRT6-deficient tumors may represent a molecularly-defined subset of PDAC that is sensitive to therapeutic inhibitors of glycolysis.

Public Health Relevance

Pancreatic cancer remains one of the most lethal tumors, with current therapies minimally prolonging survival; recent studies defined glucose metabolism as a unique distinctive feature of pancreatic cancer, one that could be exploited therapeutically. In this proposal, we will study a molecule called SIRT6, which our previous studies have identified as a key modulator of glucose metabolism, and our preliminary data defines as a key inhibitor of pancreatic cancer growth and dissemination. Taking advantage of genetically engineered mice and specific cell culture systems, we will define the precise molecular mechanisms govern by SIRT6 in pancreatic cancer, and we will test whether restoring SIRT6 or blocking specific metabolic pathways will inhibit pancreatic tumor growth. Modulation of SIRT6 activity may lead to new therapies to tackle aberrant metabolism and provide new treatment options for patients with this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA198109-02
Application #
9068871
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
2015-05-15
Project End
2017-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Etchegaray, Jean-Pierre; Mostoslavsky, Raul (2016) Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes. Mol Cell 62:695-711
Kugel, Sita; Sebastián, Carlos; Fitamant, Julien et al. (2016) SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. Cell 165:1401-1415
Kugel, Sita; Feldman, Jessica L; Klein, Mark A et al. (2015) Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer. Cell Rep 13:479-488