SIRT6 Suppresses Pancreatic Cancer via the Oncofetal Protein Lin28b
Abstract
Fiscal Year 2016 Peer Reviewed Cancer Research Program Topic Area: Pancreatic cancer. Focus Areas: “Militarily relevant risk factors associated with cancer” and “Gaps in cancer prevention, screening, early detection, diagnosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of military members, Veterans, and their beneficiaries.” Pancreatic cancer remains one of the most lethal tumors, with current therapies minimally prolonging survival. In previous studies, we identified the factor SIRT6, which modulates activation/repression of genes, as a key tumor suppressor in colon cancer. More recently, using mouse models and human studies, we found that SIRT6 is a critical tumor suppressor in pancreatic cancer as well. In this proposal, we will study the precise role for SIRT6 in pancreatic cancer, which our preliminary data defines as a key inhibitor of pancreatic cancer growth and dissemination. Furthermore, we found a unique protein called Lin28b, which is normally expressed during development and silenced in adult tissues, as a key novel protein activated in a subset of human pancreatic cancer. Taking advantage of genetically engineered mice and specific cell culture systems, we will define the precise molecular mechanisms govern by SIRT6 and Lin28b in pancreatic cancer, and we will test whether restoring SIRT6 or blocking Lin28b-driven pathways will inhibit pancreatic tumor growth. Our results may lead to new therapies for patients with this devastating disease. Military personnel appear to represent a particularly vulnerable population with increased incidence of this disease, and we plan to specifically assess, in collaboration with the Department of Veterans Affairs (VA) Boston Healthcare System, whether military personnel specifically carry this unique genetic signature. Given that pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers (> than 90% of the diagnosed patients will die in less than a year), better understanding of the molecular drivers in this disease could influence drastically the development of treatments to bring back PDAC-diagnosed military personnel to full health.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710517
Entities
People
- Raul Mostoslavsky
Organizations
- Massachusetts General Hospital
- United States Army