DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most fatal of all cancers with only 6% of the patients living longer than 5 years. It is very well known that calorie restriction is a powerful intervention to suppress cancer including pancreatic cancer. Recent studies have shown that metabolic responses characteristic of calorie restriction can be obtained with the use of energy restriction mimetics (ERM). Targeting glucose metabolism by ERM that inhibit glycolysis is very relevant to pancreatic cancer because 90% of these cancers have a mutation in the Kras gene, which is dependent on glycolysis for survival. The new ERM, OSU-CG5 decreases survival and induces apoptosis in pancreatic cancer cells in association with decreased HuR, an RNA-binding protein necessary for cell survival. We propose that the ERM OSU-CG5 decreases HuR expression resulting in reduced incidence and improved survival, which has clinical importance because silencing HuR has been shown to sensitize pancreatic cancer cells to DNA damaging chemotherapeutics (12d). Additionally, we hypothesize that OSU-CG5 improves sensitivity of pancreatic cancer cells to DNA damaging agents through downregulation of HuR. The following aims will address this hypothesis. 1. To determine the effectiveness of the ERM OSU-CG5 in delaying the development and progression of pancreatic tumors and improving survival in KrasG12D; Trp53R172H;Pdx-1Cre mice. We will evaluate the effect of OSU-CG5 on incidence of pancreatic tumors and survival of KrasG12D; Trp53R172H;Pdx-1Cre mice. To explore the mechanisms for the potential anti-tumor effect of OSU-CG5, we will measure circulating concentrations of glucose, insulin, or IGF-1, proliferation and apoptosis in tumor tissue. 2. To investigate the mechanisms mediating the decreased cell survival and induction of apoptosis in response to OSU-CG5 in KPC, Mia Paca and Panc1 pancreatic cancer cells and tumors from KrasG12D; Trp53R172H;Pdx-1Cre mice by determining: (a) HuR and Glut1 expression (b) the mechanism by which OSU-CG5 decreases HuR protein (c) the type of cell death, (d) whether the decrease in cell survival and induction of apoptosis in pancreatic cancer cells is mediated by HuR, and (e) whether OSU-CG5 will improve sensitivity to DNA damaging agents.

PUBLIC HEALTH RELEVANCE: The objective of this proposal is to test the hypothesis that inhibition of glucose transporter protein1 (Glut1) with a newly identified ERM OSU-CG5 will reduce incidence of pancreatic cancer and improve survival of KrasG12D; Trp53R172H;Pdx-1Cre mice. To explore the mechanisms by which OSU-CG5 decreases cell survival and induces apoptosis in KPC, Mia Paca and Panc1 pancreatic cancer cells and tumors from KrasG12D; Trp53R172H;Pdx-1Cre mice we will determine: (a) HuR and Glut1 expression (b) the mechanism by which OSU-CG5 decreases HuR protein (c) the type of cell death, (d) whether the decrease in cell survival and induction of apoptosis in pancreatic cancer cells is mediated by HuR, and (e) whether OSU-CG5 will improve sensitivity to DNA damaging agents.