Advanced glycation endproduct (AGE) inhibitory strategy with FL-926-16 for protection against the increased risk of pancreatic cancer conferred by diabetes
Diabetes mellitus (DM) has been identified as a risk factor for pancreatic cancer (PaC). Since no effective therapy is available to treat PaC ( 5-year survival
1. effect of DM on progression of early murine PaC and eligibility of AGEs as a therapeutic target for PaC risk reduction in DM;
2. mechanistic insights into the regulation of PaC tumorigenic pathways by AGEs.
This project consists of in vivo and in vitro studies addressing specific aims #:
1. PaC-prone, Pdx1-Cre:KrasG12D/+ (KC mice), will be crossbred with MITO-Luc mice which express the luciferase reporter specifically in proliferating cells. KC-MITO mice will be rendered diabetic with streptozotocin (STZ) and treated or not for the entire period of the study (16 weeks) with FL-926-16, an efficient sequestering agents of reactive carbonyls and, therefore, an effective AGE inhibitor. In vivo bioluminescence imaging for cell proliferation will be performed every other week. At the end of the study, pancreas will be analyzed at the histological and molecular level.
2. Human PaC cells will be treated with carbonyl precursors of AGEs, in the presence or absence of FL-926-16, or cultured in growth medium containing 40% of serum from diabetic patients. The effects of AGEs on the regulation of cell behavior and tumorigenic pathways (i.e., NF-kB, interleukin 6, pSTAT3 etc.) will be investigated.
The demonstration that AGEs play a prominent role in DM-associated risk of PaC would allow designing therapeutic approaches aimed at reducing AGE formation, suitable for risk management and prevention of PaC in high-risk diabetic patients