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
Biochemical mechanisms of hyperglycaemic injury are potential targets for novel therapeutic/preventative intervention aimed at reducing glucose toxicity and diabetes-associated risk of PaC. This research project investigates a novel mechanistic link between the toxic by-products of glucose metabolism (i.e., AGEs) and PaC progression, providing new explanation for the excess risk of PaC observed in diabetic individuals. Moreover, we postulate that a novel carnosine derivative resistant to carnosinase activity, which has been shown to be highly effective in preventing diabetes-associated vascular complications through inhibition of AGE accumulation, might help to protect against the PaC-promoting effect of diabetes.
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 more detail, although a role for AGEs has been tentatively proposed to explain the increased risk of various cancers (including PaC) in diabetic individuals, surprisingly, their role in pancreatic carcinogenesis has never been investigated. Moreover, there is no evidence in the literature to demonstrate a direct effect of carnosine (or its derivatives) on the risk of cancer conferred by diabetes. Information about this potential effect of carnosine derivatives may contribute to identify a novel molecular mechanism underlying the higher risk of developing PaC associated with diabetes.
In conclusion, this study deals with a novel mechanistic link between the toxic by-products of glucose AGEs and the increased risk of PaC , which would provide new explanation for the effect of diabetes on PaC development and progression. Therefore, this study has the potential to provide a novel paradigm and therapeutic opportunity for the prevention of PaC in high-risk diabetic patients.