HHSN2612012000131/HHSN26100010Base Contract Title: Preclinical Efficacy and Intermediate Endpoint Biomarkers. Task Order Title: Preclinical Studies to Evaluate the Combination of Metformin and As

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Pancreatic cancer (PC) remains a devastating disease with a low 5-year survival rate and for both men and women is the fourth leading cause of cancer related deaths in the US. The lack of early detection methods and ineffective therapeutic options contribute to the poor prognosis. Pancreatic intraepithelial lesions (PanINs) are precursors that evidence suggests progress slowly over many years prior to developing into invasive pancreatic ductal adenocarcinoma (PDAC). Therefore, developing an effective chemoprevention treatment aimed at inhibiting the progression of PanINs could provide an important strategy to reduce the burden of PC. The etiology of PC and laboratory studies suggests that inflammation plays a significant role in pancreatic tumorigenesis. Aspirin and other NSAIDs show promise as chemopreventive agents due to their effects on inflammation that are attributed to inhibition of COX enzymes and modulation of NFκB or STAT3 pathways. Furthermore, the use of aspirin is associated with a decreased risk of pancreatic cancer. However, long term use of aspirin has potential dose related adverse effects such as gastrointestinal irritation and bleeding. Therefore, developing a chemopreventive strategy for PC that demonstrates efficacy with lower doses of aspirin is desirable. Diabetes, obesity and chronic pancreatitis are reported to increase the risk of PC. Metformin use in patients with diabetes has been associated with a decreased risk of several cancers including PC. Laboratory studies demonstrate that metformin inhibits cell proliferation that may be mediated by inducing AMPK and inhibiting the mTOR pathway. Taken together, these observations suggest metformin may be a useful agent for PC chemoprevention. The clinical use of metformin can be complicated by a rare but serious adverse effect of metabolic acidosis in some at risk patients. Therefore careful patient selection or lower clinical doses may be helpful strategies to manage risk for the chemopreventive use of this agent. Aspirin and metformin likely mediate their effects on cell proliferation and inflammation through both overlapping and independent mechanisms. However, they do not appear to have overlapping adverse effects. Both agents are already approved for use in humans by the FDA. These are all important factors that favor their potential use for combination therapy. In addition, recently reported in vitro studies indicate these two agents may display synergistic effects in combination. Therefore, animal model studies will be an important next step in assessing the potential for improved risk to benefit ratio for the combined use of metformin and aspirin for chemoprevention of PC.