Pancreatic carcinoma is the fourth leading cause for cancer death in men and women in the US. The overall 5- year survival rate is less than 5%, and effective therapies are largely lacking. Surgical resection is the only chance at cure, but most patients present with advanced, unresectable disease. New therapeutic strategies are urgently needed. Metformin is a widely prescribed drug used as first-line therapy for diabetes mellitus type 2, and is now reported to have antitumor efficacy in pancreatic cancer. The primary systemic effect of metformin is to lower blood glucose, but it also reduces hyperinsulinemia associated with insulin resistance. At a cellular level, metformin stimulates AMP-activated protein kinase (AMPK). Metformin-induced activation of AMPK inhibits downstream mTORC1 which integrates signals from a diverse array of tumor cell pathways to regulate cell survival and growth. Metformin inhibits pancreatic cancer growth in part via AMPK-mediated inhibition of mTORC1 activation, but metformin is also known to disrupt critical cross-talk between insulin/IGF-1 and GPCR signaling pathways and ERK;as well as Rag GTPases and mTOR. Laboratory studies show that metformin markedly inhibits growth of human pancreatic cancer cells xenografted in nude mice. This preclinical work is supported by clinical cohort studies showing that metformin users have a reduced risk of pancreatic cancer;and that metformin use correlates with a survival benefit in patients with diabetes and pancreatic cancer. However, in some studies, median survival is only prolonged by 4 months in cancer patients who are metformin users. Of special note, antitumor effects of metformin are enhanced by increased drug doses or by IV administration. These findings suggest that discovery of more potent anticancer analogs of metformin may be needed to boost clinical benefit and patient survival. Thus, we plan to design, synthesize and test antitumor activity of new analogs of metformin using pancreatic cancer cell models. Nonmalignant cells will be used as controls. We hypothesize that analogs can be prepared with enhanced anticancer activity and minimal non- target toxicity. We will perform an extensive structure-activity study to investigate metformin analogs that have never been tested before. Antitumor activity of analogs will be evaluated in vitro using assays for cell proliferation, apoptosis, migration/invasion and underlying signaling pathways. Feedback from these preclinical experiments will be used to modify drug designs to achieve optimal antitumor efficacy and minimal toxicity. About 2-3 drug candidates will be selected for in vivo studies based on in vitro screening assays to assess optimal antitumor efficacy and target specificity. We will use human pancreatic cancer cell xenografts in nude mouse models to assess antitumor activity and exploratory study of drug pharmacokinetics. Endocrine- metabolic effects of metformin analogs will also be studied in vivo in an established insulin-resistant obese mouse model. Discovery and validation of potent antitumor action and tolerability of metformin analogs in vivo may lead to timely clinical trials and possibly a significant breakthrough in pancreatic cancer therapy.
Pancreatic carcinoma is a highly lethal disease, and it is the fourth-leading cause for cancer death in men and women in the US (1). The overall 5-year survival rate is approximately 4%. Conventional treatment approaches have had little impact on the course of this disease. The proposed studies aim to discover and develop new structural analogs of metformin for potential use as new therapeutics for pancreatic cancer.