Still Seeking Efficacy in Metformin

FigureNEW YORK—Metformin should be the ideal cancer chemopreventive agent: It's well tolerated, there is extensive information on it from the diabetes arena, it's cheap, and preclinical data suggest that it works very well in carcinogenesis models.FigureBut the most important factor would be efficacy in humans, and that hasn't been seen yet, though not for want of clinical trials. At the moment there are more than 60 clinical trials underway evaluating metformin in multiple tumor types. One completed clinical trial that did not show any clinical effect was described here at the Chemotherapy Foundation Symposium, sponsored by Mount Sinai School of Medicine. The trial of 45 obese patients with a history of colorectal adenomas was led by Jason Zell, DO, MPH, Assistant Professor in the Division of Hematology/Oncology in the Departments of Medicine and Epidemiology at the Chao Family Comprehensive Cancer Center, University of California, Irvine. The primary endpoint for the study, which was sponsored by the National Cancer Institute's Division of Cancer Prevention, was a 35 percent or greater decrease in colorectal mucosa activated pS6serine235 from baseline after patients had 12 weeks of metformin at 1 g bid. But that biomarker did not show any change, Zell reported, a finding he first made this fall in a metformin symposium at the American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research. But Zell said he is still optimistic: None of the secondary endpoints have been looked at, “and sometimes in this field it's the secondary endpoints that reveal new hypotheses,” he said in an interview. “So while we didn't see an effect with that biomarker, there still might be a clinical effect, and there may be better biomarkers.” He said that although chemoprevention is a hot topic, the focus has switched from primary prevention to secondary prevention in high-risk groups: “Chemoprevention trials of colorectal cancer have shifted towards high-risk populations in the era of personalized medicine, and in an effort to maximize potential benefit while minimizing potential risk.” He defined chemoprevention as the use of synthetic or naturally occurring substances. “Metformin may be the ideal chemopreventive candidate—if it works,” he said. “We have great mouse model data showing that metformin works, but unfortunately the human data did not recapitulate that. That's often the theme in cancer prevention, and that's why we need to target high-risk groups and focus on some of these small trials before we launch large trials.”JASON ZELL, DO, MPH. JASON ZELL, DO, MPH, said one proposed metformin mechanism of action relevant to neoplasia is that it activates reduction of circulating insulin levels following reduced hepatic gluconeogenesis due to AMPK activation in hepatocytes.Metformin and the Warburg Effect Zell said one proposed metformin mechanism of action relevant to neoplasia is that it activates reduction of circulating insulin levels following reduced hepatic gluconeogenesis due to AMPK activation in hepatocytes. Obesity is associated with insulin levels and with adenomas, and adenomas are associated with colon cancer, so obese patients with a history of adenomas seemed like the perfect high-risk group to go after, he said. Another speaker here also discussed the link between malignancy and cellular metabolism. It's not a new idea, acknowledged Benjamin Levy, MD, Assistant Professor of Medicine and Associate Director of Mount Sinai's Cancer Clinical Trials Office. What is called the Warburg Effect—that malignant, rapidly growing cancer cells typically have glycolytic rates up to 200 times higher than their normal tissues of origin—was first described by the 1931 Nobel Prize Winner Otto Warburg. Levy said it's intuitive that diabetes and cancer have shared clinical features, including older age, obesity, and smoking, but there may also be shared genetic underpinnings that can explain this link.BENJAMIN LEVY, MD. BENJAMIN LEVY, MD: This research is very exciting for a lot of us, especially when you think of how costly some of the new agents are.”“We know metformin targets mitochondria, which decreases ATP production, which in turn activates AMP kinase leading to downregulation of cellular processes such as fatty acid and protein synthesis,” he said, citing a 2012 paper by Michael N. Pollak of McGill University in Cancer Discovery (2012;2:778-790). “It also inhibits downstream pathways that include and incorporate mTOR, so it's thought that metformin may be a weak mTOR inhibitor. There are trials now combining metformin with mTOR inhibitors.” Metformin may have cytotoxic and cytostatic effects, Levy said, suggesting that the cytotoxic effects might be more pronounced in particular genetic alterations. Those include PTEN and PI3 kinase mutations, so these are possible biomarkers for sensitivity to metformin. “This is very exciting for a lot of us, especially when you think of how costly some of the new agents are,” Levy concluded.

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