1. Carlson, Robert H.

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CHICAGO-The inexpensive, generic diabetes treatment metformin appears to slow the proliferation rate in prostate tumors, according to data reported here at the American Association for Cancer Research Annual Meeting.

Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

Results of the Phase II, open-label ANIMATE ("Assessment of Neoadjuvant Intervention with Metformin Against Tumor Expression of signaling in prostate cancer") study (Abstract CT-04) were presented in a Clinical Trials Symposium by Anthony M. Joshua, MBBS, PhD, a staff medical oncologist at Princess Margaret Hospital, University Health Network, in Toronto.


Metformin, sold in generic form and derived from the French lilac plant, is widely used to treat type 2 diabetes because it lowers blood glucose and insulin levels without causing weight gain. In the past few years, however, he explained, interest has intensified for the drug's potential as an anticancer treatment because it also appears to have direct and indirect antitumor effects.


In the study, 22 men (median age of 64, median PSA of 6 ng/mL) with confirmed prostate cancer received 500 mg of metformin three times a day for a median of 41 days prior to undergoing prostatectomy - a dose lower than the one prescribed for people with diabetes, Joshua noted.


Use of metformin significantly reduced the levels of fasting glucose and insulin growth factor-1 as well as body mass index and waist-to-hip ratio.


Comparing biopsies with specimens after surgery, the researchers saw that the antigen Ki-67, a measure of cellular proliferation, was reduced by an absolute value of 1.65%, a relative decrease of 32%. There was also a significant increase in staining of the mTOR pathway marker p4EBP1.


"The differences found between treated and untreated tissue suggest a direct effect of metformin on prostate cancer," he said, adding that the drug was very well tolerated, with no Grade 3 adverse events.

ANTHONY M. JOSHUA, M... - Click to enlarge in new windowANTHONY M. JOSHUA, MBBS, PHD: "Although these are preliminary results, metformin appeared to reduce the growth rate of prostate cancer in a proportion of men. It also appeared to reduce one of the main growth pathways that may have contributed to the overall growth of the tumor."

Combination Potentially Spectacular

At a news conference highlighting selected late-breaking clinical trials, the moderator, Jose Baselga, MD, PhD, Associate Director and Chief of Hematology/Oncology at Massachusetts General Hospital Cancer Center, said that metformin is very attractive as an anticancer agent. Clinical trials are going on in prostate and breast cancers, and the drug appears to be an mTOR inhibitor, he noted.


"But in addition, in mice, metformin and PIK3 (phosphatidylinositol-3 kinases) inhibitors are synergistic, so you could see a combination [of those] that could be spectacular."


He said his laboratory is testing such combinations in clinical trials with experimental PI3K inhibitors such as BKM-120, BYL-719, and GDC0941, among others-"In the trials, whenever we see hyperglycemia we start our patients on metformin."


Effects on mTOR

Joshua said that besides reducing circulating insulin by inhibiting the mTOR pathway, there are several potential mechanisms for metformin's effect on cancer.


"Classically, it's been thought that metformin activates AMPK [adenosine monophosphate protein kinase], which acts on the mTOR pathway to shut it off. Research in prostate cancer also suggests it may have a more direct effect [on cancer] through the RED1 protein which might also downregulate mTOR."


Metformin may also stress tumor cells, he said, and if the cells do not have the ability to respond to that stress, they may then die.


In his presentation, Dr. Joshua noted that the study was limited by the lack of a control group, by inter- and intra-patient heterogeneity, and because use of the Ki-67 index is not a clinically relevant endpoint.


The study was funded by the Princess Margaret Hospital Foundation, the Jewish General Hospital Foundation (Montreal), and the Terry Fox Foundation.


Research Funding Problem

In addition to prostate cancer, there were also at least eight other cancer types that were the subject of other metformin studies reported at the AACR meeting.


In a session titled "Will Metformin Prevent or Cure Cancer?," the moderator, Pamela J. Goodwin, MD, of the University of Toronto Mount Sinai Hospital, described her work on the effects of metformin in breast cancer: "As of March 25, [2012], there are 37 metformin studies registered at for breast, GI, prostate, pediatric, head and neck, gynecologic, glioblastoma multiforme, and other cancers," she said, adding, though, that because metformin is a generic drug, funding is difficult to find.