Diabetes drug kills cancer stem cells in combination treatment in mice

In a one-two punch, a familiar diabetes drug reduced tumors faster and prolonged remission in mice longer than chemotherapy alone, apparently by targeting cancer stem cells, report Harvard Medical School researchers in the Sept. 14 advance online Cancer Research.

"We have found a compound selective for cancer stem cells," said senior author Kevin Struhl, the David Wesley Gaiser professor of biological chemistry and molecular pharmacology at HMS. "What's different is that ours is a first-line diabetes drug."

The findings add to a growing body of preliminary evidence in cells, mice, and people that metformin may improve breast cancer outcomes in people. In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes.

The results fit within the cancer stem cell hypothesis, an intensely studied idea that a small subset of cancer cells has a special power to initiate tumors, fuel tumor growth, and promote recurrence of cancer. Cancer stem cells appear to resist conventional chemotherapies, which kill the bulk of the tumor.

"There is a big desire to find drugs specific to cancer stem cells," Struhl says. "The cancer stem cell hypothesis says you cannot cure cancer unless you also get rid of the cancer stem cells. From a purely practical point of view, this could be tested in humans. It's already used as a first-line diabetes drug."

The possible usefulness of a diabetes drug against cancer lends credence to an emerging idea that, in the vast and complex alphabet soup of molecular interactions within cells, relatively few biological pathways will turn out to be most important for many different diseases, Struhl suggested.

In experiments led by postdoctoral fellows Heather Hirsch and Dimitrios Iliopoulos, the combination of metformin and the cancer drug doxorubicin killed human cancer stem cells and non-stem cancer cells in culture. The researchers used four genetically distinct breast cancer cell lines.

In mice, pretreatment with the diabetes drug prevented the otherwise dramatic ability of human breast cancer stem cells to form tumors. In other mice where tumors were allowed to take hold for 10 days, the dual therapy also reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone. In the two months between the end of treatment and the end of the experiment, tumors regrew in mice treated with chemotherapy alone, but not in mice that had received both drugs. By itself, metformin was ineffective in treating tumors.

"This is an exciting study," said Jennifer Ligibel, a medical oncologist at Dana-Farber Cancer Institute and an HMS instructor in medicine, who was not involved in the study. Ligibel and colleagues at the National Cancer Institute of Canada Clinical Trials Group are developing a large-scale phase II trial to study metformin's impact on recurrence in women treated for early stage breast cancer.