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.
"There is a lot of interest in studying metformin in breast cancer, but so far we do not have direct evidence that metformin will improve outcomes in patients," Ligibel said. "That's what this trial is for."
So far, observational studies have suggested a lower risk of cancers, including breast cancer, and better response to chemotherapy in diabetics taking metformin, she said. Basic science studies also have suggested plausible biological mechanisms. The study from the Struhl lab suggests a potential new pathway through which metformin could have an effect on breast cancer cells, she said.
In their search for compounds that selectively destroy cancer stem cells, scientists hope to improve cancer outcomes. But the story is never as simple in human cancers, said Kornelia Polyak, a breast cancer researcher at Dana-Farber Cancer Institute and HMS associate professor of medicine, who was not involved in the study
Cancer stem cells are a shifty target, Polyak said. For example, any cancer cell can acquire the properties of a cancer stem cell, and cancer stem cells can change into non-stem cancer cells, which can be just as deadly. Clinical trials in people are needed to test these ideas, Polyak said.
The Struhl paper is an offshoot of a larger project in his lab to systematically track how gene activity changes when cells transform into cancer. These changes were remarkably similar to gene dynamics in diabetes and other inflammatory conditions.
The researchers reasoned that if a common genetic pathway underlies different diseases, drugs that work against one disease might work against another. In a screen, the most effective drug inhibiting the transformation of cells into cancer was metformin, which led to the experiments in this paper.
The team was further encouraged by the low dose of metformin needed for the effect in the laboratory, compared to the amount needed for analogous molecular experiments in basic diabetes research. The relative dosage in people for treating or preventing cancer is unknown and untested.
HMS has applied for a patent for a combined therapy of metformin and a lower dose of chemotherapy, which is being tested in animals. The research was funded by the National Institutes of Health and the American Cancer Society.
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