A familiar diabetes drug, in combination with cancer therapy, reduced tumors faster and prolonged remission longer than chemotherapy alone, apparently by knocking out cancer stem cells. The findings, in cell culture and mice, were reported by HMS researchers on Sept. 14 in the 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 metformin is a first-line diabetes drug.”
In mouse experiments led by postdoctoral fellows Heather Hirsch and Dimitrios Iliopoulos, pretreatment with metformin prevented the otherwise marked ability of cancerous stem cells to form tumors. In another group of mice, in which tumors were allowed to take hold for 10 days, the drug in combination with the anticancer agent doxorubicin reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone. In contrast, once the tumors took hold, metformin alone had no effect against the deadly mass, composed mostly of non-stem cancer cells.
The discovery adds 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 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 have 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.
“This is really the first study that shows that metformin may have an effect on these very resistant cancer cells,” 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 is collaborating with colleagues at the University of Toronto and the National Cancer Institute of Canada Clinical Trials Group to develop a large-scale trial to study metformin’s impact on recurrence in women after they are treated for early stage breast cancer. The study may start next year.
Struhl hopes the results will encourage additional clinical trials of metformin in combination with a reduced dose of chemotherapy and to prevent recurrence in treated people for breast cancer and other forms of the disease.
Students may contact Kevin Struhl at kstruhl@hms.harvard.edu for more information.
Funding Sources: The research was funded by the National Institutes of Health and the American Cancer Society.
Conflict Disclosure: HMS has applied for a patent for a combined therapy of metformin and a lower dose of chemotherapy, which is being tested in animals.
