Common Diabetic Drug Fights Cancer Stem Cells

http://online.wsj.com/article/SB10001424052970203278404574413273870984920.html

The drug metformin, a mainstay of diabetes care for 15 years, may have a new life as a cancer treatment, researchers said.

In a study in mice, low doses of the drug, combined with a widely used chemotherapy called doxorubicin, shrank breast-cancer tumors and prevented their recurrence more effectively than chemotherapy alone.

The findings add to a growing body of evidence that metformin, marketed as Glucophage by Bristol-Myers Squibb Co. and available in generic versions, could be a potent antitumor medicine.

They also lend support to an emerging theory that cancer's ability to survive and resist therapy is regulated by cancer stem cells that drive a tumor's growth and survival.

Chemotherapy is effective against many tumors, said Kevin Struhl, a Harvard Medical School researcher and principal investigator of the study. "The problem is cancer stem cells acquire resistance" to treatment, he said. "They are able to regenerate the tumor and as a result you end up with a relapse."

About 5% to 10% of a tumor's cells are believed to be cancer stem cells, he said.

In the report, being published in the Oct. 1 edition of Cancer Research, a journal of the American Association for Cancer Research, researchers said the combination of metformin and doxorubicin killed both regular cancer cells and cancer stem cells.

In contrast, doxorubicin alone had limited effect on the stem cells.

Mice that grew tumors generated from human breast-cancer cells have remained tumor-free for nearly three months on the combined treatment, while tumors have recurred in those not given the diabetes remedy.

Researchers said the results have potentially broad implications for cancer treatment.

"If we could get some magic bullet to hit that stem-cell population, the thought is we could have more effective treatments," said Raymond DuBois, provost and executive vice president, University of Texas M.D. Anderson Cancer Center.

It is too early to tell whether and how metformin might be used to treat cancer patients.

A clinical trial testing metformin alone in early-stage breast-cancer patients, after they have had surgery and chemotherapy to treat their tumors, is being sponsored by the National Cancer Institute of Canada and could begin enrolling patients next year, said Jennifer Ligibel, a breast-cancer doctor at Dana-Farber Cancer Institute, Boston. The idea is to see if metformin is effective in preventing the cancer from recurring. U.S. cancer researchers are participating.

The new findings, she said, suggest that additional trials should evaluate metformin in combination with chemotherapy. She wasn't involved in the current research.

Metformin, which was approved in 1994 to lower blood sugar in people with Type 2 diabetes, achieved peak sales of $2.3 billion in 2001 before patent expirations opened the market to generic competition.

Several recent studies have observed the drug's potential effects against cancer.

One study from M.D. Anderson Cancer Center, for instance, found that diabetic patients treated with metformin were less likely to develop pancreatic cancer than those who weren't taking the drug for blood sugar.

How metformin affects cancer isn't certain, but one possibility is that it deprives tumor cells of sugar.

"Cancer cells are gluttons for glucose," said George Prendergast, president and chief executive officer of Lankenau Institute for Medical Research, Wynnewood, Pa. "It is likely that metformin is taking advantage of this gluttony of the cancer cell in order to attack it."

Another possibility is that the drug affects the immune system and helps stave off a tumor's recurrence, Dr. Struhl said.

The study was sponsored by the National Institutes of Health and the American Cancer Society.

Dr. Struhl and Harvard Medical School have applied for a patent that would cover a combination of metformin and a lower dose of chemotherapy to treat cancer.

Write to Ron Winslow at ron.winslow@wsj.com

Corrections and amplifications:

The diabetes drug metformin is marketed by Bristol-Myers Squibb Co. under the brand name Glucophage. The medication's name was misspelled as Glugophase in a previous version of this article.