By William J. Cromie

Gazette Staff

In a case of double serendipity, Harvard researchers studying the production of fat cells discovered how a new diabetes drug works; now that drug holds promise for treating a rare form of cancer.

The researchers also are looking to extend their lucky streak to a successful treatment for breast, colon, and perhaps other cancers.

Two years ago, pharmaceutical companies introduced a more effective drug to help the 15 million Americans with adult-onset diabetes, but they had no idea how it worked. Bruce Spiegelman, a professor of cell biology at the Medical School, found the answer, which entails molecules that play a role in creating fat cells. Spiegelman and his colleagues then discovered that the same molecules might arrest the progress of malignancies called liposarcomas, tumors that grow in connective tissues.

The latter finding came as one of Spiegelman's students, Peter Tontonoz, assisted Samuel Singer, director of cancer surgery at Brigham and Women's Hospital, during removal of a large liposarcoma malignancy. During the surgery, Singer asked Tontonoz if Spiegelman's group had investigated cancerous fat cells to see if they contained the same molecules as the fat cells that play a key role in diabetes.

Singer, Tontonoz, and Spiegelman enlisted the help of George Demetri, an assistant professor of medicine at the Dana-Farber Cancer Institute and a specialist in liposarcomas. The team grew malignant fat cells from 12 tumors in the lab, then added the diabetes drug.

"The results were very exciting," Demetri recalls. "The tumor cells stopped their rapid growth and began to mature into normal- looking fat cells."

Working Without Pay

Liposarcoma turns out to be the most common connective tissue cancer in adults; some 1,600 people are diagnosed with it each year in the United States. Standard treatment involves highly toxic chemicals (chemotherapy); for advanced cases, even that doesn't work very well.

"Improvements in treatment are desperately needed," Demetri says. With Food and Drug Administration approval, he has started giving the diabetes drug, called troglitazone, to liposarcoma patients. The hope is that the drug will halt the growth of advanced tumors.

In his office, Demetri showed a visitor images of a patient's lungs pocked with liposarcomas. "There's no change compared to six weeks ago when we started him on the drug," he noted. "That could mean the drug is working, or that the tumors wouldn't have grown even without the drug. It's too early to tell."

Demetri and his colleagues plan to treat 19 more patients with the drug to determine if it works. They are thrilled enough about the possibilities to work without pay.

Parke-Davis, maker of the drug, known commercially as Rezulin, provides it at no cost. The Food and Drug Administration approved its use in this country for diabetes earlier this year.

"The phenomenal result so far has been the virtual lack of side-effects," Demetri points out. "More than 8,000 diabetics worldwide have taken the drug during the past eight years. In people without diabetes, it has no unwanted effects, such as a risk of low blood sugar. Cancer patients avoid the nausea, hair loss, fatigue, bleeding, and other dreaded symptoms of chemotherapy."

Spiegelman has begun to look into troglitazone as a treatment for breast and colon cancers. He envisions a "fantastic possibility -- nontoxic chemotherapy."

In women who have primary breast tumors removed surgically, the biggest threat to their lives is growth of tumors that spread to other parts of their bodies. Spiegelman and Demetri wonder if giving such women a troglitazone-type drug immediately after surgery might prevent a recurrence of their malignancy.

In another scenario, women most likely to get breast cancer might use the drug as a prophylactic. "Women with certain gene mutations have a lifetime risk of developing the disease that exceeds 85 percent," Spiegelman points out. "At present, their choices are to do nothing or have a mastectomy, both far from ideal. Since troglitazone drugs are nontoxic, these women might be able to take them for a lifetime to avoid cancer."

A Fat Molecule

In 1994, Spiegelman's lab discovered a molecule called PPAR-gamma, which, when activated in a certain way, turns unspecialized connective-tissue cells into fat cells. That immediately fueled a tantalizing speculation. If the activity of that molecule could be blocked, the blocking substance should make an effective anti-obesity drug.

Before Spiegelman could pursue such a wonder drug, however, he and colleague Ronald Evans, of the Salk Institute for Biological Studies in California, discovered the connection between activation of PPAR-gamma and adult-onset diabetes. In this type of diabetes, insulin does not properly stimulate the absorption of glucose, the body's chief source of energy, into fat and muscle. Several drug companies, including Parke-Davis, had jointly developed a drug that solved this problem, but they didn't know how it worked. Spiegelman and Evans showed them.

Troglitazone combines with PPAR-gamma and restores the ability of muscle cells to get energy efficiently from insulin. The drug has none of the side-effects of other medications, including dangerous drops in the level of glucose, or blood sugar. Despite the varying amounts of carbohydrates a diabetic eats, troglitazone helps insulin keep blood-sugar levels within close limits.

The drug works on liposarcomas because these cancer cells also contain PPAR-gamma. Normally, this molecule combines with other molecules and the combination activates genes that turn unspecialized cells into plump, round fat cells.

In liposarcoma, however, the precursor cells are spindly, twisted, and otherwise misshapen. These deformed cells grow uncontrollably, forming tumors. If these cells can be made to differentiate, that is, form mature fat cells, they stop growing at a wild pace, thus halting spread of the cancer.

The researchers reasoned that troglitazone might do that because promoting the growth of normal fat cells is what the drug does for diabetics. When the team put the drug on fast-growing cells taken from liposarcoma, they confirmed this idea.

Meanwhile, back in the lab, Spiegelman, Demetri, and Singer took note of the fact that some breast cancer cells contain PPAR-gamma. They have found it in 30 to 50 percent of breast cancer cells grown in the laboratory, as well as in cells from patients with advanced breast cancer.

"We're trying to determine how many women have the PPAR-gamma receptor," Demetri explains. "It might be possible to turn aggressively growing cells likely to become malignant into mature breast cells that won't grow into a tumor. If we can do that, it would be an even more outstanding case of serendipity -- one that could have enormous benefit for cancer patients."