Embargoed for Release: March 29, 1998 5 p.m. Eastern Time
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STUDY PROVIDES FIRST EVIDENCE THAT NOVEL ANTICANCER TREATMENT CAN SLOW GROWTH OF TUMOR CELLS IN PATIENTS
Dana-Farber Researchers use Diabetes Drug to Fight Cancer
Boston, MA - In a study that points the way to a new form of cancer therapy, researchers at Dana-Farber Cancer Institute and Harvard Medical School report that a drug commonly used to treat diabetes has caused tumor cells to shift to a slower-growing, less-menacing state in patients with a rare type of cancer.
The study, published in the March 30th issue of The Proceedings of the National Academy of Sciences, is the first to demonstrate that so-called "differentiation" therapy - which prods tumor cells to return to the path of normal development and maturation, where they grow and divide more slowly - can be effective in patients with solid tumors.
The study is the result of basic laboratory research that began at Dana-Farber in the 1980s.
"Our team's previous work showed that the diabetes drug troglitazone could cause laboratory samples of liposarcoma cells to mature, or differentiate," says the study's lead author, George Demetri, M.D., of Dana-Farber. (Liposarcoma is a rare cancer that occurs in fat cells.) "This study shows that the same results can be achieved in patients with advanced cases of liposarcoma. It's an exciting example of a technique that works in the laboratory being directly applicable to people with disease."
The research report describes three patients, all women, each of whom had liposarcoma. They took troglitazone in pill form every day, and their health was monitored regularly. At the end of six to eight weeks, biopsies were taken of the women's tumor cells and compared with tumor cells taken at the start of the study.
In each case, the patients' cancer cells were found to be more fully differentiated - and proliferating less actively - than they had been at the study's start. The degree of differentiation was determined by analyzing cells' microscopic structure, biochemical composition, and pattern of gene activation. (Troglitazone therapy was continued daily as long as the disease remained stable.)
In addition to the three patients described in detail in the study, other liposarcoma patients have had good results with troglitazone therapy. The report notes that a second group of patients who have taken troglitazone also show evidence that their tumor cells have become more fully differentiated.
Demetri notes that while troglitazone therapy did not cause any of the patients' tumors to shrink, the fact that it did trigger differentiation in the cancer cells opens enticing prospects for the further development of this new approach to cancer therapy.
The new study is a direct outgrowth of research into fat cell differentiation that began at Dana-Farber more nearly 15 years ago. In 1994, researchers led by Dana-Farber's Bruce Spiegelman, Ph.D., were the first to identify a receptor in the nucleus of fat cells that controls the cells' differentiation process. Spiegelman's team was also the first to clone the receptor, called PPARg.
The cloning of PPARg made it possible to study the receptor in the laboratory. In 1995, Spiegelman and his colleagues made the surprising discovery that troglitazone and similar diabetes drugs activated PPARg, causing liposarcoma cells to begin differentiating.
"That discovery led us to consider whether drugs that stimulate PPARg could be the basis of a new type of therapy against cancer," Spiegelman says. "The new study begins to bear out those hopes."
Spiegelman's work was augmented by research by Samuel Singer, M.D., a surgical oncologist at Dana-Farber and Brigham and Women's Hospital and who heads a laboratory at the Massachusetts Institute of Technology.
While noting that much needs to be done to refine the progress made thus far, Singer states that "differentiation therapy could one day take its place as an adjunct to surgery and other conventional treatments for solid tumors."
Because other types of cancer cells, including most colon cancers and many types of breast and prostate cancers, have PPARg receptors, troglitazone may well be able to spur differentiation in those diseases as well. Clinical studies are now under way to determine whether they can.
Co-authors of the study with Demetri, Singer, and Spiegelman are: Elisabetta Mueller, Ph.D., Pasha Sarraf, and Ryan Naujoks, of Dana-Farber; and Christopher Fletcher, M.D., and Natalee Campbell of Brigham and Women's Hospital.
Dana-Farber Cancer Institute is a principal teaching affiliate of Harvard Medical School and is one of 35 federally designated Comprehensive Cancer Centers in the United States. The Institute was ranked the number one cancer care center in New England by U.S. News & World Report and is world-renowned for its unique blend of basic and clinical cancer research.
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