University of Pennsylvania Cancer Center
Last Modified: May 16, 1999
Researchers in Boston have used a new diabetes drug to push cancer cells to mature, shifting them from rapidly dividing and dangerous undifferentiated cells to slower growing and less aggressive cells. The study is the first to demonstrate that such so-called "differentiation therapy" can be effective in patients with certain solid tumors.
The research, led by Dr. George Demetri of Harvard Medical School, was conducted on 60 patients with liposarcoma, a cancer of the fat cells. This rare malignancy includes cancer cells that range from almost primitive to well-differentiated, and so offers a unique opportunity to study cancer cell maturation. Previous research has shown that fat cells have a receptor called PPAR-gamma, that when activated, pushes cells to mature, or differentiate. In addition, a drug called Troglitazone, recentty approved under the tradename Rezulin to control diabetes, works by activating the PPAR-gamma receptor. This study tested whether Troglitazone could turn on PPAR-gamma in liposarcoma, thus forcing cancerous cells to mature. Demetri reports that while Troglitazone therapy did not cause any of the patients' tumors to shrink, there was evidence of increased differentiation and maturity, especially in the more primitive and aggressive forms of liposarcoma. The author notes that the approach may show promise in treating other cancer cells that have PPAR-gamma receptors, including most colon, breast, prostate, and lung cancers.
Dr. Demetri said that "cancer acts like an unruly adolescent," which is undifferentiated and out of control. This novel approach hopes to bring order to the growth of cancer and change this disease from a state of unhindered growth to an indolent, chronic disease. This is what "differentiation therapy" hopes to accomplish. This study was done with leiomyosarcoma because the DNA for the PPAR gamma receptor which promotes differentiationin to mature adipose tissue is present in these cells. It has since been discovered that these receptors are found on other tumor tissue as well, including some prostate cancers, 30% of breast cancers, and all colon cancers, thus showing promise for utilizing this therapy in other cells.
Interestingly, triglidazone (Rezulin), the popular diabetes drug, has been in the news recently for its discovered rare association with serious liver toxicity. Dr. Demitri reports that none of the participants in this trial had this side effect. The hope is that this family of drugs will have wide use in cancer therapy. Trials are are underway utilizing rezulin-like therapy, and will be done for other cancers as well. There will also be trials using this strategy as adjuvant therapy in a variety of settings. Dr. Demitri warns that this study is a "proof of concept study" and further studies are needed to determine efficacy and safety of this class of drugs.