Washington, D.C – Researchers at Georgetown University's Lombardi Comprehensive Cancer Center have decoded the step-by-step process by which a class of popular anti-diabetes drugs inhibits cancerous tumor growth. With the discovery of this molecular chain of events, as reported in the September 2003 issue of Molecular and Cellular Biology, the Georgetown researchers are now studying whether these anti-diabetes drugs, called glitazones, could one day be effective anti-cancer drugs.
Glitazones are taken by more than two million people with Type 2 diabetes. They are marketed under the names AvandiaTM and ActosTM, by SmithKline Beecham and Eli Lilly, respectively. Glitazones bind to a particular target on a cell, and in diabetics, they work by reducing insulin resistance at the sites of insulin action in the muscle and liver. Previous studies have also shown that glitazones also have the ability to inhibit tumor growth. However, until this study no one understood how this process worked.
"This study shows for the first time a direct link between a gene causing breast and other cancers and a gene linked to diabetes and the production of fat cells," said Richard Pestell, M.D., PhD, director of Lombardi Comprehensive Cancer Center. "The link between these cellular components may be a lynchpin in some cancers – linking some cancers and metabolism directly. Potentially, we could be on the way to finding new therapeutic leads that would improve both diseases."
Pestell and his colleagues describe a complex relationship between a cancer causing gene, Cyclin D1, and a cancer-blocking receptor called PPAR gamma, which is involved in fat cell development. They are respectively found in breast cancer tissue and normal breast tissue. When PPAR is "turned on" by glitazones, tumor growth is inhibited. Conversely, when Cyclin D1 is activated in cells, it causes cancer cells to divide uncontrollably and excessively.
The new study reports that the anti-tumor effects of the PPAR gamma receptor are actually controlled by the cancer-causing Cyclin D1. In short, too much Cyclin D1 trumps the PPAR gamma receptor, turning off its ability to inhibit tumor growth.
Based on these findings, the Georgetown researchers believe that reduction in PPAR expression coupled with the increase in Cyclin D1 may represent a key genetic alteration underlying the transition from normal breast tissue to breast cancer. These findings suggest that drugs that block the effects of Cyclin D1 may be useful in stopping the conversion of normal tissue to malignant tissue.
The discoverer of the human Cyclin D1 gene, Andrew Arnold, M.D., professor and Director of the Center for Molecular Medicine at the University of Connecticut School of Medicine, agrees with the Georgetown researchers.
"This link between Cyclin D1 and PPAR gamma biochemical pathways is fascinating and clearly worthy of further exploration, including the potential for yielding new treatment modalities for cancer," said Dr. Arnold.
The study published in Molecular and Cellular Biology was funded by the National Cancer Institute.
The Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi is one of only 39 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington DC area. For more information, go to http://www.georgetown.edu/gumc.
The Nina Hyde Center for Breast Cancer Research promotes and supports the diverse breast cancer research conducted at the Lombardi Cancer Center. Named in honor of the acclaimed Washington Post fashion editor who died of breast cancer in 1990 at the age of 57, the center was founded in 1990 by her longtime friends Ralph Lauren and former Washington Post owner Katharine Graham. The breast cancer researchers affiliated with the Nina Hyde Center are internationally recognized in an elite class of scientific innovators.
Materials provided by Georgetown University Medical Center. Note: Content may be edited for style and length.
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