Scientists stalk PPAR-gamma, find novel cancer connection

12/07/04

Research shows existing diabetes drugs may kill multiple myeloma

In laboratory tests on multiple myeloma cells, University of Rochester researchers found that this type of cancer expresses a protein that makes it an easy target for an existing class of diabetes drugs. After more investigation, they hope the discovery will lead to a new, targeted therapy for myeloma patients.

"To our knowledge, this is the first time anyone has shown that multiple myeloma cells are sensitive to these agents, and we found multiple myeloma cells are killed quite effectively," says lead author Richard P. Phipps, Ph.D., professor of Environmental Medicine and of Oncology at the University of Rochester Medical Center.

The research was reported in the November issue of Clinical Immunology.

The drugs in question are from the thiazolidinedione (TZD) class of anti-diabetic therapies, known as PPAR-gamma ligands. They bind to PPAR-gamma, a protein associated with multiple myeloma and many other cancers, as well as chronic inflammation and diabetes. When the drugs bind to PPAR-gamma, at least in laboratory experiments, the cancerous cells are destroyed.

PPAR-ligands are emerging as a new type of cancer therapy because they directly target errant cells and stop tumor growth, at least in animal models. Phipps' laboratory also found that the PPAR-ligands currently used in anti-diabetic drugs could induce a type of cell death called apoptosis. This is significant because multiple myeloma is very difficult to treat, as it is usually resistant to drug-induced apoptosis.

Another encouraging factor is that the anti-diabetes drugs were able to kill the multiple myeloma cells, despite the fact that myeloma produces its own growth factor (Interleukin 6), which usually enables the cancer to multiply more effectively. Furthermore, the Phipps lab found that the effectiveness of the TZD drugs was enhanced when combined with Vitamin A-like compounds.

Co-investigator Steven Bernstein, M.D., who treats myeloma patients at the University's James P. Wilmot Cancer Center, is cautious but hopeful about the prospects of this research leading to a new treatment. "Although we are optimistic about these early findings, we need to do further investigation to understand how the TZD class of drugs work against multiple myeloma, before clinical trials are warranted."

Each year doctors diagnose about 14,000 people in the United States with multiple myeloma, which accounts for about 10 percent of the blood cancers. Myeloma is characterized by an abnormal number of white blood cells called plasma cells. They crowd out healthy blood cells in the bone marrow, and make proteins that lead to bone destruction, kidney damage, and recurrent infections.

High-dose chemotherapy and stem-cell transplant are the standard treatments. Recently, patients have also experienced some success with two new, biologically targeted therapies: thalidomide, which was given decades ago to women for morning sickness, and the proteosome inhibitor Velcade, which targets the parts of the cell that regulates protein expression, Bernstein said. The latest research may offer a third novel approach.

The myeloma research emerged from a larger investigation conducted by Phipps' laboratory into inflammation, the culprit of many serious illnesses. One area of focus is how the immune system reacts to PPAR-ligands.

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