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GENE ALTERATIONS MAY PREDICT RESPONSE TO NEW CANCER THERAPY

COLUMBUS, Ohio -- Researchers have identified a possible new tumor-suppressor gene that plays a role in colon cancer and perhaps other cancers.

The finding promises to improve doctors' understanding of cancer, and it may one day provide a routine way to treat some cancer patients with a drug now used primarily by diabetics.

"These results give us a novel target for therapy, perhaps a way to predict who will respond to this therapy, and another molecular tool to understand the cancer process," said Charis Eng, associate professor of medicine and of human cancer genetics at Ohio State University.

The gene produces a protein, known as peroxisome proliferator-activated receptor gamma (PPAR-gamma or PPARg), that helps fat cells mature. The protein is also important for the metabolism of fats and sugars by cells.

The study was published in a recent issue of Molecular Cell.

Eng, who is director of the Clinical Cancer Genetics Program at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, did this work as a follow-up to earlier work done on the PPAR-gamma gene's possible involvement in other diseases. Work by other investigators had shown that exposing colon-cancer cells in the test tube to the antidiabetes drug troglitazone caused many -- but not all-- of the tumor cells to look and behave more normally.

Eng wondered about the colon-cancer cells that didn't respond to the drug in the troglitazone studies. "We hypothesized that the colon-cancer lines that didn't respond to the drug may have mutations in PPAR-gamma," said Eng.

To test this hypothesis, the researchers looked at the PPAR- gamma gene in 55 sporadic colon-cancer tumors. Malignant cells from four of the samples contained obvious mutations in the gene. Further testing revealed that all four mutations either eliminated or greatly impaired the function of the PPAR-gamma protein. Thus, the PPAR-gamma protein couldn't perform its normal function in the cell, contributing to the cancer process.

This testing also revealed a surprise. In addition to testing the function of the mutated forms of the PPAR-gamma protein with the manufactured drug troglitazone, researchers also tested it against a substance known as PGJ2 that is found naturally in the body and that can also activate the receptor. In the case of one of the mutations, the researchers found that the antidiabetes drug could activate the receptor, while PGJ2 could not. "That was surprising and very exciting because it means troglitazone may be a potential therapy for people who have tumors with this particular mutation," said Eng.

Eng and her colleagues are now looking for mutations in the PPAR-gamma gene in tumors of the breast, lung, melanoma, bladder, prostate and brain. She also hopes that a clinical trial using troglitazone in colon-cancer patients may be forthcoming.

Eng's research was funded by a grant from the National Cancer Institute to the Ohio State University Comprehensive Cancer Center.

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