Gleevec Expands Its Cancer Targets

Studies show its power against a gut tumor and a leukemia

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By
HealthDay Reporter

WEDNESDAY, Aug. 14, 2002 (HealthDayNews) -- Two new reports herald the beginning of an era in medicine centered on a family of molecules you should get familiar with: tyrosine kinases.

These molecules are involved in the regulation of cell growth. If something such as a genetic mutation causes them to overproduce, the unregulated cell proliferation called cancer can result.

The two studies, which appear in tomorrow's The New England Journal of Medicine, describe promising results with the first tyrosine kinase inhibitor to reach the market, a molecule whose formal name is imatinib mesylate. Better known as Gleevec, this anticancer drug is marketed in the United States by Novartis Pharmaceuticals Corp.

One of the papers describes a multi-center study showing impressive results against a cancer of the gut called gastrointestinal stromal tumor.

Until Gleevec came along, this cancer was virtually untreatable; patients lived an average of 20 months. The journal paper describes a good response and the possibility of long-term survival in a substantial percentage of patients given Gleevec, and the study is ongoing. The side effects were relatively minor, compared to those of conventional chemotherapy, because Gleevec acts specifically against cancer cells, while other drugs attack all rapidly dividing cells.

Many of the patients "are still doing wonderfully" in the months after the journal report was written, says study author Dr. George D. Demetri, director of the Dana-Farber Cancer Institute's Center for Sarcoma and Bone Oncology in Boston.

"In many patients, the disease is fully controlled," he says. "Some patients have developed resistance to the drug, as we expected."

The odd thing, says Dr. David Parkinson, vice president for clinical research at Novartis, is the company did not have these tumors in mind when it began to look for tyrosine kinase inhibitors more than a decade ago.

Imatinib mesylate was selected for development because it inhibits a tyrosine kinase called ABL, which acts on the bone marrow. "When it gets turned on all the time, you end up with chronic myelogenous leukemia," Parkinson says.

"But interestingly enough, Gleevec also was found to inhibit another tyrosine kinase, KIT," he adds. "It is different from ABL, but is in the same structural family. Originally, that was undesirable, because we were trying to develop a molecule that was very, very specific for leukemia. But then it was shown that Gleevec could inhibit cell lines of these gastrointestinal stromal tumors. When it was tried in patients, it was dramatically effective."

Gleevec has been approved by the U.S. Food and Drug Administration (FDA) for treatment of the intestinal cancer.

Dr. Manish Shah, of Memorial Sloan-Kettering Cancer Center, took part in the trials that led to FDA approval. It is now standard treatment for the cancer, "and we think survival will be much better with the use of Gleevec," he says.

The really important fact about Gleevec is that "this is the first time we have been able to identify a target of mechanism of action in cancer and use that target to develop a drug to attack a cancer," Shah says.

The question that Novartis and a small army of researchers now are trying to answer is: How many other diseases can Gleevec be used against?

One indication comes from the second journal paper, which describes its use against a rare condition that combines the overgrowth of blood cells seen in leukemia with a disfiguring skin disorder.

In this case, the guilty tyrosine kinase is something called platelet-derived growth factor receptor beta (PDGFB). Gleevec treatment achieved a normal blood count and began to heal the skin condition in four patients within weeks after treatment was started, the report says.

"We know that PDGFB is a very interesting molecule that is involved in several rare diseases," Parkinson says. "The bigger question is whether it is important in other kinds of tumors. The answer is not in yet, but it seems to be involved in some brain tumors."

Cancer is not the only disease in which there is an overgrowth of tissue related to tyrosine kinase activity, says Dr. David Feldman, a Novartis researcher. There is a liver disease called IgA nephropathy for which Gleevec might be effective, he says. There are also some cardiac conditions that could be treated, such as the regrowth of cells in the arteries after they have been opened by angioplasty.

"There is a possibility that this drug can stop deposition of connective tissue after an injury," Feldman says.

Meanwhile, Gleevec is in clinical trials against a number of cancers, particularly brain tumors but also cancer of the prostate, Parkinson says. And other companies "are engaged in developing drugs against other tyrosine kinases," he says.

What To Do

You can learn more about Gleevec from the U.S. Food and Drug Administration or Novartis Pharmaceuticals Corp.

SOURCES: David Parkinson, M.D., vice president, clinical research; and David Feldman, M.D., research scientist, Novartis Pharmaceuticals Corp., Lynbrook, N.J.; Manish Shah, M.D., clinical assistant attending physician, Memorial Sloan-Kettering Cancer Center, New York City; George D. Demetri, M.D., director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston; Aug. 15, 2002, The New England Journal of Medicine

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