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New Drug Battles Gleevec Resistance

Can help leukemia patients who don't respond

THURSDAY, July 15, 2004 (HealthDayNews) -- A new compound appears to help patients with chronic myeloid leukemia (CML) who do not respond to Gleevec, the drug widely hailed as one of the major success stories in cancer treatment, researchers report.

Gleevec can halt the progression of CML in most patients. However, as many as 20 percent of those patients either have or develop resistance to the drug. The new drug has been successful against a mouse model of leukemia, says a report in the July 16 issue of Science, and now is in early trials in human patients who have not benefited from Gleevec.

"We are certainly excited by what we are seeing, but the actual clinical data will be presented in December," said study author Dr. Neil P. Shah, an assistant professor of hematology and oncology at the University of California, Los Angeles, Jonsson Cancer Center.

Detailed knowledge of the way Gleevec works on the molecular level led to development of the new drug, Shah said.

CML, which strikes about 4,500 Americans each year, causes overproduction of white blood cells, which in turn is caused by overactivity of an enzyme designated BCR-ABL. Gleevec binds to BCR-ABL, stopping its cell-producing activity.

But there are many mutations of BCR-ABL, some of which have shapes different enough so that Gleevec cannot bind to them. Some CML patients have this type of mutated form of the enzyme at the time of diagnosis, while mutations can develop in other patients during the course of treatment. In either case, Gleevec is ineffective.

The development of the new drug began with a report in 2000 by John Kuriyan, a researcher at Rockefeller University whose work is funded by the Howard Hughes Medical Institute, detailing the way in which Gleevec binds to BCR-ABL. A precise match of the Gleevec molecule to the enzyme shape is needed, Kuriyan found.

That report prompted Dr. Charles L. Sawyers, another professor of hematology and oncology at UCLA, to speculate that a molecule that bound in a different way to BCR-ABL could be effective against the various mutated forms of the enzyme.

Sawyers and Kuriyan began a collaboration that resulted in a report in 2002 about 15 mutations of BCR-ABL that caused resistance to Gleevec. In each case, the mutation changed the shape of the enzyme just enough to prevent Gleevec from forming the precise link that turned it off.

ABL is a member of a broader family of enzymes called Src proteins, which are involved in many forms of cancer.

"I was giving scientific talks on the structural implications of Gleevec mutations, and stating that I thought that an Src inhibitor would be a good thing," Sawyers said.

It happened that the drug company Bristol-Myers Squibb was developing an ABL-Src inhibitor. Bristol-Myers Squibb got in touch with Sawyers, and the result was a research program that resulted in the journal report and the clinical trials of BMS-354825, as the molecule is now designated.

The ultimate use of that molecule in CML treatment must still be determined by the human trials that are just beginning, Shah said.

"It depends on what the weaknesses of this compound are," he said. "There is one mutation we would predict would make CML resistant not only to Gleevec but to this compound. Whether it can replace Gleevec depends on what other mutations render it ineffective. It is possible that it will be a smaller circle in the large circle of Gleevec."

More information

Read about CML and its treatment at the National Library of Medicine.

SOURCES: Neil Shah, M.D., Ph.D., and Charles L. Sawyers, M.D., professors of hematology and oncology, University of California, Los Angeles, Jonsson Cancer Center; July 16, 2004 Science
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