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Compound Might Aid Leukemia Patients Resistant to Gleevec

Human trials could begin by middle of year, researcher says

WEDNESDAY, Jan. 26, 2005 (HealthDayNews) -- Scientists have developed a compound that may be able to treat cases of chronic myelogenous leukemia that are resistant to the so-called miracle drug Gleevec.

Human trials could start in as little as six months, said Prem Reddy, senior author of a study appearing in this week's issue of the Proceedings of the National Academy of Sciences.

Other experts are expressing cautious optimism.

"It's very preliminary," said Dr. Marshall Lichtman, executive vice president of research and medical programs at the Leukemia & Lymphoma Society. "They have a compound that's very interesting and potentially would be useful if they could convert it into a drug that's tolerable in humans, but these are all big questions."

Chronic myelogenous leukemia (CML) is caused by a genetic abnormality in blood cells called the Philadelphia chromosome. An abnormal gene, called BCR-ABL, produces an abnormal protein that leads to changes in cell growth, according to the Leukemia & Lymphoma Society.

Gleevec, hailed as a "wonder drug" when it emerged about five years ago, works by binding to the BCR-ABL gene, thereby blocking its activity.

The trouble is that Gleevec eventually stops working in many people taking the drug, Reddy said.

"Gleevec is dramatically effective in a very high proportion of patients but, over the course of several years, a proportion of these patients become resistant to it," Lichtman said.

Experts believe that certain cells have mutations in the BCR-ABL gene that enable them to elude the grasp of Gleevec.

"Essentially, Gleevec eliminates all those cancer cells which don't have a mutation and slowly, over a period of several months, these clones that are resistant to Gleevec start growing out," said Reddy, a professor of biochemistry and director of the Fels Institute for Cancer Research at Temple University School of Medicine in Philadelphia. "It's a question of time."

In trying to overcome this problem, scientists came up with two drugs that attack some of the mutations but not all of them, Reddy said.

Gleevec and these two other drugs work by binding to a molecule called ATP which, in turn, binds to the BCR-ABL gene.

"These new compounds overcome the resistance of some mutants but not all," Reddy said. "There are several mutations which still remain resistant to these two drugs. The fear for many clinical oncologists is that when you start treating these patients with these new drugs, the mutant forms that are resistant to these drugs will grow out so this is not a permanent solution."

Reddy and his team decided to focus their attention on another area of the gene that didn't appear to be mutating.

"We created a small molecule that blocks this particular site," Reddy said. The drug seems to work both on Gleevec-resistant cells and on cells that have not yet been treated. The molecule, called ON012380, is licensed to Onconova Therapeutics Inc., which helped fund the study.

In human tumor cells and in animals, ON012380 killed cells with all of the known Gleevec mutations. The drug also appeared to be safe, at least in mice.

Reddy and his colleagues are in the process of putting together enough safety and efficacy information to convince the U.S. Food and Drug Administration to let them start a human study.

"I'm very optimistic about how it will work in humans," Reddy said. "In the case of those patients who have come to the clinic for the first time with a diagnosis of CML, a combination therapy [Gleevec and ON012380] will cure the disease." The potential new drug should also be able to work alone in patients who have become resistant to Gleevec, he said.

Lichtman added: "If this agent could be converted into a drug and if it was tolerable to patients with CML and if it didn't do unexpected things, then it would be a useful step forward. But a human being has not seen this drug yet."

More information

The Leukemia & Lymphoma Society has more on chronic myelogenous leukemia.

SOURCES: Prem Reddy, Ph.D., professor, biochemistry, and director, Fels Institute for Cancer Research, Temple University School of Medicine, Philadelphia; Marshall Lichtman, M.D., executive vice president, research and medical programs, Leukemia & Lymphoma Society, White Plains, N.Y.; Jan. 24-28, 2005, Proceedings of the National Academy of Sciences
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