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Researchers identify leukemia-linked pathway targeted by a new kinase inhibitor

BAR HARBOR, MAINE--Three years ago, using the first of a new class of drugs known as "small molecule kinase inhibitors," medicine slammed shut a door used by cancer. Researchers at The Jackson Laboratory just found another door that kinase inhibitors may close to cancer.

The gene BCR-ABL1 causes two types of leukemia: chronic myelogeneous leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). In both cancers, enzymes that should regulate the growth and development of white blood cells go awry, resulting in uncontrolled growth of the cells. The Swiss-based pharmaceutical company Novartis developed Gleevec, the first kinase inhibitor used to fight cancer by blocking the errant enzyme. It proved effective against chronic phase of CML, but not the advanced phase or against B-ALL. In some patients, it seems CML can develop a resistance to Gleevec.

In the May 2004 issue of Nature Genetics, a research team headed by Shaoguang Li, M.D., Ph.D., of The Jackson Laboratory, announces success with another kinase inhibitor that blocks a different path used by cancer. Studying mice, the researchers discovered that the BCR-ABL1 gene activates three additional enzymes that lead to B-ALL leukemia. One of these enzymes may also be involved when CML patients no longer respond to Gleevec.

"Because of drug resistance, it becomes increasingly difficult to stop progression of and cure this disease by targeting at only one place in a multi-molecule-involved signaling pathway used by cancer," says Dr. Li. "So we needed to find a combined drug therapy targeting simultaneously more than one places in the pathway."

First, the team developed the first efficient and accurate mouse models of both forms of BCR-ABL1-induced leukemia. Next, they discovered that three of the Src kinase class of enzymes are required for B-ALL but not for CML, suggesting that different therapeutic strategies should be used for treating these two diseases although they are induced
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Contact: Joyce Peterson
joyce@jax.org
207-288-6058
Jackson Laboratory
18-Apr-2004


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