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


New target blocks B-ALL, boosts Gleevec’s effectiveness against CML in mice

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 by the same BCR-ABL1 cancer-causing gene. Finally, in drug treatment studies, they found that the kinase inhibitor, known as CGP76030 produced by Novartis, blocked those three critical Src kinase enzymes. The drug impaired the proliferation of B-lymphoid leukemic cells and prolonged the survival of mice with B-ALL. Their findings suggest additional therapeutic agents for treating this type of leukemia in humans.

ALL is the type of leukemia that predominantly strikes children. Among ALL cases, 85% are of the B-ALL type.

According to oncologist-turned-researcher Dr. Li, the preclinical studies suggest a specific prediction: "Drugs targeting the Src kinases may be useful for the therapy of BRC-ABL1-induced acute leukemia, particularly B-ALL. While these drugs are not effective or useful during the chronic phase of myeloid leukemia, there may be a rationale for dual kinase inhibitor therapy of more advanced leukemia. Increased activation of Src kinases has been observed in CML patients who have become resistant to Gleevec."

Dr. Li and his team are currently developing additional mouse models lacking in different combinations of the Src kinases, in an effort to make available a range of targeted therapies for this category of cancer.

Collaborating with Dr. Li and members of his laboratory (Dr. Yiguo Hu, Dr. Yuhua Liu and Shawn Pelletier) were Drs. Richard Van Etten (Tufts-New England Medical Center, USA), Elisabeth Buchdunger and Doriano Fabbro (Novartis Pharma AG, Switzerland), Markus Warmuth (Novartis Pharma AG, USA), and Michael Hallek (Universität zu Köln, Germany). The research was supported by grants from the Irving A. Hansen Foundation and The V Foundation for Cancer Research to Shaoguang Li, and the National Institutes of Health and a Leukemia and Lymphoma Society SCOR grant to Richard A. Van Etten.

Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Y. Hu, Y. Liu, S. Pelletier, E. Buchdunger, M. Warmuth, D. Fabbro, M. Hallek, R.A. Van Etten, S. Li. Nature Genetics: vol. 35, no. 5, published online April 18, 2004.

Joyce Peterson | EurekAlert!
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