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Inventive combination of research approaches identifies new target for treating leukemia

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October 5, 2009

Boston, Mass. -- New research integrates sophisticated interdisciplinary approaches to solve a molecular mystery that may lead to alternative therapeutic strategies foracute myeloid leukemia (AML). The study, led by Kimberly Stegmaier, MD, from Children's Hospital Boston, Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT, identifies a previously unrecognized AML target that responds well to pharmacological inhibition and may be an excellent candidate for use in future clinical trials. It was published in the October issue of the journal Cancer Cell.

AML is a type of blood cancer that disrupts normal blood cell production. "Long term survival for patients with AML remains poor despite dose-intensive chemotherapy regimens," explains Stegmaier, the study's senior author. "For older adults, long-term survival is dismal, and many older patients are unable to tolerate standard cytotoxic therapy." Unfortunately, identification of new treatment strategies has proven difficult as many potential targets are proteins that do not respond well to standard pharmacological methods.

Another challenge has been to unravel the molecular mechanisms associated with compounds that inhibit or reverse AML progression. Target identification is necessary for optimization of drug treatment. Dr. Stegmaier and colleagues had previously demonstrated that epidermal growth factor receptor (EGFR) inhibitors exhibited anti-AML activity. However, this finding was somewhat puzzling as EGFR is not expressed in AML. The researchers made use of sophisticated cross-disciplinary approaches to study gene expression (genomics) and protein structure and function (proteomics) to elucidate the molecular basis for the effect of EGFR inhibitors in AML.

Spleen tyrosine kinase (Syk) was identified as a target in AML. Syk is expressed in blood cells and is critical for proper blood cell differentiation. Recent research has implicated Syk in blood cancers, specifically lymphomas and leukemias. Genetic and pharmacological inactivation of Syk resulted in anti-AML activity in AML cell lines, primary patient samples and animal models of AML. Importantly, there are Syk inhibitors currently being tested in clinical trials.

These results identify Syk as a promising therapeutic target for treatment of AML. "With an orally available, well-tolerated Syk inhibitor currently in clinical development for other indications, our results should have immediate relevance for clinical testing of Syk inhibition in patients with AML," say Dr. Stegmaier. "Our study also validates the feasibility of integrating genetic and proteomic approaches to identify small molecules and their mechanisms of action."

Press release written by Cell Press.

Contacts:
Cathleen Genova
617-397-280
cgenova@cell.com

Jamie Newton
Children's Hospital Boston
617-919-3110
james.newton@childrens.harvard.edu

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 12 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.

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- Sandra L. Fenwick, President and CEO

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