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OHSU Cancer Institute researchers identify new approach to help control drug resistance in leukemia
Date:3/24/2008

PORTLAND, Ore. Oregon Health & Science University Cancer Institute researchers have found that an experimental drug known as SGX393 is effective against Gleevec-resistant chronic myeloid leukemia (CML). The results of their study will be published the week of March 24th in the Proceedings of the National Academy of Sciences.

Gleevec, the targeted therapy identified by OHSU Cancer Institute Director Brian Druker, M.D., is the current first line therapy for CML. Gleevec works by inhibiting the activity of Bcr-Abl, an enzyme that is present only in CML cells and upon which these cells depend for survival. Although most patients with CML respond dramatically to Gleevec, some patients develop resistance to the drug. Most Gleevec-resistant CML cells carry a mutated form of Bcr-Abl, which prevents Gleevec from functioning properly. The second-generation drugs Sprycel and Tasigna have been developed as largely successful treatments for Gleevec-resistant patients. However, one mutated form of Bcr-Abl, called T315I, is resistant to all three clinical CML drugs and is a frequent cause of relapse.

Michael Deininger, M.D., Ph.D., head of the Hematologic Malignancies Section, and his research team in the OHSU Cancer Institute have shown that SGX393, developed by SGX Pharmaceuticals, Inc., San Diego, Calif., inhibits the T315I mutant and most, but not all, other Gleevec-resistant mutants. This was shown to be true using laboratory models as well as leukemia cells from patients with CML.

Researchers then took this success a step further. Using a method developed in their laboratory to rapidly and accurately forecast drug-resistant Bcr-Abl mutations, Deininger and colleagues established a resistance profile for SGX393. Though SGX393 showed a handful of mutation weak spots, the T315I mutation was absent among thousands of samples surveyed in the laboratory. In contrast, T315I was frequently recovered when running the screen with any of the other drugs.<
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Contact: Christine Decker
deckerch@ohsu.edu
503-494-8231
Oregon Health & Science University
Source:Eurekalert

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