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2007 ACVP Annual Meeting

2007 Society of Toxicologic Pathology Student Speaker Award

$1,000 and free registration to the STP meeting

THE NOVEL HSP90 INHIBITOR STA9090 EXHIBITS ACTIVITY AGAINST KIT DEPENDENT AND INDEPENDENT MALIGNANT CANINE MAST CELL TUMORS. T-Y. Lin1, M. Bear1, J. Barsoum2, C.A. London1. 1Department of Veterinary Biosciences, The Ohio State University, Columbus, OH and 2Synta Corp, Lexington, MA.
Mutations that induce ligand-independent activation of the RTK Kit are found in several human and canine cancers including gastrointestinal stromal tumors, malignant mast cell disease, and acute myelogenous leukemia. Small molecule Kit inhibitors have exhibited significant activity in the clinical setting, but they possess variable efficacy against particular forms of mutant Kit, and drug resistance often develops over time. Recently, inhibitors of HSP90, a chaperone for which Kit is a client protein, have demonstrated biologic activity in human cancers and evidence suggests they can efficiently down-regulate several mutated and Gleevec (Imatinib)-resistant forms of Kit. The purpose of this study was to evaluate a novel HSP90 inhibitor, STA9090, against wild-type (WT) and mutant Kit in normal canine bone marrow derived cultured mast cells (BMCMCs), malignant mast cell lines and malignant mast cells cultured ex vivo. HSP90 expression levels were found to be similar among the BMCMCs, cell lines and fresh malignant mast cells. Treatment of the BMCMCs, cell lines, and fresh malignant cells induced growth inhibition and subsequent apoptosis without promoting cell cycle arrest. The apoptosis was caspase3/7 dependent as evidenced by PARP cleavage. STA9090 treatment down-regulated phospho- and total Kit and Akt, but not Erk, PI-3 kinase, B-Raf or Src in malignant mast cell lines. Rapid down-regulation of Kit expression was also observed on BMCMCs and fresh malignant mast cells. Furthermore, STA9090 was active against cells expressing WT or mutant Kit, while a small molecule Kit inhibitor, SU11654, was effective only against cells expressing mutant Kit. Unlike previous reports, a direct association between Bcl-2 and HSP90 in malignant mast cells was not found. In summary, STA9090 exhibited broad activity against cells expressing WT or mutant Kit suggesting that it may be an effective agent in the clinical setting.

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