Mouse Model of Gastrointestinal Stromal Tumor (GIST)

Introduction Recent developments have firmly established the important role of receptor tyrosine kinases in human cancer. Kit is a receptor tyrosine kinase and its role as a cellular oncogene has been established in a number of cancers including gastrointestinal stromal tumors (GISTs), which belong to a group of cancers called soft tissue sarcomas. Relatively little is known about the intervening steps in the genesis of sarcomas in general or GIST in particular. Technology description UW researchers have created a mouse model of gastrointestinal stromal tumor (GIST) by introducing an activating Kit gene mutation that is associated with human familial GIST syndrome into the mouse genome. A knock-in gene targeting strategy was used to introduce a Kit gene (K641E) mutation, originally identified in sporadic human GISTs and in the germ line of familial GIST syndrome patients. Homozygous and heterozygous Kit K641E mice develop gastrointestinal pathology with complete penetrance and all Kit K641E homozygotes die by age 30 weeks due to gastrointestinal obstruction by hyperplastic interstitial cells of Cajal (ICC) or GISTs. Heterozygous mice have less extensive hyperplasia and smaller GISTs, suggesting a dose-response relationship. Business opportunity GISTs are the most common sarcoma of the gastrointestinal tract. It is estimated that between 5,000 and 10,000 Americans each year develop GISTs. This mouse model can provide unique insights into the role of Kit in the pathogenesis of GISTs as well as the biology of ICCs and normal Kit function. Furthermore, such a model is useful in the preclinical evaluation of potential anti-Kit therapies and the study of mechanisms of resistance to these therapies. Stage of development The transgenic mice have been well characterized. Studies have demonstrated that the Kit K641E mutation reproduces the pathology associated with the familial GIST syndrome. Related Publication Rubin et al., Cancer Res 2005; 65: (15). August 1, 2005

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