胃肠道间质瘤(GIST)是最常见的肉瘤，KIT 或者PDGFRA激活突变是GIST的初始事件，CDKN2A 和TP53 失活突变促进细胞增殖，但这些突变在原发GIST就已经存在，而GIST治疗最棘手的难题之一就是转移，我们首次报道了dystrophin在GIST演变过程中发生失活突变，是一个新型抑癌基因。dystrophin在原发性低危GIST中高表达，而在约96%转移GIST中由于失活突变导致表达丢失。通过一系列功能试验证明dystrophin失活促进GIST细胞侵袭、迁移、非锚定依赖性生长和细胞invadopodia形成。尽管从遗传学角度证明了dystrophin失活促进了GIST转移，但具体分子机理尚不清楚。该研究拟（1）解析dystrophin失活促进GIST转移的分子机制；（2）寻找能恢复dystrophin功能的小分子化合物并证明在转移GIST 中的潜在应用前景。

Gastrointestinal Stromal Tumors (GISTs) are the most common gastrointestinal soft tissue malignancies. Gain-of-function KIT or PDGFRA mutations are initiating genetic events in GISTs. Somatic mutations presumably contribute to tumorigenic progression in GIST, e.g. cell cycle dysregulation by CDKN2A or TP53 inactivation, but few genetic progression mechanisms in GIST have been characterized. More recently, for the first time, we (Wang et al, Nat Genet 2014) demonstrated that dystrophin is a genomically-inactivated tumor suppressor in human cancers with myogenic programs, including leiomyosarcoma, rhabdomyosarcoma, and GIST. For example, in GISTs, the major dystrophin 427kDa isoform was expressed strongly (and had no demonstrable genomic mutations) in each of 11 low-risk (indolent) GISTs, whereas dystrophin expression was undetectable in 26 of 27 (96%) metastatic GISTs, most of which had inactivating intragenic DMD mutations. Furthermore, we established immortal cell lines from several of the dystrophin-mutant clinical specimens, and showed in these in vitro models that dystrophin inactivation had profound cell response consequences, increasing cell invasion, migration and anchorage-independent growth. Our data also suggest that dystrophin could serve as a potential target of therapeutic attack. Although dystrophin inactivation during GIST progression is convincing and well documented, the biological mechanisms by which dystrophin inactivation contributes to carcinogenesis is unclear. In the Duchenne muscular dystrophy field, there are several genetic approaches targeting dystrophin inactivation in development (preclinical and clinic trial stage). Unfortunately, none of them have been approved by FDA after a decade of research. Given recent advances in chemical genomics such as gene expression-based high-throughput screening and the Connectivity Map, we hypothesized that the gene expression signature resulting from dystrophin restoration in GIST could be used to search for similar signatures in publicly available gene expression profiles. With the overarching goal of characterize the pathways dysregulation by dystrophin inactivation and to discover small compounds that reverse the dystrophin deficiency in advanced GIST, we will perform systematic screens utilizing state-of-the-art technology on our unique repository of GIST resources. Two aims are proposed for this research plan: (1) Systematic screens to identify pathways dysregulated by dystrophin inactivation in advanced GIST. (2) To reverse dystrophin deficiency in advanced GIST with small molecules. The goal of the project is to explore the molecular mechanisms of dystrophin inactivation mediated tumorgenesis and to discover small compounds that reverse the dystrophin deficiency in advanced GIST. The research could potentially lead to the development of novel agents against advanced GIST.