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    • 5. 发明申请
    • MUTANT ROS EXPRESSION IN HUMAN CANCER
    • 突变型ROS在人类肿瘤中的表达
    • WO2010093928A2
    • 2010-08-19
    • PCT/US2010/024109
    • 2010-02-12
    • CELL SIGNALING TECHNOLOGY, INC.GU, Ting-leiTUCKER, Meghan, AnnHAACK, HerbertCROSBY, Katherine, EleanorRIMKUNAS, Victoria, McGuinness
    • GU, Ting-leiTUCKER, Meghan, AnnHAACK, HerbertCROSBY, Katherine, EleanorRIMKUNAS, Victoria, McGuinness
    • G01N33/574
    • A61K31/506A61K31/4545C12Q1/6827C12Q1/6858C12Q1/6869C12Q1/6886C12Q2600/156C12Q2600/158G01N33/57438G01N33/57484G01N2333/9121G01N2800/52
    • The invention provides the identification of the presence of mutant ROS protein in human cancer. In some embodiments, the mutant ROS are FIG-ROS fusion proteins comprising part of the FIG protein fused to the kinase domain of the ROS kinase. In some embodiments, the mutant ROS is the overexpression of wild-type ROS in cancerous tissues (or tissues suspected of being cancerous) where, in normal tissue of that same tissue type, ROS is not expressed or is expressed at lower levels. The mutant ROS proteins of the invention are anticipated to drive the proliferation and survival of a subgroup of human cancers, particularly in cancers of the liver (including bile duct), pancreas, kidney, and testes. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant ROS polypeptides (e.g., a FIG-ROS(S) fusion polypeptide), probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The identification of the mutant ROS polypeptides enables new methods for determining the presence of these mutant ROS polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides, which are also provided by the invention.
    • 本发明提供了人癌症中突变ROS蛋白存在的鉴定。 在一些实施方案中,突变ROS是包含融合于ROS激酶的激酶结构域的FIG蛋白的一部分的FIG-ROS融合蛋白。 在一些实施方案中,突变ROS是野生型ROS在癌组织(或疑似癌变的组织)中的过表达,其中在相同组织类型的正常组织中,ROS不表达或以较低水平表达。 预计本发明的突变ROS蛋白可以驱动人类癌症亚群的增殖和存活,特别是在肝癌(包括胆管癌),胰腺癌,肾癌和睾丸癌中。 因此,本发明部分地提供了编码所公开的突变ROS多肽(例如FIG-ROS(S)融合多肽)的分离的多核苷酸和载体,用于检测它的探针,分离的突变多肽,重组多肽和用于检测融合 和截短的多肽。 突变ROS多肽的鉴定使得能够确定生物样品中这些突变ROS多肽的存在的新方法,用于筛选抑制蛋白质的化合物的方法,以及抑制以突变多核苷酸或多肽为特征的癌症进展的方法 ,这也由本发明提供。