H-25893 ADVL0912, A PHASE 1/2 STUDY OF PF-02341066, AN ORAL SMALL MOLECULE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在肿瘤学中出现了一种新的范例，即可以用针对致癌受体酪氨酸激酶（RTK）的抑制剂获得临床疗效，所述致癌受体酪氨酸激酶在某些肿瘤类型中突变或以其他方式失调。这种成功干预的例子包括伊马替尼在GIST与突变的c-Kit，厄洛替尼在NSCLC与突变和/或扩增的EGFR，曲妥珠单抗在乳腺癌与扩增HER-2，和舒尼替尼靶向VHL依赖性VEGF途径在RCC。c-Met RTK在晚期癌症中经常发生改变或失调，并与肿瘤进展有关，因此代表了一种有吸引力的新型治疗靶点。已经表明Met受体在横纹肌肉瘤中PAX 3-FKHR介导的转化中起作用，并且MET可以作为这种疾病的治疗靶点。与Met癌基因具有显著同源性的间变性淋巴瘤激酶基因（ALK）在间变性大细胞淋巴瘤（ALCL）的发病机制中起作用，由于染色体易位，导致称为NPM-ALK的致癌激酶融合蛋白表达。ALK是一种孤儿酪氨酸激酶跨膜受体，与神经营养因子受体和MET癌基因同源。表达仅限于发育中的神经系统，在神经元分化的调节中发挥假定的作用。最近已经清楚，许多人类癌症通过染色体易位事件在2 p23处与各种伴侣产生ALK基因的独特致癌融合来激活ALK信号传导，导致致癌ALK融合基因及其编码蛋白的产生。最近，随着在一部分非小细胞肺癌和其他实体瘤中发现ALK易位，对ALK生物学的兴趣大大增加。现在很清楚，许多人类癌症通过染色体易位事件产生ALK与各种伴侣的独特致癌融合来激活ALK信号传导。先前的研究表明，相当大比例的人源性神经母细胞瘤细胞系表达ALK转录本和ALK蛋白，但尚未证明该致癌基因的明确作用。我们最近发现间变性淋巴瘤酪氨酸激酶区的激活突变 最近，通过用ALK激酶结构域的药理学拮抗剂筛选人癌细胞系，ALK也被确定为神经母细胞瘤中的分子靶标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. There is an emerging paradigm in oncology that clinical efficacy can be obtained with inhibitors directed toward oncogenic receptor tyrosine kinases (RTKs) that are mutated or otherwise dysregulated in certain tumor types. Examples of such successful intervention include imatinib in GIST with mutant c-Kit, erlotinib in NSCLC with mutant and/or amplified EGFR, trastuzumab in breast cancers with amplified HER-2, and sunitinib targeting the VHL-dependent VEGF pathway in RCC. The c-Met RTK is frequently altered or dysregulated in advanced cancers and has been implicated in tumor progression, and therefore represents an attractive novel therapeutic target. It has been shown that the Met receptor has a role in PAX3-FKHR-mediated transformation in rhabdomyosarcomas, and that MET can serve as a therapeutic target in this disease.The anaplastic lymphoma kinase gene (ALK), which has significant homology to the Met oncogene, plays a role in the pathogenesis of anaplastic large-cell lymphomas (ALCL), due to a chromosomal translocation that results in expression of an oncogenic kinase fusion protein known as NPM-ALK. ALK is an orphan tyrosine kinase transmembrane receptor with homology to neurotrophin receptors and the MET oncogene. Expression is restricted to the developing nervous system with a postulated role in the regulation of neuronal differentiation.It has recently become clear that many human cancers activate ALK signaling by creating unique oncogenic fusions of the ALK gene at 2p23 with a variety of partners through chromosomal translocation events, resulting in the generation of oncogenic ALK fusion genes and their encoded proteins. Recently, the interest in ALK biology has increased considerably, following the discovery of ALK translocations in a fraction of non-small-cell lung cancers and in other solid tumors. It is now clear that many human cancers activate ALK signaling by creating unique oncogenic fusions of ALK with a variety of partners through chromosomal translocation events. Previous work had shown that a substantial percentage of human-derived neuroblastoma cell lines express ALK transcripts and ALK protein, but no definitive role for this oncogene had been proven. We have recently discovered that activating mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) oncogene are the cause of hereditary neuroblastoma, and that these mutations can also be somatically acquired.ALK was also recently identified as a molecular target in neuroblastoma by a screen of human cancer cell lines with pharmacologic antagonists of the ALK kinase domain.