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.
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