This proposal is aimed at a better understanding of the oncogenic role of anaplastic large cell lymphoma kinase (ALK). ALK is aberrantly expressed (most frequently as the NPM/ALK fusion protein) and/or activated in a subset of human T-cell and B-cell lymphomas, inflammatory myofibroblastic tumors, subsets of non-small cell lung carcinoma, rhabdomyosarcoma, neuroblastoma, glioblastoma and retinoblastoma and, apparently, other malignancies. Whereas NPM/ALK is highly oncogenic, the exact mechanisms of the ALK-mediated cell transformation remain only partially elucidated. In this study we will examine these mechanisms by focusing on the key transcription factors activated by NPM/ALK: STAT3 and STAT5b including the role of STAT3 in induction of epigenetic gene silencing. We will also develop preclinical model of targeted therapy aimed at simultaneous disruption of the ALK/STAT-mediated cell signaling and ALK expression. To accomplish these goals we will: 1. Identify the genes regulated by NPM/ALK-STAT3 and NPM/ALK-STAT5b signaling pathways and examine the role of proteins encoded by the selected identified genes in the malignant cell transformation. 2. Examine the mechanisms of the STAT3-induced epigenetic silencing of the STAT5a gene. 3. Determine the effects of ALK and DNMT inhibitors on tumor growth in vitro and in vivo. This study should lead to further elucidation of pathogenesis of the ALK-driven neoplasms and may pave the road to novel, targeted therapies for these malignant disorders. Because the aberrant activation of STAT3 and STAT5 as well as the epigenetic silencing of tumor suppressor genes have been identified in the large spectrum of malignancies, results of this study may also have an impact on research and, prospectively, therapy of other types of cancer.
Understanding exact mechanisms of the aberrant activation of cell signal transduction by oncogenic tyrosine kinases such as NPM/ALK and the role of their down-stream signaling effector proteins such as STAT3 and STAT5 transcription factors should lead to novel treatment modalities based on selective inhibition of activity of the oncogenic kinase as well as its key effector proteins. Therefore, these studies may result in targeted therapies for NPM/ALK- expressing lymphomas and other malignancies expressing oncogenic form of the ALK tyrosine kinase. Given that aberrant STAT3 and STAT5 activation is present in many types of cancer, they may also impact on research pertaining to tumors unrelated to ALK.
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