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Role of STE20 protein kinases in malignant mesothelioma

STE20蛋白激酶在恶性间皮瘤中的作用

基本信息

批准号：
9891955
负责人：
JONATHAN CHERNOFF
金额：
$ 44.41万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891955
关键词：
Adhesions Affect Asbestos Biochemical Biological Biological Assay CDKN2A gene Cell Proliferation Cells Clinical Combined Modality Therapy Data Dimerization Disease Disease model Drug Targeting Elements Engineering Generations Genetic Goals Growth Homo Human In Vitro Incidence Knockout Mice Link Malignant Neoplasms Malignant mesothelioma Measures Medical Mesothelial Cell Methods Modeling Mus Neurofibromatosis 2 Neurofibromin 2 New Agents Oncogenic Pathogenesis Pathology Pathway interactions Patients Phosphotransferases Play Pleural Positioning Attribute Pre-Clinical Model Property Protein Kinase Proteins Regulation Resistance Role Series Signal Pathway Signal Transduction Sterility Techniques Technology Testing Therapeutic Therapeutic Intervention Time Transcription Coactivator Tumor Suppressor Genes Tumor Suppressor Proteins Tumorigenicity Virus base cell motility efficacy testing experimental study in vivo inhibitor/antagonist kinase inhibitor malignant phenotype member mouse model mutant neoplastic cell p21 activated kinase pre-clinical public health relevance response small molecule small molecule inhibitor targeted agent targeted treatment therapeutic candidate therapeutic target tool tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Malignant Mesothelioma (MM) is a relatively common, rapidly progressive and treatment-resistant malignancy linked to asbestos exposure. Both human MM patients and mouse models of this devastating disease show frequent loss of the neurofibromatosis type II tumor suppressor gene, Nf2, and re-expression of Nf2 in Nf2-null MM cells inhibits their proliferation/viability and restrains their motility, implying that Nf2 los plays a fundamental role in MM pathogenesis. Previously, we and others have implicated Merlin, the protein product of the Nf2 gene, in the regulation of p21-activated kinase (Pak) and mammalian sterile twenty-like (Mst) signaling. These two STE20 kinases play an important role in regulating cell proliferation, survival, adhesion, motility, spreading and invasiveness − properties connected with the malignant phenotype of Nf2-deficient MM cells. We postulate that both pathways are essential for MM tumorigenesis associated with NF2 loss, and that both pathways can be exploited for therapeutic benefit. We propose two aims. In Aim 1 we will determine the response of a Nf2-null MM mouse model to potent, newly developed preclinical Pak small molecule inhibitors. As we expect that aggressive cancers such as MM will adapt and eventually evade single targeted agents such as Pak inhibitors, we also propose to use a newly developed technology to globally measure the activity of all protein kinases prior to and during treatment with anti-Pak agents, with the goal of identifying potential secondary drug targets for combination therapy. In Aim 2 we plan to delineate the role of the Mst, the defining element in the Hippo tumor suppressor pathway, in Merlin- related signaling and pathology in vivo. Using cell-based assays, we will determine the mechanism by which Merlin controls Mst activity, focusing on our recent observation that loss of Merlin induces a switch from active Mst1/Mst1 and Mst2/Mst2 homodimers to inactive Mst1/Mst2 heterodimers. We will also assess the suitability of targeting the Hippo pathway in MM by crossing our MM mouse model into a conditional Yap1-null strain to assess the effects on Yap loss on tumor incidence and progression. The proposed studies will not only increase our understanding of cardinal oncogenic signaling pathways, but could establish Pak and Mst kinases as suitable targets for therapeutic intervention in this otherwise untreatable disease.