Functional role of the MUC1-C oncoprotein in non-small cell lung cancer

MUC1-C 癌蛋白在非小细胞肺癌中的功能作用

基本信息

批准号：
8634063
负责人：
DONALD W. KUFE
金额：
$ 51.82万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634063
关键词：
A549 Address Adenocarcinoma Anchorage-Independent Growth Applications Grants C-terminal Cancer Cell Growth Cancer Etiology Cancer Patient Cell Nucleus Cell Survival Cell membrane Cells Cessation of life Characteristics Clinical Cytoplasm Cytoplasmic Tail Databases Development Disease Down-Regulation Drug Targeting Epidermal Growth Factor Receptor Experimental Models Family member GRB2 gene Gene Expression Profile Gene Expression Regulation Genes Genetically Engineered Mouse Glycoproteins Growth Human Knowledge Link Lung Adenocarcinoma Maintenance Malignant neoplasm of lung Mucin 1 protein Mucin-1 Staining Method Mucins Mutation N-terminal Non-Small-Cell Lung Carcinoma Nude Mice Oncogene Proteins Oncogenic Outcome Pathogenesis Pathway interactions Patients Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Research Resistance Role Scientific Advances and Accomplishments Signal Transduction Tandem Repeat Sequences Tumorigenicity United States Work Xenograft procedure cancer cell cancer initiation cancer therapy extracellular improved in vivo inhibitor/antagonist mouse model mutant novel outcome forecast overexpression tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Non-small cell lung cancers (NSCLCs), particularly those harboring certain EGFR or K-RAS mutations, are often unresponsive to molecularly targeted agents and have a poor prognosis. Mucin 1 (MUC1) is a transmembrane glycoprotein that is overexpressed in most NSCLCs. However, it is not known if MUC1 is of importance to NSCLC cell growth and survival. In this regard, there are no available genetically-engineered mouse models to study MUC1 involvement in NSCLC initiation, progression or maintenance. MUC1 consists of two subunits~ an N-terminal extracellular mucin subunit (MUC1-N) and a C- terminal oncogenic transmembrane subunit (MUC1-C). The MUC1-C cytoplasmic domain functions as a substrate for EGFR and MET, and interacts with effectors, such as PI3K, that have been linked to NSCLC development. Overexpression of MUC1-C induces transformation and associated gene signatures that are predictive of decreased disease-free and overall survival in NSCLC patients. Moreover, inhibition of the MUC1-C subunit in NSCLC cells is associated with downregulation of the PI3K->AKT pathway and loss of survival. The overall objective of the proposed work is to define the functional role of MUC1-C in NSCLC. Our hypothesis is that MUC1-C contributes to the pathogenesis of NSCLC and that MUC1-C function is essential for survival of NSCLC cells with EGFR and K-RAS mutations. The proposed work will address this hypothesis in a new MUC1-C-driven mouse model of NSCLC and through the use of recently developed MUC1-C inhibitors. The theoretical concept that MUC1-C is a target for the treatment of NSCLC is novel and could shift current research and clinical paradigms. The Specific Aims are: (1) To define involvement of MUC1-C in development of NSCLC in mouse models~ (2) To assess the role of MUC1-C in NSCLC with EGFR mutations~ (3) To determine whether MUC1-C is of importance to development of K-RAS mutant NSCLC~ and (4) To identify how MUC1-C contributes to NSCLC cell survival.

描述（由申请人提供）：非小细胞肺癌（NSCLC），特别是那些带有某些 EGFR 或 K-RAS 突变的肺癌，通常对分子靶向药物无反应，并且预后不良。粘蛋白 1 (MUC1) 是一种跨膜糖蛋白，在大多数 NSCLC 中过度表达。然而，尚不清楚 MUC1 对 NSCLC 细胞生长和存活是否重要。在这方面，目前还没有可用的基因工程小鼠模型来研究 MUC1 参与 NSCLC 的发生、进展或维持。 MUC1 由两个亚基组成：N 端细胞外粘蛋白亚基 (MUC1-N) 和 C 端致癌跨膜亚基 (MUC1-C)。 MUC1-C 胞质结构域充当 EGFR 和 MET 的底物，并与与 NSCLC 发展相关的效应因子（例如 PI3K）相互作用。 MUC1-C 的过度表达会诱导转化和相关基因特征，这些特征可预测 NSCLC 患者的无病生存率和总生存率下降。此外，抑制 NSCLC 细胞中的 MUC1-C 亚基与 PI3K->AKT 通路的下调和生存丧失相关。拟议工作的总体目标是确定 MUC1-C 在 NSCLC 中的功能作用。我们的假设是，MUC1-C 有助于 NSCLC 的发病机制，并且 MUC1-C 功能对于具有 EGFR 和 K-RAS 突变的 NSCLC 细胞的生存至关重要。拟议的工作将在新的 MUC1-C 驱动的 NSCLC 小鼠模型中并通过使用最近开发的 MUC1-C 抑制剂来解决这一假设。 MUC1-C 是 NSCLC 治疗靶点的理论概念是新颖的，可能会改变当前的研究和临床范式。具体目标是： (1) 确定 MUC1-C 在小鼠模型中参与 NSCLC 的发展~ (2) 评估 MUC1-C 在 EGFR 突变的 NSCLC 中的作用~ (3) 确定 MUC1-C 是否与对 K-RAS 突变 NSCLC 的发展具有重要意义~以及 (4) 确定 MUC1-C 如何促进 NSCLC 细胞存活。