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Targeting Translation Dependence in Colorectal Cancer Progression

针对结直肠癌进展中的翻译依赖性

基本信息

批准号：
9020761
负责人：
QING-BAI SHE
金额：
$ 31.13万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020761
关键词：
Address Animal Model Biochemical Biology Biometry Cancer Cell Growth Clinic Clinical Colonic Neoplasms Colorectal Cancer Data Dependence EIF4EBP1 gene Effectiveness Exhibits FRAP1 gene Feedback Genes Goals Growth Health Human In Vitro Knowledge MEK inhibition MEKs Messenger RNA Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogenes Operative Surgical Procedures PI3K/AKT PTEN gene Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Polyribosomes Proteomics Proto-Oncogene Proteins c-akt Recruitment Activity Research Infrastructure Resistance Role Signal Pathway Signal Transduction Solid Specimen Techniques Testing Therapeutic Translating Translation Initiation Translational Activation Translational Regulation Translational Repression Translations Tumor-Derived Tyrosine Kinase Receptor Inhibition Xenograft Model base cancer therapy cell motility clinically relevant colon cancer cell line colon cancer patients in vivo inhibitor/antagonist insight interdisciplinary collaboration mTOR Inhibitor mTOR inhibition metastatic colorectal new therapeutic target novel novel marker novel therapeutics pre-clinical prevent response survivin targeted treatment tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Mutational activation of the RAS/RAF/MEK/ERK and PI3K/AKT pathways is associated with colorectal cancer (CRC) progression and metastasis. Several small molecularly-targeted PI3K, AKT, RAF and MEK inhibitors have been tested in the clinic for the treatment of CRC but have shown only limited activity as a single agent. We have recently discovered that inhibition of both the ERK and AKT pathways exhibits potent, synergistic anti-CRC effects, both in vitro and in vivo, by effectively inhibiting eIF4E-initiated cap-dependent translation. Our overarching hypothesis is that the activation of cap-dependent translation by cooperative ERK and AKT signaling can selectively upregulate key oncoproteins that confer CRC progression and metastasis. By characterizing the molecular details of the activation of cap-dependent translation by cooperative ERK and AKT signaling, we aim to understand the molecular mechanisms underlying translational activation for CRC metastatic progression, and to explore the therapeutic applications of targeting translational regulation for CRC treatment. Our Specific Aims are: Aim 1. Determine the biologic and therapeutic consequences of translational activation by cooperative ERK and AKT signaling in CRC. We will determine 1) the extent to which the mTOR kinase integrates the function of ERK and AKT signaling in translational regulation of CRC cell growth and motility; 2) how mTOR inhibition-induced feedback activation of ERK and AKT deregulates cap-dependent translation and causes mTOR-independence; and 3) the molecular basis of metastatic progression-modulated translational activity using our well-established orthotopic metastastic model of CRC. Aim 2. Characterize the molecular mechanism of translational activation by cooperative ERK and AKT signaling for CRC progression and metastasis. We demonstrate that survivin is a key translational target of the ERK and AKT pathways. We will explore the possible mechanism by which the translationally-regulated survivin acts as an important growth/metastasis-promoting effector of these pathways. We will use combined polysome profiling and proteomic approaches to systematically identify other mRNAs that are selectively recruited to polysomes and translated by cooperative ERK and AKT signaling, and characterize in detail the functional importance of these genes in CRC progression and metastasis. Aim 3. Evaluate the in vivo utility of combined inhibition of the MEK/ERK and AKT/mTOR pathways and targeting the convergence of their signals on translation initiation for enhancing CRC therapy. We will use both the mouse orthotopic model of CRC and the patient tumor-derived xenograft model to determine the effectiveness of MEK, AKT and mTOR inhibitors alone and in combination, and to characterize the ability of the translation initiation inhibitor 4EGI-1 to prevent tumor progressio and metastasis. The expression and modulation of eIF4E, 4E-BP1 and survivin, and their correlation with the mutational activation status of ERK and AKT pathways will also be characterized in response to the targeted therapies and in clinical specimens.

描述（由申请方提供）：RAS/RAF/MEK/ERK和PI 3 K/AKT通路的突变激活与结直肠癌（CRC）进展和转移相关。几种小分子靶向的PI 3 K、AKT、RAF和MEK抑制剂已在临床上测试用于治疗CRC，但作为单一药剂仅显示出有限的活性。我们最近发现，抑制ERK和AKT途径通过有效抑制eIF 4 E启动的帽依赖性翻译，在体外和体内均表现出有效的协同抗CRC作用。我们的总体假设是，通过协同ERK和AKT信号传导激活帽依赖性翻译可以选择性上调赋予CRC进展和转移的关键癌蛋白。通过表征协同ERK和AKT信号传导激活帽依赖性翻译的分子细节，我们的目标是了解CRC转移进展的翻译激活的分子机制，并探索靶向翻译调节在CRC治疗中的治疗应用。我们的具体目标是：目标1。确定CRC中ERK和AKT协同信号转导的翻译激活的生物学和治疗后果。我们将确定1）mTOR激酶在CRC细胞生长和运动的翻译调节中整合ERK和AKT信号传导功能的程度; 2）mTOR抑制诱导的ERK和AKT反馈激活如何解除帽依赖性翻译并导致mTOR非依赖性; 3）使用我们完善的CRC原位转移模型，转移性进展调节翻译活性的分子基础。目标2.通过协同ERK和AKT信号转导表征CRC进展和转移的翻译激活的分子机制。我们证明了生存素是ERK和AKT通路的关键翻译靶点。我们将探讨可能的机制，通过这种机制，免疫调节生存素作为一个重要的生长/转移促进效应的这些途径。我们将使用组合的多聚核糖体分析和蛋白质组学方法来系统地鉴定选择性地募集到多聚核糖体并通过协同ERK和AKT信号转导翻译的其他mRNA，并详细描述这些基因在CRC进展和转移中的功能重要性。目标3.评价联合抑制MEK/ERK和AKT/mTOR通路并靶向其信号在翻译起始上的会聚以增强CRC治疗的体内效用。我们将使用CRC的小鼠原位模型和患者肿瘤来源的异种移植物模型来确定MEK、AKT和mTOR抑制剂单独和组合的有效性，并表征翻译起始抑制剂4 EGI-1预防肿瘤进展和转移的能力。eIF 4 E、4 E-BP 1和生存素的表达和调节，以及它们与ERK和AKT通路的突变激活状态的相关性也将在对靶向治疗的响应和临床标本中表征。