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：
8635319
负责人：
QING-BAI SHE
金额：
$ 30.19万
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/8635319
关键词：
Address Animal Model Biochemical Biological Markers Biology Biometry Cancer Cell Growth Cancer Patient Cancer cell line Clinic Clinical Colonic Neoplasms Colorectal Cancer Data Dependence Drug Targeting Effectiveness Exhibits Feedback Genes Goals Growth Human In Vitro Knowledge MEK inhibition MEKs Messenger RNA Modeling Molecular Mus Mutation Neoplasm Metastasis Oncogene Proteins 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 human FRAP1 protein in vivo inhibitor/antagonist insight interdisciplinary collaboration mTOR Inhibitor mTOR inhibition metastatic colorectal novel pre-clinical prevent public health relevance response survivin therapeutic target 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（由申请人提供）：RAS/RAF/MEK/ERK和PI3K/AKT途径的突变激活与结直肠癌（CRC）的进展和转移有关。已经在诊所测试了几种小分子PI3K，AKT，RAF和MEK抑制剂以治疗CRC，但仅显示有限的活性作为单一药物。我们最近发现，通过有效抑制EIF4E引起的帽依赖性翻译，对ERK和AKT途径均表现出有效的协同抗CRC效应。我们的总体假设是，合作ERK和AKT信号传导的帽依赖性翻译激活可以选择性地上调赋予CRC进展和转移的关键癌蛋白。通过表征合作ERK和AKT信号传导CAP依赖性翻译的分子细节，我们旨在了解CRC转移性进展的转化激活的分子机制，并探索针对CRC治疗的靶向转化调节的治疗应用。我们的具体目的是：目标1。确定CRC中合作ERK和AKT信号转化激活的生物学和治疗后果。我们将确定1）MTOR激酶在CRC细胞生长和运动性转化中的ERK和AKT信号传导的功能的程度； 2）MTOR抑制作用诱导的ERK和AKT的反馈激活如何消除CAP依赖性翻译并导致MTOR独立； 3）使用我们建立的Orthotopic转移模型，转移性进展调节活性的分子基础。 AIM 2。通过合作ERK和AKT信号传导来表征CRC进展和转移的AKT信号的分子机制。我们证明了Survivin是ERK和AKT途径的关键转化目标。我们将探讨翻译调节的Survivin充当这些途径的重要生长/转移效应子的可能机制。我们将使用合并的多聚体分析和蛋白质组学方法系统地识别其他有选择地募集到多聚体的mRNA，并由合作ERK和AKT信号转换，并详细介绍了这些基因在CRC进展和转移中的功能重要性。 AIM 3。评估MEK/ERK和AKT/MTOR途径联合抑制的体内实用性，并针对其信号的收敛于翻译起始，以增强CRC治疗。我们将同时使用CRC的小鼠原位模型和患者肿瘤衍生的异种移植模型来确定MEK，AKT和MTOR抑制剂的有效性，并在结合使用中，并表征翻译起始抑制剂4EGI-1的能力，以防止肿瘤进步和转移。 EIF4E，4E-BP1和Survivin的表达和调节，以及它们与ERK和AKT途径的突变激活状态的相关性也将以响应靶向疗法和临床标本来表征。