Targeting Translation Dependence in Colorectal Cancer Progression

针对结直肠癌进展中的翻译依赖性

• 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
• 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

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 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 PI3K、AKT、RAF 和 MEK 抑制剂已在临床上测试用于治疗 CRC，但作为单一药物仅显示有限的活性。我们最近发现，通过有效抑制 eIF4E 启动的帽依赖性翻译，抑制 ERK 和 AKT 通路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，通过合作的 ERK 和 AKT 信号传导激活帽依赖性翻译可以选择性上调导致 CRC 进展和转移的关键癌蛋白。通过表征 ERK 和 AKT 信号协同激活帽依赖性翻译的分子细节，我们旨在了解 CRC 转移进展的翻译激活的分子机制，并探索靶向翻译调控在 CRC 治疗中的治疗应用。我们的具体目标是： 目标 1. 通过 ERK 和 AKT 信号传导协同确定 CRC 中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的调节并导致 mTOR 独立性； 3）使用我们完善的结直肠癌原位转移模型进行转移进展调节翻译活性的分子基础。目标 2. 表征 ERK 和 AKT 信号传导协同作用对 CRC 进展和转移的翻译激活分子机制。我们证明生存素是 ERK 和 AKT 途径的关键翻译靶标。我们将探索翻译调节的生存素作为这些途径的重要生长/转移促进效应器的可能机制。我们将使用组合的多核糖体分析和蛋白质组学方法来系统地识别其他选择性招募到多核糖体并通过合作的 ERK 和 AKT 信号转导翻译的 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. 评估 MEK/ERK 和 AKT/mTOR 通路联合抑制的体内效用，并以翻译起始时信号的收敛为目标，以增强 CRC 治疗。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 4EGI-1 预防肿瘤的能力进展和转移。 eIF4E、4E-BP1 和生存素的表达和调节，以及它们与 ERK 和 AKT 通路突变激活状态的相关性，也将根据靶向治疗和临床样本进行表征。