Investigating the Role of the Mek5-Erk5 Kinase Module in Small Cell Lung Cancer

研究 Mek5-Erk5 激酶模块在小细胞肺癌中的作用

基本信息

批准号：
9122752
负责人：
Sandra Cristea
金额：
$ 4.36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2019-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122752
关键词：
Accounting Alleles Apoptosis Apoptotic Automobile Driving Bioinformatics Biological Assay Biology Cancer Biology Cancer Patient Cancer cell line Cancerous Cell Cycle Cell Death Cell Survival Cells Collaborations Data Defect Development Diagnosis Disease Epithelium Event Fibrinogen Genetic Genetically Engineered Mouse Goals Growth Human In Vitro Individual Infection Knock-out Laboratories Life Light Lung Maintenance Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Methodology Modeling Molecular Mus Mutation Neuroendocrine Cell Nuclear Localization Signal Oncogenic Outcome Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Play Process Proteomics Recurrence Role Series Signal Pathway Signal Transduction Structure TP53 gene Testing Time Transactivation Tumor Suppressor Proteins Xenograft Model Xenograft procedure addiction base cancer cell cancer initiation comparative effective therapy genome sequencing human subject in vivo knock-down loss of function lung small cell carcinoma mouse model mutant new therapeutic target novel novel therapeutic intervention overexpression phosphoproteomics public health relevance research study therapeutic target tool transcription factor tumor tumor progression tumorigenic

Accounting Alleles Apoptosis Apoptotic Automobile Driving Bioinformatics Biological Assay Biology Cancer Biology Cancer Patient Cancer cell line Cancerous Cell Cycle Cell Death Cell Survival Cells Collaborations Data Defect Development Diagnosis Disease Epithelium Event Fibrinogen Genetic Genetically Engineered Mouse Goals Growth Human In Vitro Individual Infection Knock-out Laboratories Life Light Lung Maintenance Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Methodology Modeling Molecular Mus Mutation Neuroendocrine Cell Nuclear Localization Signal Oncogenic Outcome Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Play Process Proteomics Recurrence Role Series Signal Pathway Signal Transduction Structure TP53 gene Testing Time Transactivation Tumor Suppressor Proteins Xenograft Model Xenograft procedure addiction base cancer cell cancer initiation comparative effective therapy genome sequencing human subject in vivo knock-down loss of function lung small cell carcinoma mouse model mutant new therapeutic target novel novel therapeutic intervention overexpression phosphoproteomics public health relevance research study therapeutic target tool transcription factor tumor tumor progression tumorigenic

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项目摘要

DESCRIPTION (provided by applicant): Small cell lung cancer (SCLC) claims more than 200,000 lives globally every year, and there are still no effective therapies in use for this fatal disease. Besides universal loss of the RB and P53 tumor suppressors required for SCLC initiation, the key pathways driving SCLC progression have still not been identified. Our long-term goal is to understand the molecular events that result in the aggressive itinerary of SCLC. Recent efforts to sequence the genomes of over 100 human SCLC tumors have identified rare oncogenic mutations and some regions undergoing amplification, but these analyses failed to shed light on a central oncogenic pathway that may drive the development of this cancer. Recently, the concept of non-oncogene addiction has emerged, which states that cancers may require certain active molecular pathways that are unmarked by mutations. Therefore, active but non-mutated signaling transductors such as kinases may play crucial roles in the development of cancers while remaining undiscovered by sequencing approaches. Using novel proteomic methodology, we recently obtained a first view of the active kinome of SCLC. Among active kinases in SCLC, Mek5 is particularly intriguing. Mek5 and its downstream target, Erk5, comprise a still poorly characterized signaling pathway; emerging evidence suggests that, similar to the more studied Mek1/2- Erk1/2 pathway, the Mek5/Erk5 axis may also regulate cell survival and cycling. Mek5 and Erk5 have never been studied in SCLC cells and little is still known about their role in cancer in general. Here we hypothesize that the Mek5/Erk5 module is crucial to the growth of SCLC. This hypothesis is supported by our preliminary observations that Mek5- or Erk5-deficient SCLC cells show severe growth deficiencies and increased apoptotic cell death. However, we lack a complete understanding of the requirement for this axis in SCLC development in the organismal context, and of how Mek5/Erk5 may be performing these roles. To investigate the role of the Mek5/Erk5 kinase axis in SCLC, we will utilize patient-derived xenografts (PDXs) and a genetically-engineered mouse model of SCLC. We first propose to determine if the Mek5/Erk5 axis is necessary for SCLC initiation and progression in mice in vivo. Second, we will investigate the role of Mek5/Erk5 in SCLC maintenance using genetic and pharmacological approaches. Third, we will perform structure-function studies and use advanced proteomics to investigate the mechanisms of action of Erk5 in SCLC cells. This study will characterize a novel non-mutated tumorigenic signaling pathway in the development of SCLC. We hope that a better understanding of the mechanisms underlying SCLC development will aid to identify novel therapeutic approaches for patient treatment.

描述（由适用提供）：小细胞肺癌（SCLC）每年在全球享有超过200,000人的生命，并且对于这种致命而没有有效的疗法疾病。除了SCLC启动所需的RB和p53肿瘤补充剂的通用损失外，仍未确定驱动SCLC进展的关键途径。我们的长期目标是了解导致SCLC进攻性行程的分子事件。对100多个人类SCLC肿瘤的基因组进行测序的最新努力已经确定了罕见的致癌突变和一些正在放大的区域，但是这些分析未能揭示可能驱动这种癌症发展的中心致癌途径。最近，出现了非癌基因成瘾的概念，该概念指出癌症可能需要某些没有被突变标记的活性分子途径。因此，活跃但未突变的信号传导传感器（例如激酶）可能在癌症的发展中起关键作用，同时通过测序方法未被发现。使用新颖的蛋白质组学方法，我们最近获得了SCLC活性Kinome的第一视图。在SCLC中的活跃激酶中，MEK5特别有趣。 MEK5及其下游靶标ERK5构成了仍然表征较差的信号通路。新兴的证据表明，类似于较为研究的MEK1/2-ERK1/2途径，MEK5/ERK5轴也可能调节细胞存活和循环。 MEK5和ERK5从未在SCLC细胞中研究过，并且对它们在癌症中的作用一般鲜为人知。在这里，我们假设MEK5/ERK5模块对于SCLC的生长至关重要。我们的初步观察结果支持了这一假设，即MEK5或ERK5缺陷型SCLC细胞表现出严重的生长缺乏并增加凋亡细胞死亡。但是，我们对在有机环境中SCLC开发中对该轴的需求以及MEK5/ERK5如何执行这些角色的要求完全了解。为了研究MEK5/ERK5激酶轴在SCLC中的作用，我们将利用患者衍生的Xenographing（PDXS）和SCLC的遗传工程小鼠模型。我们首先提出的是确定MEK5/ERK5轴是否需要SCLC倡议和体内小鼠的进展。其次，我们将使用遗传和药物方法研究MEK5/ERK5在SCLC维持中的作用。第三，我们将进行结构功能研究，并使用晚期蛋白质组学来研究ERK5在SCLC细胞中的作用机理。这项研究将表征SCLC发育中新型的非突变肿瘤信号传导途径。我们希望更好地了解SCLC开发的机制将有助于确定新型的患者治疗方法。