Studying the initiation, progression and therapy of lung cancer in mouse models

研究小鼠模型肺癌的发生、进展和治疗

基本信息

批准号：
8225394
负责人：
MARTIN MCMAHON
金额：
$ 33.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225394
关键词：
Adenocarcinoma Adenoviruses Alleles Apoptosis Applications Grants BRAF gene Benign Biochemistry Biological Cancer Biology Cancer Patient Cancer cell line Cell Cycle Cell Cycle Progression Cell Line Cell Proliferation Cells Cellular biology Cessation of life Development Disease Dissociation Employee Strikes Engineering Epidermal Growth Factor Receptor Epithelium Evaluation Event Extracellular Signal Regulated Kinases Gene Dosage Gene Expression Gene Mutation Gene Silencing Genes Genetically Engineered Mouse Goals Health Histology Human In Vitro Infection Investigation KRAS2 gene Lung Lung Neoplasms MAP Kinase Signaling Pathways MAP2K1 gene MEK inhibition MEKs Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mission Modeling Monitor Mus Mutate Mutation National Cancer Institute Oncogene Activation Oncogenes Oncogenic Pathogenesis Pathway interactions Patients Phase I Clinical Trials Physiology Play Prevalence Relapse Research Role Signal Pathway Signal Transduction Signal Transduction Pathway Specimen Testing Therapeutic Time Tumor Biology Tumor Burden Tumor Suppressor Genes anticancer research cancer cell cancer genetics cancer initiation cancer therapy design drug mechanism head-to-head comparison in vivo inhibitor/antagonist lung carcinogenesis lung tumorigenesis mortality mouse model neoplastic cell outcome forecast programs recombinase research study response senescence tumor tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is an extraordinarily common, devastating and poorly understood disease responsible for ~160,000 deaths/year in the USA and 1.4 million deaths/year worldwide. Despite its prevalence and strikingly high mortality rates, the origins of the disease remain poorly understood and therapeutic approaches to treat lung cancer patients have proven disappointingly ineffective. The dismal prognosis for patients with advanced lung cancer emphasizes the urgent need for new chemotherapeutic approaches to treat this disease. The overarching, long-term goal of this research program is to aid development of rational therapeutic strategies to treat lung cancer patients, in full accord with the central mission of the National Cancer Institute. However, the immediate objective of this proposal is to explore the role of the Ras-activated RAF->MEK->ERK MAP kinase signal transduction pathway in the initiation, progression and therapy of lung cancer. This pathway is directly implicated in the aberrant physiology of lung cancer cells due to the prevalence of mutations in genes encoding the EGF receptor, KRAS or BRAF observed in primary patient specimens and human lung cancer derived cell lines. The central hypothesis of this grant proposal is that oncogenic KRasG12D or BRafV600E can initiate and maintain tumorigenesis in mouse models of human lung cancer through activation of the RAF->MEK->ERK pathway. Consequently we shall use genetically engineered KRasLSL and BRafCA mice, in which oncogene expression is initiated in the lung epithelium by infection with an adenovirus expressing Cre recombinase, to conduct an in-depth exploration of the role of oncogenic KRasG12D or BRafV600E in lung tumor initiation, progression and therapy. In Aim 1 we will conduct a head-to-head comparison between KRasG12D- and BRafV600E-induced lung tumorigenesis to determine why the former progresses to adenocarcinoma while the latter does not. Next, to test the importance of RAF->MEK->ERK signaling downstream of KRasG12D-induced lung tumorigenesis, we will test the anti-tumor effects of potent, specific and selective pharmacological inhibitors of either RAF (SB590885) or MEK1/2 (PD0325901) using the KRasLSL mouse model of lung tumorigenesis. In Aim 2 we will test the hypothesis that the loss of the Ink4a/Arf, Pten or Trp53 tumor suppressor genes can influence the response of KRasG12D- or BRafV600E-induced lung tumors to pharmacological inhibition of RAF or MEK using mice, and human and mouse lung cancer derived cell lines. Finally, in Aim 3, we will utilize our recently derived BRafFA mice, in which oncogenic BRafV600E expression is initiated by Flp recombinase, to assess how temporal dissociation of oncogene activation and tumor suppressor gene silencing influences tumor initiation, progression and senescence. Although this proposal is focused primarily on studies of the role of tumor suppressor and oncogene action on tumor biology and on mechanisms of drug response in mouse models of lung cancer, this research has potentially important translational significance in the design and evaluation of new targeted strategies to treat lung cancer patients. PUBLIC HEALTH RELEVANCE: Lung cancer is a remarkably common, devastating and poorly understood disease responsible for ~160,000 deaths/year in the USA and 1.4 million deaths/year worldwide. Here, we propose the use of sophisticated genetically engineered mouse models of cancer and new targeted pharmacological inhibitors of cell signaling pathways to explore the importance of tumor suppressors and oncogenes in lung cancer initiation, progression and therapy. The long-term goal of these experiments is the development of new and rationally designed strategies to more effectively treat lung cancer patients.

描述（由申请人提供）：肺癌是一种非常普遍的，毁灭性的且理解不足的疾病，造成约160,000人死亡，在美国，全球140万人死亡。尽管该疾病的起源率很高，但该疾病的起源仍然很糟糕，治疗肺癌患者的治疗方法仍然令人失望地无效。晚期肺癌患者的惨淡预后强调了对治疗这种疾病的新化学治疗方法的迫切需求。该研究计划的总体长期目标是帮助制定理性的治疗策略来治疗肺癌患者，这完全符合国家癌症研究所的核心任务。但是，该提案的直接目的是探索RAS激活的RAF-> Mek-> Mek-> ERK MAP激酶信号转导途径在肺癌的启动，进展和治疗中的作用。该途径直接与肺癌细胞的异常生理有关，因为在原发性患者标本和人类肺癌衍生的细胞系中观察到的编码EGF受体，KRAS或BRAF的基因的普遍存在。该赠款提案的中心假设是，通过激活RAF-> MEK-> ERK途径，致癌性KRASG12D或BRAFV600E可以在人肺癌小鼠模型中启动和维持肿瘤发生。因此，我们将使用基因设计的KRASLSL和BRAFCA小鼠，其中通过表达CRE重组酶的腺病毒感染在肺上皮中发起癌基因表达，以深入探索致癌性Krasg12d或Brafv600E在肺中的肿瘤tumor tumor tumoraper anditiation，progiperiation，progiperiation and theriperiation and theriveriation and therive and theriperiation and theriperiation and therive and therive and therive and therive and therive and the and CrafV600E。在AIM 1中，我们将在KRASG12D-和BRAFV600E诱导的肺部肿瘤发生之间进行正面比较，以确定为什么前者会发展为腺癌而后者没有。接下来，为了测试KRASG12D诱导的肺部肿瘤发生下游的Raf-> Mek-> ERK信号传导的重要性，我们将测试使用RAF（SB59085）的有效，特定和选择性药理抑制剂的抗肿瘤作用（SB59085）或MEK1/2（MEK1/2）使用KRASER模型。在AIM 2中，我们将检验以下假设：INK4A/ARF，PTEN或TRP53肿瘤抑制基因的丧失会影响KRASG12D-或BRAFV600E诱导的肺肿瘤对使用小鼠的RAF或MEK药理抑制RAF或Hunder Lung Lung肺癌细胞系的反应。最后，在AIM 3中，我们将利用我们最近衍生的Braffa小鼠，其中FLP重组酶发起了致癌性BRAFV600E表达，以评估癌基因激活和肿瘤抑制基因沉默的时间分离如何产生肿瘤的起步，进展和衰老。尽管该建议主要集中在研究肺癌小鼠模型中肿瘤抑制剂和癌基因作用对肿瘤生物学的作用以及对药物反应机制的作用，但该研究在设计和评估治疗肺癌患者的新靶向策略方面具有潜在的重要翻译意义。公共卫生相关性：肺癌是一种非常普遍的，毁灭性的且知识熟悉的疾病，造成约16万人死亡，全球约16万人死亡，每年140万人死亡。在这里，我们提出使用复杂的癌症基因工程小鼠模型以及细胞信号通路的新靶向药理抑制剂，以探索肿瘤抑制因子和癌基因在肺癌开始，进展和治疗中的重要性。这些实验的长期目标是开发新的和理性设计的策略，以更有效地治疗肺癌患者。