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：
8987941
负责人：
MARTIN MCMAHON
金额：
$ 32.98万
依托单位：
UNIVERSITY OF UTAH
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 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8987941
关键词：
1-Phosphatidylinositol 3-Kinase Address Alleles Apoptosis Behavior Benign Biochemistry Biological Markers Biological Models Cancer Patient Cell Cycle Cell Line Cellular biology Cessation of life Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats DNA Sequence Alteration Databases Dependency Development Disease Disease Resistance Dissociation Drug resistance Evaluation Event Experimental Models Extracellular Signal Regulated Kinases Foundations Future Gene Silencing Genes Genetic Genetic study Genetically Engineered Mouse Genome Genomics Goals Grant Growth Human In Vitro Investigation Lesion Ligands Lipids Lung Lung Adenocarcinoma Lung Neoplasms MEKs Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mining Minority Molecular Molecular Abnormality Molecular Mechanisms of Action Mus Mutagenesis Mutation Normal Cell Oncogene Activation Oncogenes Oncogenic PDPK1 gene PTEN gene Pathogenesis Pathway interactions Patients Phase Physicians Play Porcupines Process Prognostic Marker Protein Array Analysis Proto-Oncogene Proteins c-akt Publishing RNA Sequences Radiosurgery Research Resources Risk Role Scientist Scourge Signal Pathway Signal Transduction Sleeping Beauty Solid Specimen Staging Stratification Subfamily lentivirinae System Testing The Cancer Genome Atlas Therapeutic Transferase Tumor Suppressor Genes Ursidae Family Validation WNT Signaling Pathway X-Ray Computed Tomography anticancer research antitumor effect base beta catenin cDNA Expression cancer genetics cancer initiation cancer therapy chemotherapy clinically relevant design evidence base in vivo in vivo Model inhibitor/antagonist innovation lung carcinogenesis lung tumorigenesis mouse model neoplastic cell novel public health relevance research study response senescence statistics targeted treatment therapeutic target tool transcriptome sequencing tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is a global scourge responsible for 1.4 million deaths worldwide and ~160,000 deaths in the USA this year alone. Despite the grim clinical picture, cancer genetics has revealed that lung cancers can be divided into genetically-defined subsets based on driver oncogene mutations that, in turn, serve as predictive biomarkers for the clinical deployment of new first-line pathway-targeted therapies in lung cancer patients. However, to date, only a minority of such patients have benefitted from these advances such that treatment options for most patients remain poor and are limited to conventional approaches including surgery, radiation, and/or conventional chemotherapy that are ineffective against tumor cells and toxic to normal cells. The overarching, long-term goal of this research is to aid the deployment of rational, evidence-based therapeutic strategies to treat lung cancer patients. However, the immediate objectives of this proposal are to mechanistically define how parallel pathways, such as WNT→ß-catenin→c-MYC or PI3'-kinase→PDK→AKT signaling, cooperate with oncogenic KRASG12D or BRAFV600E in the genesis and maintenance of lung cancer. To do so we will use: State-of-the-art genetically engineered mouse models of lung cancer; Lung cancer- derived cell lines whose aberrant behavior is driven by relevant genetic abnormalities; Pathway-targeted therapeutics, many of which are in cancer clinical trials and one of which is specifically being tested in lung cancer and; An innovative transposon mutagenesis system to simultaneously elicit lung cancer progression and identify its underlying genetic cause. Building on a solid foundation of studies published in the previous cycle of this grant, in Aim 1 we will identify the tumor cell autonomous mechanisms by which WNT→ß-catenin signaling cooperates with oncogenic KRASG12D or BRAFV600E in the genesis and maintenance of lung cancer. In Aim 2 we will explore the mechanisms by which PI3'-kinase signaling promotes the proliferative expansion and maintenance of both early- and late-stage BRAFV600E-induced lung tumors. BRAFV600E-induced lung tumors remain uniformly benign unless cooperating genomic events unleash malignant progression. In Aim 3 document the use of Sleeping Beauty (SB) transposon mutagenesis to promote progression of BRAFV600E- driven lung cancers. Genetic progression factors identified will be validated using lentivirus-mediated cDNA expression or by in vivo CRISPR/Cas9-mediated tumor suppressor gene silencing in the mouse lung. Moreover, we will mine the TCGA lung adenocarcinoma genome, RNA sequencing and RPPA databases to credential genes implicated in our SB screen in mice as being directly relevant to bona fide human lung cancer. Finally, although this proposal is focused primarily on studies of genetic cooperation in the genesis of lung cancer, we will test the anti-tumor effects of novel pathway-targeted inhibitors of BRAFV600E, WNT or PI3'- kinase signaling that are likely to have important translational implications for the design and evaluation of new pathway-targeted strategies to treat patients with this ubiquitous, devastating and poorly understood disease.

描述（由适用提供）：肺癌是全球造成全球140万人死亡的全球气泡，仅在今年美国，美国的死亡人数约为160,000人。尽管存在严峻的临床情况，但癌症遗传学表明，基于驱动器癌基因突变，肺癌可以分为遗传定义的子集，而肺癌患者中新的一线线途径针对新的一线途径疗法的预测生物标志物。但是，迄今为止，只有少数此类患者从这些进步中受益于大多数患者的治疗选择，并且仅限于传统方法，包括手术，放射线和/或常规化学疗法，这些方法对肿瘤细胞无效，对正常细胞有毒。这项研究的总体长期目标是帮助部署理性的，基于证据的治疗策略来治疗肺癌患者。但是，该提案的直接目标是机械定义平行途径，例如Wnt→ß-catenin→C-Myc或Pi3'-kinase→PDK→PDK→AKT信号传导，与致癌性KRASG12D或BRAFV600E相协调。为此，我们将使用：最先进的肺癌基因工程小鼠模型；肺癌衍生的细胞系，其异常行为是由相关遗传异常驱动的；针对途径的疗法，其中许多是在癌症临床试验中，其中一项是在肺癌中进行的，其中之一是在肺癌中进行的。一种创新的转座子诱变系统，可同时引起肺癌的进展并确定其潜在的遗传原因。基于本赠款上一个赠款周期发表的坚实的研究基础，在AIM 1中，我们将确定Wnt→ß-catenin信号通过与致癌的Krasg12d或Brafv600E合作的肿瘤细胞自主机制。在AIM 2中，我们将探讨PI3'-激酶信号传导促进早期和晚期BRAFV600E诱导的肺肿瘤的增殖扩张和维持的机制，除非除非具有恶性进展，否则除非进行基因组进展，否则在AIM 3中，记录了使用“睡美人”（SB）转座子诱变来促进BRAFV600E驱动的肺癌的进展。遗传进展因子将使用慢病毒介导的cDNA表达或体内CRISPR/CAS9介导的小鼠肺中的肿瘤抑制基因沉默来验证。此外，我们将把TCGA肺腺癌基因组，RNA测序和RPPA数据库挖掘为在我们的SB筛查中实现的凭证基因，因为它与真正的人类肺癌直接相关。最后，尽管该提案主要集中在肺癌生成中的遗传合作研究上，但我们将测试新型途径针对BRAFV600E，WNT或PI3'-激酶信号的抗肿瘤效应，这些抑制剂可能对新的Pathway策略疾病的差异和评估有重要的翻译和评估，这些疾病可能对dep dep dep dep deptiquity ob deventiquical of the ub deptip of the ub deventip and teperation。