EGFR PATHWAY ALTERATIONS IN LUNG TUMORS

肺肿瘤中 EGFR 通路的改变

• 批准号: 7382082
• 负责人: Angeline Sanderson Andrew
• 金额: $ 5.5万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382082
• 关键词: EGFR; PATHWAY; ALTERATIONS; LUNG; TUMORS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed research project capitalizes on existing institutional strengths in toxic metals research, lung carcinogenesis, and builds on the current lung COBRE projects. Specifically, this proposal brings Dr. Andrew¿s extensive nickel toxicology and molecular epidemiology research experience together with the airborne particulate matter nickel monitoring efforts of COBRE Project 4, exposure information and biologic samples collected through a new lung cancer case-control study (COBRE Project 5), and the Dmitrovsky group¿s expertise in the epidermal growth factor receptor (EGFR) pathway obtained through molecular characterization and clinical trials. Background ¿ Epidermal growth factor receptor (EGFR) over-expression is frequently observed in lung tumors and bronchial pre-neoplasia and induces tumor formation in animal studies. EGFR regulates cell survival, cell-cycle progression, tumor invasion, and angiogenesis. In previous work, EGFR affected expression of the common downstream cell cycle regulator, cyclin D1 both in vitro and in vivo using clinical material. Therapeutic efficacy with EGFR tyrosine kinase inhibitors (EGFR-TKI) is already being observed in clinical trials that aim to treat non-small cell lung cancer (NSCLC) by blocking EGFR activation. Yet, these EGFR-TKI clinical trials clearly show that responsiveness between patients varies dramatically, and reliable predictors have not been identified or validated. Despite the clinical importance of this pathway, those specific factors that cause alterations in EGFR remain largely unknown. Specifically, somatic mutations of unknown environmental origin in the EGFR tyrosine kinase domain correlated tightly with EGFR-TKI efficacy and the mutation rate was higher in non-smokers. Hypothesis - As a genotoxic, mutagenic and carcinogenic metal of concern, we hypothesize that nickel exposure via inhalation of airborne particulate matter alters EGFR signaling and or promotes mutations in the EGFR gene. Previous studies and our own preliminary data suggest that nickel induces EGFR expression in cell culture [Mollerup, 1996 #5129]. We propose to investigate the role of nickel in EGFR pathway regulation in two experimental systems: 1) in cell culture using the BEAS2B human lung epithelial cell lines, and 2) in tumor specimens obtained from early stage non-small cell lung cancer cases. Relevance - These studies will provide new mechanistic insights into specific components of air pollution (e.g. nickel) that promote lung carcinogenesis. Characterizing an exposure that impacts the EGFR signaling pathway will help optimize use of targeted screening and molecular diagnostics. We can then identify subsets of potentially responsive cases and who will benefit from pharmacologic EGFR inhibition as a therapeutic strategy in the lung. Specific Aims: 1) To evaluate whether toxic metal (arsenic, nickel) exposure is associated with A) EGFR TK domain somatic activating mutations B) EGFR, p-EGFR, cyclin D1 protein levels 2) To investigate the effect of EGFR, cyclin D1 genetic polymorphisms on EGFR pathway protein levels and lung cancer risk. EGFR SNPs a stabilizing cyclin D1 genetic variation 3) To validate the clinical strategy of targeting EGFR and cyclin D1 Co-regulation of p-EGFR and cyclin D1 EGFR mutations vs. clinical response to combination therapy

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。拟议的研究项目利用现有的机构优势，在有毒金属研究，肺癌，并建立在目前的肺COBRE项目。具体而言，该提案将Andrew博士丰富的镍毒理学和分子流行病学研究经验与COBRE项目4的空气颗粒物镍监测工作、暴露信息和通过新的肺癌病例对照研究收集的生物样本结合在一起（COBRE项目5），和Dmitrovsky集团通过分子表征和临床试验获得的表皮生长因子受体（EGFR）途径的专业知识。 背景？表皮生长因子受体（EGFR）过度表达经常在肺肿瘤和支气管癌前病变中观察到，并在动物研究中诱导肿瘤形成。 EGFR调节细胞存活、细胞周期进展、肿瘤侵袭和血管生成。在以前的工作中，EGFR影响表达的共同下游细胞周期调节因子，细胞周期蛋白D1在体外和体内使用临床材料。 EGFR酪氨酸激酶抑制剂（EGFR-TKI）的疗效已在旨在通过阻断EGFR活化治疗非小细胞肺癌（NSCLC）的临床试验中观察到。然而，这些EGFR-TKI临床试验清楚地表明，患者之间的反应性差异很大，可靠的预测因子尚未确定或验证。尽管该途径具有临床重要性，但导致EGFR改变的那些特定因素在很大程度上仍然未知。具体而言，EGFR酪氨酸激酶结构域中未知环境来源的体细胞突变与EGFR-TKI疗效密切相关，并且非吸烟者的突变率更高。 假设-作为一种遗传毒性、致突变性和致癌性金属，我们假设通过吸入空气颗粒物暴露于镍会改变EGFR信号传导和/或促进EGFR基因突变。 先前的研究和我们自己的初步数据表明，镍诱导细胞培养物中的EGFR表达[Mollerup，1996 #5129]。我们建议在两个实验系统中研究镍在EGFR通路调节中的作用：1）在使用BEAS 2B人肺上皮细胞系的细胞培养中，和2）在从早期非小细胞肺癌病例获得的肿瘤标本中。 相关性-这些研究将为空气污染中促进肺癌发生的具体成分（如镍）提供新的机理见解。表征影响EGFR信号通路的暴露将有助于优化靶向筛查和分子诊断的使用。然后，我们可以确定潜在的反应病例的子集，谁将受益于药理学EGFR抑制作为肺部治疗策略。 具体目标：1）评价毒性金属（砷、镍）暴露是否与A）EGFR TK结构域体细胞激活突变B）EGFR、p-EGFR、cyclin D1蛋白水平相关2）研究EGFR、cyclin D1基因多态性对EGFR通路蛋白水平和肺癌风险的影响。 EGFR SNP a稳定性细胞周期蛋白D1遗传变异3）验证靶向EGFR和细胞周期蛋白D1的临床策略p-EGFR和细胞周期蛋白D1 EGFR突变的共调节与对组合疗法的临床应答