Lung Cancer in Never-smokers: Role of Estrogen and its Metabolites

从不吸烟者的肺癌：雌激素及其代谢物的作用

• 批准号: 10310863
• 负责人: MARGIE L. CLAPPER
• 金额: $ 19.92万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310863
• 关键词: Advocate; Affect; Amputation; Area; Award; Biological Assay; Catechols; Cell Culture Techniques; Cells; Clinical Research; Culture Media; DNA Damage; Data; Disease; EGFR gene; Epithelial Cells; Estrogen Metabolism; Estrogens; Etiology; Female; Funding; Goals; Grant; Human; In Vitro; Incidence; Injury; Interruption; Investigation; Leg; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measurement; Mentors; Methods; Mutation; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Oral; Parents; Patients; Postmenopause; Premenopause; Production; Reporting; Research; Research Personnel; Role; Smoking; Structure of parenchyma of lung; Training; Urine; Woman; Writing; bronchial epithelium; carcinogenicity; career; career development; disability; experimental study; in vivo; insight; inter-individual variation; lung tumorigenesis; never smoker; novel; small molecule; tissue culture; tumor; tumor metabolism; urinary; Advocate; Affect; Amputation; Area; Award; Biological Assay; Catechols; Cell Culture Techniques; Cells; Clinical Research; Culture Media; DNA Damage; Data; Disease; EGFR gene; Epithelial Cells; Estrogen Metabolism; Estrogens; Etiology; Female; Funding; Goals; Grant; Human; In Vitro; Incidence; Injury; Interruption; Investigation; Leg; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measurement; Mentors; Methods; Mutation; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Oral; Parents; Patients; Postmenopause; Premenopause; Production; Reporting; Research; Research Personnel; Role; Smoking; Structure of parenchyma of lung; Training; Urine; Woman; Writing; bronchial epithelium; carcinogenicity; career; career development; disability; experimental study; in vivo; insight; inter-individual variation; lung tumorigenesis; never smoker; novel; small molecule; tissue culture; tumor; tumor metabolism; urinary

Project Summary/Abstract The incidence of non-small cell lung cancer (NSCLC) among never-smokers is increasing rapidly and its etiology remains unknown. This disease entity is distinct from that attributed to smoking, given that the majority of never- smokers with NSCLC are women and tumors with mutations in the Epidermal Growth Factor Receptor (EGFR) gene are prevalent (~50%). The predominance of females affected by this disease has prompted an investigation of the contribution of estrogen to lung tumorigenesis, the focus of the parent R01. The Clapper lab is the first to report that the human lung can extensively metabolize estrogen to reactive catechols. Most recently, the ability of the estrogen metabolite 4-hydroxyestrogen (4-OHE) to transform normal human lung cells has been demonstrated by this group. To compliment these experiments, Dr. Krzizike, a highly skilled independent investigator and candidate for this Diversity Supplement, has recently established a highly sensitive assay for the quantitation of 11 estrogens (parent estrogens and metabolites) in urine and tissue culture media. Application of his new mass spectrometry method to the experimentation funded under the parent R01 will further leverage the in vitro, in vivo and clinical studies in progress by allowing us to: correlate the production of carcinogenic 4- OHE with the established ability of estrogen to transform normal human bronchial epithelial cells and cause DNA damage (Aim 1); establish a UPLC-MS/MS assay inhouse for the extraction and quantitation of estrogen species in lung tissue (Aim 2); and compare the urinary estrogen metabolite profile of healthy, cancer-free women with that of patients with NSCLC and establish the inherent inter-individual variability in metabolite levels in pre- and post-menopausal women (Aim 3). Dr. Krzizike is an independent investigator whose career trajectory was interrupted by an injury resulting in more than 30 surgeries and the ultimate amputation of his leg. Despite these adversities, he remains dedicated to becoming the Director of a mass spectrometry facility. His primary mentor will be Dr. Margie Clapper, with whom he has been collaborating for the past 18 months on the estrogen project. Dr. Greg Gorman, an expert in the analysis of biospecimens, will serve as a co-mentor. The fields of small molecule quantitation, lung cancer, and estrogen metabolism are completely new to Dr. Krzizike and present exciting opportunities for career development. Mentoring will include formal technical training, facility management, grant writing, oral presentation of findings, mentoring others and serving as an advocate for cancer researchers with similar disabilities. Importantly, Dr. Krzizike’s results will serve as preliminary data for his first grant submissions to the NCI. His emerging expertise in the measurement of estrogen species in biosamples will uniquely leverage the studies under the parent R01. The present award will allow him to both contribute significantly to our understanding of the etiology of NSCLC in never-smokers and resume his career trajectory towards his goal of becoming the Director of a mass spectrometry facility.

项目摘要/摘要 从未吸烟者中非小细胞肺癌（NSCLC）的事件正在迅速增加及其病因 仍然未知。鉴于大多数从未 - NSCLC的吸烟者是女性和表皮生长因子受体（EGFR）突变的肿瘤 基因普遍（〜50％）。受这种疾病影响的女性的占主导地位已引发了调查 雌激素对肺肿瘤发生的贡献，是母r01的重点。拍手实验室是第一个 报告说，人肺可以将雌激素广泛代谢为反应性儿茶酚。最近，能力 雌激素代谢产物4-羟基雌激素（4-OHE）以转化正常的人肺细胞 由这个小组展示。为了补充这些实验，Krzizike博士是一个高技能的独立 该多样性补充的研究者和候选人最近建立了一种高度敏感的测定法 尿液和组织培养基中11种雌激素（母雌激素和代谢产物）的定量。应用 他的新质谱法针对父母R01资助的实验将进一步利用 体外，体内和临床研究正在进行中，通过允许我们：致癌4-的产生 OHE具有雌激素改变正常人支气管上皮细胞并引起DNA的既定能力 损坏（目标1）；建立用于提取和定量雌激素物种的UPLC-MS/MS分析 在肺组织中（AIM 2）；并比较健康的无癌女性的尿中雌激素代谢物与 NSCLC患者的代谢物水平和代谢水平的遗传性变异 绝经后妇女（AIM 3）。 Krzizike博士是一名独立调查员，其职业轨迹被伤害打断了 超过30次手术和腿的最终截肢。尽管有这些逆境，他仍然敬业 成为质谱设施的主任。他的主要导师将是Margie Clapper博士， 在过去的18个月中，他一直在雌激素项目上合作。 Greg Gorman博士，专家 生物测量的分析将作为同事。小分子定量，肺癌的领域 雌激素代谢对Krzizike博士来说是全新的，并为职业生涯提供了令人兴奋的机会 发展。指导将包括正式的技术培训，设施管理，赠款写作，口头 介绍发现，指导他人并担任具有类似癌症研究人员的倡导者 残疾。重要的是，Krzizike博士的结果将作为其首次提交给他的赠款的初步数据 NCI。他在生物样本中测量雌激素物种方面的新兴专业知识将唯一利用 父母R01的研究。目前的奖项将使他既可以为我们的 了解NSCLC在永不吸烟者中的病因，并恢复他的职业轨迹 成为质谱设施的主任。