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

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.

项目总结/摘要 非小细胞肺癌（NSCLC）在不吸烟人群中的发病率正在迅速增加，其病因 仍然未知。这种疾病实体与归因于吸烟的疾病实体不同，因为大多数从未- 患有NSCLC的吸烟者是表皮生长因子受体（EGFR）突变的女性和肿瘤 基因是普遍的（~50%）。受这种疾病影响的女性占多数，这促使人们进行调查。 雌激素对肺肿瘤发生的作用，这是亲本R 01的重点。克拉珀实验室是第一个 报告说，人的肺可以广泛代谢雌激素反应儿茶酚。最近， 雌激素代谢物4-羟基雌激素（4-OHE）转化正常人肺细胞的作用已经被证实。 这一组的表现。为了配合这些实验，Krzizike博士，一个高度熟练的独立 该多样性补充物的研究者和候选者，最近建立了一种高度敏感的测定方法， 尿液和组织培养基中11种雌激素（母体雌激素和代谢物）的定量。应用 他的新质谱法的实验资助下的母公司R 01将进一步利用 体外，体内和临床研究的进展，使我们能够：相关的生产致癌4- OHE具有雌激素转化正常人支气管上皮细胞并导致DNA 损伤（目标1）;建立用于提取和定量雌激素物质的内部UPLC-MS/MS测定法 在肺组织中（目标2）;并比较健康，无癌妇女的尿雌激素代谢产物， NSCLC患者的代谢物水平，并确定治疗前和治疗后代谢物水平的固有个体间变异性。 绝经后妇女（目标3）。 Krzizike博士是一名独立调查员，他的职业轨迹因受伤而中断， 超过30次手术，最后截肢。尽管有这些逆境，他仍然致力于 成为质谱仪的主管他的主要导师将是玛吉·克拉珀博士， 在过去的18个月里，他一直在与她合作研究雌激素项目。格雷格·戈尔曼博士， 生物样本分析，将作为一个共同导师。小分子定量，肺癌， 和雌激素代谢是完全新的博士Krzizike和目前令人兴奋的职业机会 发展指导将包括正式的技术培训，设施管理，赠款写作，口头 介绍研究结果，指导他人，并作为癌症研究人员的倡导者， 残疾。重要的是，Krzizike博士的研究结果将作为他首次向美国国家科学院提交资助申请的初步数据。 NCI他在测量生物样品中雌激素种类方面的新兴专业知识将独特地利用 在父R 01下进行研究。目前的奖项将使他既作出重大贡献，我们的 了解从不吸烟者中NSCLC的病因，并恢复他的职业轨迹， 成为一个质谱分析机构的主管