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.

项目概要/摘要 从不吸烟者中非小细胞肺癌（NSCLC）的发病率正在迅速增加，其病因学 这种疾病与吸烟引起的疾病不同，因为大多数人从未吸烟。 患有 NSCLC 的吸烟者是表皮生长因子受体 (EGFR) 突变的女性和肿瘤患者 基因普遍存在（~50%），女性受这种疾病影响的比例较高，这促使人们进行了一项调查。 关于雌激素对肺部肿瘤发生的贡献，母公司 R01 实验室的重点是第一个。 报道称，人类肺部通常可以将雌激素代谢为反应性儿茶酚。 雌激素代谢物 4-羟基雌激素 (4-OHE) 转化正常人肺细胞的研究已被证实 为了补充这些实验，Krzizike 博士是一位技术精湛的独立人士。 该多样性补充品的研究者和候选人最近建立了一种高度灵敏的检测方法 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。 他的新质谱方法对母公司 R01 资助的实验将进一步发挥作用 正在进行的体外、体内和临床研究使我们能够： 将致癌 4- 的产生关联起来 OHE 具有雌激素转化正常人支气管上皮细胞并引起 DNA 的既定能力 损伤（目标 1）；建立内部 UPLC-MS/MS 测定法，用于雌激素种类的提取和定量 肺组织中的雌激素代谢谱（目标 2）；并将健康、无癌症女性的尿雌激素代谢谱与 NSCLC 患者的代谢水平，并确定治疗前和治疗前代谢水平的固有个体间差异 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，导致 尽管经历了这些逆境，他仍然坚持不懈地进行了 30 多次手术并最终截肢。 他的主要导师是玛吉·克拉珀 (Margie Clapper) 博士，并成为质谱设施的主任。 过去 18 个月里，他一直在雌激素项目上与格雷格·戈尔曼 (Greg Gorman) 博士合作。 生物样本分析，将作为小分子定量、肺癌、 雌激素代谢对于 Krzizike 博士来说是全新的，并提供了令人兴奋的职业机会 指导将包括正式的技术培训、设施管理、资助写作、口头交流。 展示研究结果、指导他人并为具有类似情况的癌症研究人员提供支持 重要的是，Krzizike 博士的结果将作为他向该机构提交的第一笔拨款的初步数据。 NCI 在测量生物样本中雌激素种类方面的新兴专业知识将独特地利用 在父母 R01 的指导下进行的研究将使他能够为我们做出重大贡献。 了解从不吸烟者的非小细胞肺癌的病因，并恢复他的职业轨迹以实现他的目标 成为质谱设施的主任。