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

项目摘要/摘要 非吸烟者中非小细胞肺癌(NSCLC)的发病率迅速上升及其病因 仍然不为人知。这种疾病与吸烟所致的疾病是不同的，因为大多数从不- 患有非小细胞肺癌的吸烟者是表皮生长因子受体(EGFR)突变的女性和肿瘤患者 基因占优势(~50%)。受这种疾病影响的女性占多数，这促使了一项调查 雌激素在肺癌发生中的作用，是亲本R01关注的焦点。克拉珀实验室是第一个 有报道称，人的肺可以将雌激素广泛代谢为反应性儿茶酚。最近，这种能力 雌激素代谢产物4-羟基雌激素(4-OHE)转化正常人肺细胞的研究进展 由这群人证明。为了赞扬这些实验，Krzizike博士，一位高度熟练的独立人士 研究人员和这一多样性补充的候选人，最近建立了一种高度敏感的分析方法 尿液和组织培养上清液中11种雌激素(母体雌激素和代谢物)的定量。应用 他的新的质谱学方法在母公司R01下资助的实验将进一步发挥杠杆作用 正在进行的体外、体内和临床研究使我们能够：将致癌物质4- 雌激素具有转化正常人支气管上皮细胞并产生DNA的能力 损害(目标1)；建立UPLC-MS/MS室内分析方法，用于雌激素种类的提取和定量 肺组织中的雌激素代谢产物(目标2)；并比较健康、无癌妇女和 并建立非小细胞肺癌患者体内代谢产物水平的个体间固有变异。 绝经后妇女(目标3)。 Krzizike博士是一名独立调查员，他的职业轨迹因一次受伤而中断 30多次手术和最终的腿部截肢。尽管有这些逆境，他仍然全力以赴。 成为一家质谱学机构的负责人。他的主要导师将是Margie Clapper博士， 在过去的18个月里，他一直在与他合作进行雌激素项目。格雷格·戈尔曼博士是一位 生物标本的分析，将作为共同导师。小分子定量、肺癌、 和雌激素代谢对Krzizike博士来说是全新的，并提供了令人兴奋的职业机会 发展。辅导将包括正式的技术培训、设施管理、赠款撰写、口头 介绍研究结果，指导其他人，并为具有类似知识的癌症研究人员提供倡导 残疾人士。重要的是，Krzizike博士的结果将作为他向 美国国家情报局。他在生物样本中雌激素种类测量方面的新兴专业知识将独特地利用 在父母R01的指导下学习。这一奖项将使他既能为我们的 了解非吸烟者非小细胞肺癌的病因，并恢复他的职业轨迹，朝着他的目标 成为一家质谱学机构的负责人。

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.