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

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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.