This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed research project capitalizes on existing institutional strengths in toxic metals research, lung carcinogenesis, and builds on the current lung COBRE projects. Specifically, this proposal brings Dr. Andrew s extensive nickel toxicology and molecular epidemiology research experience together with the airborne particulate matter nickel monitoring efforts of COBRE Project 4, exposure information and biologic samples collected through a new lung cancer case-control study (COBRE Project 5), and the Dmitrovsky group s expertise in the epidermal growth factor receptor (EGFR) pathway obtained through molecular characterization and clinical trials. Background Epidermal growth factor receptor (EGFR) over-expression is frequently observed in lung tumors and bronchial pre-neoplasia and induces tumor formation in animal studies. EGFR regulates cell survival, cell-cycle progression, tumor invasion, and angiogenesis. In previous work, EGFR affected expression of the common downstream cell cycle regulator, cyclin D1 both in vitro and in vivo using clinical material. Therapeutic efficacy with EGFR tyrosine kinase inhibitors (EGFR-TKI) is already being observed in clinical trials that aim to treat non-small cell lung cancer (NSCLC) by blocking EGFR activation. Yet, these EGFR-TKI clinical trials clearly show that responsiveness between patients varies dramatically, and reliable predictors have not been identified or validated. Despite the clinical importance of this pathway, those specific factors that cause alterations in EGFR remain largely unknown. Specifically, somatic mutations of unknown environmental origin in the EGFR tyrosine kinase domain correlated tightly with EGFR-TKI efficacy and the mutation rate was higher in non-smokers. Hypothesis - As a genotoxic, mutagenic and carcinogenic metal of concern, we hypothesize that nickel exposure via inhalation of airborne particulate matter alters EGFR signaling and or promotes mutations in the EGFR gene. Previous studies and our own preliminary data suggest that nickel induces EGFR expression in cell culture [Mollerup, 1996 #5129]. We propose to investigate the role of nickel in EGFR pathway regulation in two experimental systems: 1) in cell culture using the BEAS2B human lung epithelial cell lines, and 2) in tumor specimens obtained from early stage non-small cell lung cancer cases. Relevance - These studies will provide new mechanistic insights into specific components of air pollution (e.g. nickel) that promote lung carcinogenesis. Characterizing an exposure that impacts the EGFR signaling pathway will help optimize use of targeted screening and molecular diagnostics. We can then identify subsets of potentially responsive cases and who will benefit from pharmacologic EGFR inhibition as a therapeutic strategy in the lung.
Specific Aims : 1) To evaluate whether toxic metal (arsenic, nickel) exposure is associated with A) EGFR TK domain somatic activating mutations B) EGFR, p-EGFR, cyclin D1 protein levels 2) To investigate the effect of EGFR, cyclin D1 genetic polymorphisms on EGFR pathway protein levels and lung cancer risk. EGFR SNPs a stabilizing cyclin D1 genetic variation 3) To validate the clinical strategy of targeting EGFR and cyclin D1 Co-regulation of p-EGFR and cyclin D1 EGFR mutations vs. clinical response to combination therapy
Showing the most recent 10 out of 133 publications
