The goal of the Colorado lung cancer SPORE is to conduct translational studies that can lead to reduction in the lung cancer deaths through improved early diagnosis, prevention and treatment. This SPORE has 5 scientific projects designed to elucidate the role of altered signal pathways in the pathogenesis and progression of lung cancer and to use these alterations as biomarkers for risk, for developing and evaluating new chemoprevention and treatment strategies. Project 1 evaluates the role of semaphorins and VEGF in the angiogenesis and metastases of lung cancer and the role of the WNT pathway and E-cadherin in pathogenesis and progression. Project 2 evaluates the erbB1 pathway and activated signal proteins in the pathogenesis of lung cancer and the relationship between the expression of these activated proteins with proliferation, apoptosis and prognosis using human tissue samples (neoplastic and preneoplastic). These investigators will also study changes induced by EGFR inhibitors in ongoing clinical trials. Project 3 evaluates neuropeptide receptor signaling, especially in lung cancers with neuroendocrine features. This project also evaluates the role of alterations on prognosis in both NSCLC and SCLC with a special emphasis on the development of novel inhibitors (CU201, CU301, CU429) for chemoprevention and therapy. Project 4 studies the role of the eicosanoid pathway. Human tissues are used to define the frequency and prognostic relevance of abnormalities of PLA2, COX2, PGE-2, PGI-2, PGIR, PPAR's and others. A novel chemoprevention strategy, the use of a long acting oral prostacyclin analog (iloprost) is studied pre-clinically (mechanism, combinations) and clinically. Project 5 studies the development of biomarkers of risk and intermediate biomarkers for assessing chemoprevention agents to enhance early detection and prevention. There are 3 initial pilot projects and a career development program. These projects are supported by 5 shared core resources: 1) the Tissue Bank core (contains one of the largest banks of tissues and preneoplastic tissues with matched clinical data and both NSCLC and neuroendocrine tissue microarrays); 2) the Clinical Trial core (has enrolled more than 3200 subjects on various clinical trials and collected samples with clinical data from the subjects); 3) the Biostatistics core has created and maintained the relational database containing clinical and laboratory information; 4) our Animal core provides immunodeficient and genetically altered rodents; and 5) the Administrative core. The prior success is documented by: 1) preclinical and clinical studies of iloprost, and the sunlidac metabolite, exisulind; 2) preclinical studies of CU201 that will lead to clinical trials during the next grant cycle; 3) development of chemoprevention and therapeutic trials using the EGFR inhibitor ZD1839 with analysis of tissue samples to assess response; 4) development of bronchial histology, angiogenic squamous dysplasia, Ki67 and mcm2 as biomarkers; 5) nested case control studies showing that sputum dysplasia and methylation of tumor suppressor genes in sputum can be used to assign risk.
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