Abstract A136: A systems approach to the preclinical evaluation of targeted chemoprevention for lung cancer

A136

The possibility of an “individualized medicine” approach to chemoprevention targeted to the specific molecular abnormalities in the individual at risk has been suggested as a means to tailor prevention strategies (Markowitz, N Engl J Med. 2007;356:2195-8). In order to initiate targeted chemoprevention for lung cancer, we have developed a pre-clinical system to assess potential chemoprevention agents against mutated human bronchial epithelial cell lines (HBEC). HBECs are exposed to drugs such as rosiglitazone, erlotinib and celecoxib and selected proliferative responses, gene expression, micro-RNA profiles and protein panels are assessed. This data is then assessed by systems analysis to determine the optimal chemopreventive agents against specific mutations. These data will ultimately be utilized both for agent selectivity and agent specific biomarker identification. In preliminary studies, we evaluated rosiglitazone, erlotinib and celecoxib against three genetically altered HBEC cell lines harboring mutations relevant in the pathogenesis of human lung cancer (p53 knockdown, K-ras^V12 and EGFR L858R mutations). As a model of long-term tobacco exposure, NNK- treated HBEC cells are also being utilized. In addition to selected proliferation assays, we assessed each agent against HBEC cell lines and evaluated a 50 protein luminex profile as well as a panel of more than 700 micro RNAs. These potential chemopreventive agents reveal specific patterns of alterations in proliferation, gene expression, protein secretion and microRNA profiles. Based on these findings, assessment of combinations of preventive agents are in progress. We anticipate that these methods will assist in the development of agent specific biomarkers and a personalized approach to chemoprevention for lung cancer.

This work is supported by the UCLA SPORE in Lung Cancer P50 90388, UT Southwestern SPORE in Lung Cancer P50CA75907 and The Flight Attendant Medical ResearchInstitute (FAMRI) Young Clinical Scientist Awards.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A136.