Chemoprevention

Lung cancer remains the leading cause of cancer death in the world for both men and women. Prevention studies have largely been ineffective. A chemoprevention trial using the prostacyclin analogue iloprost demonstrated improvement in endobronchial histology in former smokers. An ongoing trial is investigating lung cancer chemoprevention with pioglitazone, which decreases lung cancer risk in diabetics. The effects of iloprost and pioglitazone are mediated by PPARγ and its downstream targets. We hypothesize that response to iloprost and pioglitazone depends on expression of PPARγ and that measures of prostacyclin and PPARγ activity will correlate with histology. We will measure a PPARγ expression in biopsy tissues to determine if expression can predict response to iloprost. We will assess methylation and acetylation in tissues with loss of PPARγ expression, which could identify a potential role for demethylation or deacetylation agents in creating a response to chemoprevention. We will measure activity of iloprost and pioglitazone through QPCR of downstream targets. Previously generated tissues from mouse models of lung cancer chemoprevention will be used to correlate markers with human samples. miRNA have the potential to be important markers but there is little information on miRNA associated with lung cancer chemoprevention. We identify potential miRNA markers of iloprost and pioglitazone activity in dysplastic cell lines treated with iloprost or pioglitazone and in tissues from mouse models of chemoprevention. Data from this project will inform future clinical trials using iloprost and pioglitazone, improve targeted lung cancer chemoprevention, and identify relevant miRNA markers for future chemoprevention studies.