Lung cancer is the leading cause of cancer death in athe United States, accounting for more mortality than athe combination of breast, prostate, colon and rectal cancer. Smokers unquestionably have an increased risk for lung cancer and tobacco abuse accounts for nearly 90% of all lung cancers. There is evidence, however, that a subset of 15-25% of tobacco smokers are more highly susceptible and that this susceptibility is inherited. Our research group has previously reported that a subset of individuals have significant elevations of levels of bombesin-like peptides in the lower respiratory tract and urine. During the previous period of SPORE funding, we have completed studies which suggest that elevations of bombesin-like peptides are neither a marker of exposure to tobacco, nor of early tobacco-induced disease, but rather a marker of susceptibility to tobacco-induced disease, should an individual smoke. Furthermore, we have initiated studies examining peptidases as candidate genes regulating bombesin-like peptide levels, found wide variation in expression of one peptidase, neutral endopeptidase, and determined that neutral endopeptidase acts as a growth modulator for both small cell and non-small cell lung cancer. We now propose to test three hypotheses: 1. Bombesin-like peptide levels are genetically determined. 2. Peptidase expression affects bombesin-like genetic susceptibility to lung cancer and tumor biology. They are likely to translate into new means to define susceptible, high-risk populations, novel approaches to chemoprevention, biologic markers for early detection and additional therapeutic strategies.