Advances in the biology of lung cancer chemoprevention.

The heavy burden of lung cancer, which includes the highest worldwide mortality of any cancer, and its resistance to standard approaches (smoking cessation, screening, and therapy), have motivated an intense interest in chemoprevention of this disease. Randomized controlled trials of agents (including retinoids, beta-carotene, and vitamin E) to prevent lung cancer have produced only disappointing clinical results to date. New, molecular-targeted approaches are advancing rapidly, however, with many promising targets and interactive signaling pathways for developing novel agents and combinatorial approaches in this setting. This promise is illustrated by recent studies of 15-hydroxyprostaglandin dehydrogenase, which plays a critical role in polyunsaturated fatty acid metabolism and (like another important target, prostacyclin) is downstream of cyclooxygenase-2. 15-hydroxyprostaglandin dehydrogenase degrades prostaglandin E(2), appears to have tumor suppressor activity, and can be induced both by peroxisome proliferator-activated receptor-gamma ligands and an epidermal growth factor receptor inhibitor. Other important targets/pathways include the insulin-like growth factor axis, phosphoinositide 3-kinase pathway, cyclin D and E family members, and epigenetic events. Defining highest lung cancer risk (eg, establishing molecular risk models through long-term analyses of high-risk cohorts) will facilitate the clinical development of molecular-targeted prevention that will potentially reduce the enormous burden of lung cancer.