Lung cancer remains the number one cause of death from cancer in the United States. Ex-smokers in particular have an elevated lung cancer risk due to the presence of persistent genetic abnormalities in their airways and chronic inflammation from COPD/emphysema induced by previous tobacco exposure. Chemoprevention is an obvious avenue for reducing future cancer for this at-risk group, but safe and efficacious agents are currently lacking. Signal transducer and activator of transcription 3 (STAT3) is one of the seven members of a family of transcription factors that regulates cell proliferation, differentiation, apoptosis, and the immune response. Although the activation of STAT3 is transient and highly regulated in normal cells, it is constitutively active in several types of cancer, including lung cancer. Recent findings suggest that targeting activated STAT3 with a cyclic STAT3 decoy (CS3D) could be a successful preventive intervention in non-small cell lung cancer as well as other tobacco-related cancers. CS3D, developed by Dr. Jennifer Grandis and colleagues, is a circularized double-stranded oligonucleotide containing a 15 base-pair sequence corresponding to the STAT3 response element of the STAT3 target genes. CS3D interacts with STAT3 dimers, acting as a molecular sink to competitively inhibit binding of the dimer to the promoters of STAT3 target genes and inducing p-STAT3 proteasomal degradation. CS3D is non-toxic, thermally stable, and remains active after systemic administration. The purpose of this Task Order is to evaluate CS3D for the prevention of lung cancer in mice exposed to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).