Lung cancer is the leading cause of cancer-related deaths worldwide. Despite improvements in early diagnosis that were made possible by emerging imaging technologies and newly developed targeted chemotherapeutic agents that improve initial treatment responses, the overall 5-year survival for lung cancer patients has remained a dismal 10-15% over the past 3 decades. Although the primary preventive strategy for smoke related diseases is quitting smoking, even after smoking cessation the risk of developing lung cancer remains significantly higher than in non-smokers for 15 years. Thus, the development of chemopreventive strategies that could prevent the progression of lung lesions to malignant cancers would reduce the mortality and morbidity resulting from this deadly disease. The population of tobacco smokers and ex-smokers constitutes a readily identifiable group of individuals at risk for lung cancer who would benefit from intervention with chemopreventive regimens.
The aim of the proposed study is to evaluate the efficacy of a novel chemopreventive strategy based on the delivery of microRNA mimetics in an experimental model of lung carcinogenesis in mice. MicroRNAs are noncoding small RNAs acting as post-transcriptional repressors and regulators of gene expression. MicroRNAs are grossly dysregulated in human cancers, including lung cancer. The microRNAs that are under-expressed in cancer can be functionally classified as tumor-suppressors while those that are over-expressed act as oncogenes. The let-7 microRNA family is a well characterized family of tumor suppressors whose genes map to different chromosomal regions that are frequently deleted in lung cancer. Let-7 microRNAs negatively regulate multiple oncogenes, including ras, myc, hmga2, and cell-cycle progression regulator genes, such as cdc25a, cdk6, and cyclin D2. . Accordingly, microRNA delivery has been proposed as a new strategy for lung cancer therapy. Previous studies by Kumar et al. (Proc.Natl.Acad.Sci. 105: 3903-8, 2008) and Trang et al. (Oncogene 29: 1580-7, 2010) have shown that intratracheal or intranasal exposure of genetically engineered mice to viral vectors expressing let-7 miRNA mimetics resulted in reduced lung tumor burdens. However, these studies were done in genetically engineered mouse models that developed highly aggressive tumors more relevant for a treatment regimen. In addition, Kumar et al. noted that some tumors emerged that were resistant to the let-7 miRNA. The success of this approach may thus be limited by the fact that the patterns of altered microRNAs continuously change due to the instability of cancer cell genome. In healthy and premalignant cells, the alterations in microRNA expression may be less unstable and more likely to be reversible with agent treatment. Thus, testing of let-7 miRNA in murine models of chemical carcinogenesis utilizing chemical carcinogens implicated in tobacco smoke-induced disease would be important for determining the potential use of these agents in prevention strategies. This model develops tumors with a longer latency and allows an assessment of agent effects at the earliest stages of tumor initiation and progression. It will be important to develop an intranasal or aerosol delivery system that could be subsequently tested for safety and efficacy of microRNA administration aimed at preventing lung cancer by blocking the progression of the carcinogenesis process.
