CHEMOPREVENTION WITH AEROSOLIZED LET-7 MICRORNA IN MOUSE MODELS OF NON-SMALL CELL LUNG CANCER (ADENOCARCINOMA AND SQUAMOUS CELL CARCINOMA)

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

Investigators

Abstract

The aim of the proposed study is to evaluate the efficacy of a novel chemopreventive strategy based on the delivery of microRNA mimetics in experimental models 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, and HMGA2, as well as cell-cycle progression regulator genes such as CDC25A, CDK6, and cyclin D2. Recent results have reported on the development of an aerosolized let-7B mimetic that inhibited benzo[a]pyrene-induced lung adenoma volume by 72% in A/J mice (Nano Lett., 19: 2231-2242, 2019), although mice in this model rarely develop adenocarcinomas. As lung adenocarcinomas and squamous cell carcinomas account for ~80% of all human cancer histological subtypes, the objectives of this Task Order are to determine 1) if aerosolized let-7b will be effective against the two most common lung tumor subtypes, and 2) if aerosolized delivery of let-7b to the lungs could minimize potential systemic side effects.