Modeling lung squamous cell carcinoma premalignancy and prevention

Significant improvement in lung squamous cell carcinoma (SCC) mortality requires preventive medical intervention at the premalignant lesion (PML) stage to prevent progression to tumors. Historically, phase III lung cancer prevention agent clinical trials were based on population data and the agents tested had no effect or were even harmful to patients. More recently, phase I/II clinical trials of prevention agents supported instead by strong preclinical evidence have generated promising results. This highlights a critical need for preclinical models to support translation of prevention discoveries to clinical trials. However, previous mouse models of lung SCC require intense time and effort and do not include human-relevant exposures. The main objectives of this proposal are to validate the human relevance of a novel lung SCC mouse model and use the model in a system for screening and testing lung cancer prevention agents. Preclinical prevention studies for lung SCC have been limited to using N-nitroso-tris-cholorethylurea (NTCU) for eight months to induce SCC lesions. We improved this model by including a human-relevant exposure, combining NTCU with cigarette smoke (NTCU/S) and inducing PMLs in only three months. However, the NTCU/S model is not credentialed for translationally relevant questions, so we propose to validate the model with previously generated human data. We will then incorporate tissue from the NTCU/S model into our bioengineered Precision Cut Lung Slice (PCLS) model, which maintains the complex microarchitecture, cellular diversity, and functional response of mouse tissue for six weeks in ex vivo culture. We hypothesize that the NTCU/S model will generate data relevant to humans and can be successfully employed in an innovative ex vivo-to-in vivo prevention agent testing strategy. To achieve our main objectives, we propose three aims: 1) Define the human relevance of the in vivo NTCU/S mouse model, 2) Validate an ex vivo PCLS approach to screening new prevention agents for the NTCU/S, 3) Use the NTCU/S ex vivo to in vivo testing strategy to determine the preventive efficacy of combined PD-1 and MEK inhibition. The expected outcome from this project is validation of the NTCU/S model of lung SCC as a robust representation of human biology, advancing the preclinical models available for translational lung cancer questions. We will establish a novel ex vivo-to-in vivo strategy for rigorously screening and testing prevention agents and investigate a new prevention agent combination approach. This work represents a paradigmshift from the historical path of prevention agent development by leveraging human-relevant preclinical models to boost research efficiency and advance only the most effective agents to clinical studies. Our interdisciplinary team is well-positioned to translate preclinical data to the clinic to achieve our long-term goal of delivering effective prevention agents to patients. Generating human-relevant preclinical models of lung PMLs and prevention addresses critical needs of the NCI Division of Cancer Prevention and PAR-23-281, “Research Projects to Enhance the Applicability of Mammalian Models for Translational Research”.