Engineering ex vivo models of lung cancer and chemoprevention

Lung cancer is a particularly devastating diagnosis accounting for 24% of all cancer deaths in the United States. A new lung cancer diagnosis occurs every 2.3 minutes in the U.S. and more than half of these diagnoses are in former smokers. This identifiable high-risk population is an ideal target for chemoprevention. Intercepting the emergence of lung tumors is key to reducing the burden of lung cancer mortality, however, studies on prevention drugs rely on animal models and are costly, time consuming, and require large numbers of animals. Precision-cut lung slices (PCLS) address these challenges by retaining the complexity of living tissue while enabling disease studies outside the animal. These thin slices of mouse lung tissue grown in a dish can be used for studying exposures that cause cancer and testing drugs that prevent cancer. PCLS have not yet been used for studies of early lung cancer due to breakdown of the tissue slices outside the animal. We have developed a new approach that uses bioengineered materials to support extended life of lung tissue grown outside a mouse. We propose to use this model to study early lung cancer and prevention drugs. We will optimize the conditions of our bioengineered PCLS to further increase the stability of lung tissue grown outside a mouse. We will expose PCLS to tobacco carcinogens to induce abnormalities in lung cells that are known to precede lung tumors in mice. When we can induce early lung cancer in the PCLS, we will test the effects of drugs known to prevent lung tumor development in mice to see if they also prevent or reverse development of early lung cancer in PCLS. We will also test four emerging prevention drugs to validate the use of our system for screening the efficacy of new compounds. Our bioengineered system could have a significant impact on how we generate the data supporting clinical trials of lung cancer prevention drugs. By making many individual slices from a single mouse lung, it will reduce the number of animals and cost of the studies required to test multiple conditions and drugs. This approach will also significantly shorten the time needed to study how prevention drugs work and their impact on lung biology by studying live tissue in a dish rather than in an animal. Developing this system for mouse tissue will build the foundation for using human tissue. This will directly impact patients at risk of lung cancer and improve how they are screened for clinical trials or individual treatments. With this exploratory award, we anticipate delivering a new model of early lung cancer that will support further funding for advanced studies, leading to an increase in the use of prevention drugs in high risk populations and a reduction in lung cancer mortality.