Persistence and regression in lung premalignant lesions

Project Summary Lung cancer is the leading cancer killer. Preventing lung cancer is vital to reducing the global cancer burden. Pharmacological prevention is an appealing strategy because it reduces the burden of treating tumors and pro- vides options for former smokers or lung cancer survivors who are highly motivated to minimize their lung can- cer risk. Prevention agents can be targeted to high-risk patients with premalignant lesions (PMLs), but lung PMLs often spontaneously progress and regress, making it difficult to avoid overtreatment. Recently, we identi- fied molecular patterns that separate lung PMLs likely to persist to carcinoma from those likely to regress. However, there is an urgent need to identify interception targets in these persistent PMLs. Identifying key mechanisms in PML persistence targeted by prevention agents will empower a precision approach focused on intercepting PMLs, which could significantly reduce tumor development high-risk patients. Our long-term goal is to use targeted prevention agents to intercept lung tumor development in high-risk populations. The main objective of this proposal is to identify interception targets in persistent lung PMLs. We identified a profile that differentiates lung dysplasias likely to persist from those likely to regress. This profile implicates loss of cell cy- cle control, altered adherens junction components, decreased M1 macrophages, and increased regulatory T- cells in dysplasia persistence and includes a gene expression panel for persistence. We chose Iloprost and PD-1 inhibition as valuable tools for investigating persistence pathways in lung PMLs, based on their efficacy in clinical trials and known targeting of epithelial or immune cells, both components of the persistence profile. We hypothesize that persistence pathways can be targeted to intercept the lung PMLs most likely to progress to carcinomas, and that changes in the persistence profile correlate with response to prevention agents. We will use an innovative and human-relevant reverse translational approach to test this hypothesis in the following specific aims: 1) Identify interception targets in the persistence profile in clinical trial biopsies, 2) Determine ef- fects of prevention agents on persistence pathways in vivo, 3) Identify the mechanistic targets in persistence pathways for prevention agent activity. After successful completion of this work, the expected outcome is demonstration that prevention agents targets persistence mechanisms in lung PMLs at risk of progressing to carcinoma. This project is innovative because it uses state-of-the-art assays and shifts the prevention research paradigm away from bench to beside translation, instead using clinical data to inform human-relevant mecha- nistic studies at the bench and cage. Our results will provide a strong basis for further development of precision application approaches for medical prevention, which would significantly impact populations at high risk of lung cancer by targeting the patients most at risk of progressing to invasive carcinoma. This project will advance lung cancer prevention research and address a critical need of the NCI Division of Cancer Prevention.