Abstract B35: Biomarkers for precision application of prostacyclin lung cancer chemoprevention

Abstract

Abstract Lung cancer remains the leading cause of cancer death in the United States, and chemoprevention offers an appealing area of investigation in the face of limited therapeutic success. Improvement in endobronchial histology was demonstrated in former smokers after oral iloprost chemoprevention in a phase II clinical trial. Of the 48 patients who received iloprost in the chemoprevention trial, 23 had regressive histology and 25 had stable or progressive histology. Identifying markers that predict which patients will respond to treatment will help refine target populations for future trials and clinical applications. Markers of drug activity will also facilitate clinical application by allowing monitoring during treatment. Preclinical studies indicate that iloprost, a prostacyclin analogue, acts through peroxisome proliferator activated receptor gamma (PPAR) to reduce transformed lung epithelial cell growth and markers of epithelial-to-mesenchymal transition (EMT). We hypothesize that PPAR expression status predicts response to prostacyclin chemoprevention and that expression changes in known downstream targets of PPAR and prostacyclin indicate response to prostacyclin treatment. Prostacyclin may also induce expression of PPAR, leading to increased antitumor signaling. We found that expression of PPAR and markers of prostacyclin signaling (15pgdh, CES1, and PTGS2) and EMT markers (Snail, Vimentin, Ecadherin, and CRB3) changed in cultured human bronchial epithelial cells (HBEC) in response to cigarette smoke condensate (CSC) and that iloprost reversed these changes. Expression in mice also changed in response to cigarette smoke carcinogens and prostacyclin. miR-34c is inversely correlated with bronchial histology grade and suppresses lung cancer progression. In our study, the level of miR-34c was lower in the NSCLC cell line H322 compared to HBEC. In H322, miR-34c increased with PPAR agonist treatment and decreased with PPAR antagonist treatment. In HBEC and mouse models of lung cancer chemoprevention, miR-34c increased with prostacyclin and decreased with cigarette smoke carcinogen exposure. In cultured primary progressive dysplastic bronchial epithelial cells, treatment with iloprost resulted in similar expression changes in Vimentin, Snail, Ecadherin, CRB3, CES1, and miR-34c. This study has the potential to improve iloprost lung cancer chemoprevention by allowing future trials to more effectively target high-risk patients, by providing a clinical biomarker for identification of chemoprevention candidates, and by identifying biomarkers for intermediate monitoring of response. Future studies will test expression of these markers in lung tissue biopsy and liquid biopsy samples from the oral and inhaled iloprost chemoprevention trials. Citation Format: Melissa New, Debbie McArthur, Lori Nield, Dan Merrick, Robert L. Keith, Meredith A. Tennis. Biomarkers for precision application of prostacyclin lung cancer chemoprevention [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B35.