Abstract 188: Preventive effect of aerosolized bexarotene in three major subtypes of lung cancer: adenocarcinoma, squamous cell carcinoma and small cell lung cancer in mice

Abstract

Abstract Lung cancer is the leading cause of cancer-related deaths in the United States. The 5 year survival rate for lung cancer patients has remained a dismal 15% for 3 decades. Thus, the development of chemopreventive agents that could prevent lung cancer could potentially reduce the incidence and mortality of pulmonary neoplasms. Bexarotene has exhibited inhibitory effects in preclinical in vivo models of mammary and lung tumorigenesis, has been approved for clinical use in the treatment of cutaneous T-cell lymphoma, and has shown efficacy in phase I/II trials of non-small cell lung cancer (NSCLC). Preclinical studies have demonstrated that it is highly effective in the prevention of all three major subtypes of lung cancer in mouse models: adenocarcinoma (AD), squamous cell carcinoma (SCC), and small cell lung cancer (SCLC). The major side effects of bexarotene when administered orally to rodents or human patients have been hypertriglyceridemia and hypercholesterolemia. Previous studies in a mouse model of lung AD have demonstrated that aerosol delivery of bexarotene through nasal inhalation exhibited potent chemopreventive activity similar to that observed following oral administration (59 to74% reductions in lung tumor multiplicity). The significant decreases in tumor multiplicity and tumor load were achieved without hypertriglycerides that accompany oral bexarotene administration. In this study, aerosolized delivery of 10-30 mg/ml bexarotene showed a significant chemopreventive effect in all three major subtypes. In the N-nitroso-tris-chloroethylurea (NTCU) induced mouse SCC model, 1 week after the first dose of NTCU a dose dependent decrease in tumor formation was observed, with the highest dose causing 75% (p<0.001) and 42% (p<0.01) decreases in SCC tumor burden and the percentage of SCC tumors, respectively. Tumor load was decreased by 73% in A/Jp53 mouse AD model and by 41% in A/Jp53Rb mouse SCLC model. Aerosol delivery of bexarotene had no effect on animal body weight and other signs of toxicity, and no effect on triglyceride and cholesterol level. Aerosolized bexarotene formulation was effective against all 3 major lung cancer cell types and would be a major advance achieving significant reductions in preventing lung cancer incidence in persons at high risk of lung cancer e.g. former or present smokers. Citation Format: Qi Zhang, Jing Pan, Marker S. Miller, Ronald A. Lubet, Yian Wang, Ming You. Preventive effect of aerosolized bexarotene in three major subtypes of lung cancer: adenocarcinoma, squamous cell carcinoma and small cell lung cancer in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 188. doi:10.1158/1538-7445.AM2017-188