Abstract A019: Targeting STAT3 for lung cancer prevention

Abstract

Abstract Former smokers have an elevated risk of lung cancer and account for a large proportion of newly diagnosed lung cancer. Former smokers with airway dysplasia have received modest benefit in randomized chemoprevention trials, while active smokers have not. More effective chemoprevention agents for former smokers at risk for lung cancer are needed. We previously reported that a cyclic double-stranded DNA oligonucleotide STAT3 decoy (CS3D) administered intravenously (IV) had strong anti-tumor effects in lung cancer xenograft models and was also effective as a chemoprevention agent using a tobacco carcinogen (NNK)-induced lung cancer mouse model that mimics “ex-smokers”. CS3D prevents the binding of activated STAT3 dimers to the promoter of target genes and induces p-STAT3 degradation. Our goal was to develop a clinically applicable direct delivery method of CS3D to the lungs. Using fluorescently tagged CS3D, we evaluated the feasibility and determined the optimal dosing schedule of CS3D administered intratracheally (IT, a mimic of human inhalation) compared to IV in mice. IT delivery 3 times/week provided a high initial drug level that was cleared from the lungs within a few hours, while IV dosing provided lower initial drug levels but persisted up to 8 hrs, with CS3D accumulation over time in the lungs. While the pharmacodynamic effect was also greater with systemic dosing, IT delivery produced inhibition of the STAT3 pathway. Phosphorylated STAT3, VEGF, IL6 and Ki67 expression in NNK-induced lung preneoplasias was down-modulated by IT CS3D delivery after 4 weeks of treatment compared to the mutant oligonucleotide (CS3M), confirming our previous findings with IV delivery. We also demonstrated that CS3D delivered IT altered the pulmonary environment by promoting a pro-inflammatory, anti-tumor response in myeloid cells of the lung directly, or by acting on tumor and stromal components to establish an immune-reactive tumor-microenvironment. No toxicities were found during IT or IV treatment and no organ abnormalities were detected by either regimen. A long-term chemoprevention study of CS3D delivered IT in the ex-smoker lung cancer murine model is underway. Our findings suggest that blocking STAT3 may be a useful strategy for lung cancer prevention, and may involve both inhibition of oncogenic signaling and enhanced anti-tumor immunity. Citation Format: Jill M. Siegfried, Adam C. Soloff, Autumn Gaither Davis, Amy A. Powers, Seth H. Eisenberg, Laura P. Stabile. Targeting STAT3 for lung cancer prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A019.