Abstract 1490: Development of a 5-FU modified miR-129 mimic as a novel therapeutic for non-small cell lung cancer

Abstract

Lung cancer is the leading cancer type of cancer-related deaths in the U.S., with non-small cell lung cancer (NSCLC) accounting for a majority of cases. Despite innovations in cancer therapeutics, due to resistance to these therapeutics, the 5-year survival rate for patients with metastatic lung cancer has remained poor. As a result, there is an urgent need to develop new and effective therapeutics, including the study of RNA-based therapeutics. Previous studies from our laboratory have shown that 5-fluorouracil (5-FU) modified tumor suppressor miRNAs significantly enhance the therapeutic efficacy, stability, and deliverability of miRNAs in colorectal cancer (CRC) and pancreatic cancer. In this study, we have characterized the therapeutic potential of miR-129 modified with 5-FU (5-FU-miR-129) in non-small cell lung cancer in vitro via Annexin V staining, cell cycle analysis, and Western Blot. 5-FU-miR-129’s therapeutic potential was also assessed in vivo via IVIS imaging of NSCLC xenografts. We have demonstrated that 5-FU-miR-129 can induce apoptosis (7.2-fold in A549 and 2.9-fold in Calu-1) and cell cycle arrest (12.7-fold change in G1/S phase ratio in A549) in NSCLC in vitro. Furthermore, 5-FU-miR-129 has been found to retain target specificity by downregulating miR-129 targets BCL2 and HMGB1 in a cell line-dependent manner. As was observed in previous studies, we have also demonstrated the ability of 5-FU-miR-129 to be delivered in cancer cells without the use of a transfection vehicle in vitro. Finally, we were also able to demonstrate the therapeutic potential of 5-FU-miR-129 in inhibiting NSCLC tumor growth in vivo, as seen by a significantly decreased change in tumor growth by 37 days post-treatment in the 5-FU-miR-129 treated group compared to the negative control group (79.8% reduction in tumor growth). In addition, we observed a significant increase in survival probability and a reduced hazard ratio in mice treated5-FU-miR-129 when compared to the negative control group. Furthermore, we did not observe any visible side effects (hair loss) of mice treated with 5-FU-miR-129 compared to chemotherapeutic drugs 5-FU and gemcitabine (Gem). 5-FU-miR-129’s therapeutic potential in NSCLC further demonstrates the potential for modified miRNAs as a platform technology in cancer therapeutics. Citation Format: Ga-Ram Hwang, John G. Yuen, Hannah Farley, Jingfang Ju. Development of a 5-FU modified miR-129 mimic as a novel therapeutic for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1490.