Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer

作者：Prashant Dogra, Vrushaly Shinglot, Javier Ruiz-Ramírez, Joseph Cave, Joseph D. Butner, Carmine Schiavone, Dan G. Duda, Ahmed O. Kaseb, Caroline Chung, Eugene J. Koay, Vittorio Cristini, Bülent Özpolat, George A. Călin, Zhihui Wang · 发表于：medRxiv · 年份：2024 · DOI：10.1101/2024.03.14.24304306 · 被引用次数：2 · 研究领域：MicroRNA in disease regulation、Cancer Immunotherapy and Biomarkers、Cancer Cells and Metastasis

Abstract Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimen to prevent antagonistic effects. Thus, this work bridges the gap between...