背景:非小细胞肺癌(NSCLC)中microRNA-155(miR-155)表达升高可促进顺铂耐药并对治疗结果产生负面影响。然而,miR-155还可以通过抑制PD-L1表达来增强抗肿瘤免疫力。miR-155的拮抗剂靶向治疗,抗miR-155,已证明具有挑战性,由于其双重分子效应。
方法:我们开发了多尺度机械模型,用体内数据校准,然后外推到人类,研究纳米颗粒递送的抗miR-155在非小细胞肺癌中的治疗作用,单独或与标准护理药物联合使用。
结果:临床情景的模型模拟和分析显示,每三周一次以2.5mg/kg的剂量使用抗miR-155的单一疗法具有实质性的抗癌活性。它导致了6.7个月的中位无进展生存期(PFS),与顺铂和免疫检查点抑制剂相比,这是有利的。Further,我们探索了抗miR-155与标准护理药物的组合,并发现两种和三种药物组合具有很强的协同作用。抗miR-155,顺铂,pembrolizumab的平均PFS为13.1个月,而抗miR-155和顺铂的两种药物组合导致的中位PFS为11.3个月,由于其简单的设计和成本效益,它成为一种更实用的选择。我们的分析还为药物组合的不利剂量比提供了有价值的见解,强调需要优化剂量方案以防止拮抗作用。
结论:这项工作弥合了抗miR-155的临床前开发和临床翻译之间的差距,并揭示了抗miR-155联合治疗在NSCLC中的潜力。
BACKGROUND: 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. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.
METHODS: 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.
RESULTS: 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 regimens to prevent antagonistic effects.
CONCLUSIONS: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.