Translational Modeling-Based Evidence for Enhanced Efficacy of Standard-of-Care Drugs in Combination With Anti-microRNA-155 in Non-Small-Cell Lung Cancer

Authors

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
Bulent Ozpolat
George A Calin
Zhihui Wang

Publication Date

8-2-2024

Journal

Molecular Cancer

Abstract

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.

Keywords

Carcinoma, Non-Small-Cell Lung, MicroRNAs, Humans, Lung Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Standard of Care, Translational Research, Biomedical

Comments

Supplementary Material

PMID: 39095771

DOI

10.1186/s12943-024-02060-5

PMID

39095771

PMCID

PMC11295620

PubMedCentral® Posted Date

August 2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes