Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple-Negative Breast Cancer

Purpose Downregulation of miRNA-22 in triple-negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo. Methods To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations. Results Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs against TNBC, providing a basis for rational therapeutic combinations for improved response Conclusions The present study highlights the translational potential of miRNA-22 nanotherapy for TNBC in combination with standard-of-care drugs.

Automated summary

The downregulation of miRNA-22 in TNBC is associated with upregulation of eEF2K protein, and miRNA-22 nanotherapy shows potential as an investigational therapeutic agent. A mechanistic model was developed to evaluate the translational potential of miRNA-22 nanotherapy, revealing dose-response relationship and optimal treatment frequency. Combining miRNA-22 nanotherapy with immune checkpoint inhibitors and standard-of-care drugs showed promising results in improving treatment outcomes for TNBC.