TY - JOUR
T1 - Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple-Negative Breast Cancer
AU - Dogra, Prashant
AU - Ramírez, Javier Ruiz
AU - Butner, Joseph D.
AU - Peláez, Maria J.
AU - Chung, Caroline
AU - Hooda-Nehra, Anupama
AU - Pasqualini, Renata
AU - Arap, Wadih
AU - Cristini, Vittorio
AU - Calin, George A.
AU - Ozpolat, Bulent
AU - Wang, Zhihui
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - allometry
KW - cancer treatment
KW - mathematical modeling
KW - microRNA
KW - pharmacokinetics and pharmacodynamics
KW - precision medicine
KW - tumor-immune interaction
UR - http://www.scopus.com/inward/record.url?scp=85126343949&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126343949&partnerID=8YFLogxK
U2 - 10.1007/s11095-022-03176-3
DO - 10.1007/s11095-022-03176-3
M3 - Article
C2 - 35294699
AN - SCOPUS:85126343949
SN - 0724-8741
VL - 39
SP - 511
EP - 528
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 3
ER -