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 - Funding Information:
The research work was supported by the National Science Foundation grant DMS-1930583 (VC, ZW), National Institutes of Health grants 1R01CA253865 (VC, BO, ZW), 1U01CA196403 (VC, ZW), 1U01CA213759 (VC, BO, ZW), 1R01CA226537 (RP, WA, VC, ZW), 1R01CA222007 (VC, GAC, BO, ZW), U54CA210181 (VC), and the Cockrell Foundation (PD). GAC also acknowledgs the Felix L. Haas Endowed Professorship in Basic Science, and the following grant support: NCI (1R01 CA182905–01, 1R01CA222007-01A1), NIGMS (1R01GM122775–01), DoD (Idea Award W81XWH2110030), a Team DOD grant in Gastric Cancer, a Chronic Lymphocytic Leukemia Moonshot Flagship project, a CLL Global Research Foundation 2019 grant, a CLL Global Research Foundation 2020 grant, a Mathers Foundation grant, an Institutional Research and Development Grant associated with the Brain SPORE 2P50CA127001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests. GAC is the scientific founder of Ithax Pharmaceuticals. WA and RP are founders and equity stockholders of PhageNova Bio. RP is a paid consultant for PhageNova Bio and serves as its Chief Scientific Officer. RP and WA are also founders and stockholders of MBrace Therapeutics; RP serves as Chief Scientific Officer and a Board Member and WA is a member of the Scientific Advisory Board. None of these commercial relationships are related to the scope of the work presented in this manuscript.
Funding Information:
The research work was supported by the National Science Foundation grant DMS-1930583 (VC, ZW), National Institutes of Health grants 1R01CA253865 (VC, BO, ZW), 1U01CA196403 (VC, ZW), 1U01CA213759 (VC, BO, ZW), 1R01CA226537 (RP, WA, VC, ZW), 1R01CA222007 (VC, GAC, BO, ZW), U54CA210181 (VC), and the Cockrell Foundation (PD). GAC also acknowledgs the Felix L. Haas Endowed Professorship in Basic Science, and the following grant support: NCI (1R01 CA182905?01, 1R01CA222007-01A1), NIGMS (1R01GM122775?01), DoD (Idea Award W81XWH2110030), a Team DOD grant in Gastric Cancer, a Chronic Lymphocytic Leukemia Moonshot Flagship project, a CLL Global Research Foundation 2019 grant, a CLL Global Research Foundation 2020 grant, a Mathers Foundation grant, an Institutional Research and Development Grant associated with the Brain SPORE 2P50CA127001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests. GAC is the scientific founder of Ithax Pharmaceuticals. WA and RP are founders and equity stockholders of PhageNova Bio. RP is a paid consultant for PhageNova Bio and serves as its Chief Scientific Officer. RP and WA are also founders and stockholders of MBrace Therapeutics; RP serves as Chief Scientific Officer and a Board Member and WA is a member of the Scientific Advisory Board. None of these commercial relationships are related to the scope of the work presented in this manuscript.
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
KW - MicroRNAs/administration & dosage
KW - Nanoparticles/administration & dosage
KW - Humans
KW - Drug Synergism
KW - Triple Negative Breast Neoplasms/drug therapy
KW - Cell Line, Tumor
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U2 - 10.1007/s11095-022-03176-3
DO - 10.1007/s11095-022-03176-3
M3 - Article
C2 - 35294699
SN - 0724-8741
VL - 39
SP - 511
EP - 528
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 3
ER -