A General Network Pharmacodynamic Model–Based Design Pipeline for Customized Cancer Therapy Applied to the VEGFR Pathway

A unified approach to optimize multidrug chemotherapy using a pharmacokinetic (PK)/enhanced pharmacodynamic model was developed using the vascular endothelial growth factor receptor (VEGFR) signaling system. The base VEGFR network model, characterized by ligand–receptor interactions, enzyme recruitm...

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Bibliographic Details
Published inCPT: pharmacometrics and systems pharmacology Vol. 3; no. 1; pp. 1 - 9
Main Authors Zhang, X‐Y, Birtwistle, MR, Gallo, JM
Format Journal Article
LanguageEnglish
Published United States John Wiley & Sons, Inc 01.01.2014
Nature Publishing Group
Subjects
Cancer
Chemotherapy
Confidence intervals
Feedback
Genetic algorithms
Kinases
Ligands
Optimization
Original
Parameter estimation
Pharmacodynamics
Proteins
Sensitivity analysis
Signal transduction
Vascular endothelial growth factor
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Summary:A unified approach to optimize multidrug chemotherapy using a pharmacokinetic (PK)/enhanced pharmacodynamic model was developed using the vascular endothelial growth factor receptor (VEGFR) signaling system. The base VEGFR network model, characterized by ligand–receptor interactions, enzyme recruitment (Grb2‐Sos, phospholipase C γ (PLCγ), and phosphoinositide‐3 kinase (PI3K)), and downstream mitogen‐activated protein kinase and Akt cascade activation, was linked to a sunitinib (VEGFR inhibitor) PK model and underwent Sobol sensitivity analysis that revealed potential sunitinib‐enhancing mechanisms. Drugs targeting these mechanisms (a VEGF inhibitor, a PI3K inhibitor, a PLCγ inhibitor, and a mitogen‐activated protein kinase inhibitor) and sunitinib were input to optimization‐based control analyses to design multidrug regimens that maintained 80% pERK and pAkt inhibition for 28 days while minimizing drug dose. The resultant combination regimens contained both continuous and discontinuous schedules, mostly at low doses, and were altered by oncogenic mutations. This pipeline of computational analyses demonstrates how model‐based methods can capture the complexities of drug action, tailor cancer chemotherapy, and empower personalized medicine. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e92; doi:10.1038/psp.2013.65; published online 15 January 2014
Bibliography:The first two authors contributed equally to this work.
ISSN:2163-8306
2163-8306
DOI:10.1038/psp.2013.65