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

ABSTRACT: 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 a

SUBMITTER: Zhang XY 

PROVIDER: S-EPMC3910016 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature