Related Experiment Video
Updated: May 27, 2026
A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies
Stacey D Finley1, Marianne O Engel-Stefanini, P I Imoukhuede
1Department of Biomedical Engineering, Johns Hopkins University, School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA. sdfinley@jhu.edu
Background:
Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, and its role in cancer biology has been widely studied. Many cancer therapies target angiogenesis, with a focus being on VEGF-mediated signaling such as antibodies to VEGF. However, it is difficult to predict the effects of VEGF-neutralizing agents. We have developed a whole-body model of VEGF kinetics and transport under pathological conditions (in the presence of breast tumor). The model includes two major VEGF isoforms VEGF121 and VEGF165, receptors VEGFR1, VEGFR2 and co-receptors Neuropilin-1 and Neuropilin-2. We have added receptors on parenchymal cells (muscle fibers and tumor cells), and incorporated experimental data for the cell surface density of receptors on the endothelial cells, myocytes, and tumor cells. The model is applied to investigate the action of VEGF-neutralizing agents (called "anti-VEGF") in the treatment of cancer.
Results:
Through a sensitivity study, we examine how model parameters influence the level of free VEGF in the tumor, a measure of the response to VEGF-neutralizing drugs. We investigate the effects of systemic properties such as microvascular permeability and lymphatic flow, and of drug characteristics such as the clearance rate and binding affinity. We predict that increasing microvascular permeability in the tumor above 10-5 cm/s elicits the undesired effect of increasing tumor interstitial VEGF concentration beyond even the baseline level. We also examine the impact of the tumor microenvironment, including receptor expression and internalization, as well as VEGF secretion. We find that following anti-VEGF treatment, the concentration of free VEGF in the tumor can vary between 7 and 233 pM, with a dependence on both the density of VEGF receptors and co-receptors and the rate of neuropilin internalization on tumor cells. Finally, we predict that free VEGF in the tumor is reduced following anti-VEGF treatment when VEGF121 comprises at least 25% of the VEGF secreted by tumor cells.
Conclusions:
This study explores the optimal drug characteristics required for an anti-VEGF agent to have a therapeutic effect and the tumor-specific properties that influence the response to therapy. Our model provides a framework for investigating the use of VEGF-neutralizing drugs for personalized medicine treatment strategies.
Insights
This study developed a whole-body model to predict the effectiveness of vascular endothelial growth factor (VEGF)-neutralizing cancer therapies. The model shows that tumor microenvironment and drug characteristics significantly impact treatment outcomes, guiding personalized medicine strategies.
Area of Science:
- Oncology
- Biomathematics
- Pharmacology
Background:
- Vascular endothelial growth factor (VEGF) is crucial for angiogenesis and cancer progression.
- Current anti-VEGF therapies face challenges in predicting treatment efficacy.
- A comprehensive whole-body model of VEGF kinetics and transport in breast tumors was developed.
Purpose of the Study:
- To investigate the influence of model parameters on free VEGF levels in tumors under anti-VEGF treatment.
- To analyze the impact of systemic properties and drug characteristics on therapeutic response.
- To explore the role of the tumor microenvironment, including receptor dynamics and VEGF isoforms.
Main Methods:
- Development of a whole-body model incorporating VEGF isoforms (VEGF121, VEGF165), receptors (VEGFR1, VEGFR2), and co-receptors (Neuropilin-1, Neuropilin-2).
- Inclusion of receptors on parenchymal cells (muscle fibers, tumor cells) and experimental data for cell surface receptor density.
- Sensitivity analysis to assess parameter influence on free VEGF concentration and simulation of anti-VEGF treatment effects.
Main Results:
- Tumor microvascular permeability above 10-5 cm/s can paradoxically increase interstitial VEGF.
- Free VEGF concentration post-treatment varies (7-233 pM) based on receptor density and neuropilin internalization rates.
- Reduced free VEGF is predicted when VEGF121 constitutes at least 25% of secreted VEGF.
Conclusions:
- The study identifies optimal drug characteristics and tumor-specific properties for effective anti-VEGF therapy.
- The developed model serves as a framework for personalized medicine approaches in cancer treatment.
- Understanding VEGF dynamics is key to improving anti-VEGF drug development and application.
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
01:10Mechanism of Angiogenesis
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
01:15Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions
01:21Pharmacodynamics: Overview and Principles
Most drugs' effects result from their interactions with drug receptors or targets within the body. These interactions trigger specific responses at the cellular or systemic level. Drug receptors can be found on the surfaces of cells or within...