(557e) Pharmacokinetic/Pharmacodynamic Model Predicts the Response to Cancer Therapeutics Targeting VEGF

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a complex biological process involved in physiological conditions, as well as in pathological cases such as cancer. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and has been targeted in order to inhibit angiogenesis and prevent tumor vascularization. This study applies a molecular-detailed compartment model of VEGF kinetics and transport in the human body [1, 2] to investigate the effects of anti-angiogenic therapies targeting the VEGF pathway.

The model includes normal tissue (represented by skeletal muscle), blood, and tumor. We include molecular interactions between two major VEGF isoforms VEGF₁₂₁ and VEGF₁₆₅, receptors VEGFR1 and VEGFR2, and co-receptors NRP1 and NRP2. Macromolecular transport between compartments occurs via transendothelial microvascular permeability and lymphatic flow. Additionally, free VEGF is subjected to protein degradation in the tissue compartments, and species are cleared from the blood. VEGF receptors and co-receptors are localized on the abluminal and luminal endothelial surfaces, as well as on parenchymal cells. Receptor density is based on in vitro and in vivo quantitative flow cytometry [1, 3]. The model is represented by 125 ordinary differential equations and has been validated against experimental data.

We apply the model to predict the effects of therapeutics that inhibit VEGF or its receptors. We also investigate combination therapies and targeted delivery of the anti-angiogenic agents. The response to anti-angiogenic treatment is characterized by the level of free VEGF in the body and the number of VEGF/VEGFR2 complexes (considered to be pro-angiogenic). Following neutralization of VEGF with an antibody, plasma free VEGF and the number of VEGF/VEGFR2 complexes in the blood increase tenfold. The increase in plasma VEGF has been observed clinically. Interestingly, the model predicts that VEGF in the tumor interstitium can increase or decrease following administration of the VEGF antibody, depending on properties of the tumor microenvironment, including the relative rate at which VEGF₁₂₁ and VEGF₁₆₅ are secreted by the tumor and the expression level of the VEGF receptors on tumor cells. Additionally, we find that targeting VEGFR2 is effective in inhibiting the formation of pro-angiogenic complexes, while mediating the concomitant increase in free VEGF that can occur with inhibition of VEGF or VEGFR1.

We have developed a framework for investigating the systemic effects of anti-angiogenic drugs that inhibit VEGF-mediated signaling, which depend on tumor-specific properties and are difficult to quantify clinically. The model should be instrumental in optimizing personalized cancer treatment strategies that target the VEGF pathway.

This work was supported by NIH grant R01 CA138264 (ASP), NIH fellowship F32 CA154213 (SDF), and UNCF/Merck Postdoctoral Fellowship (SDF).

 

References

1.  Finley, S.D., et al., Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies. BMC Systems Biology, 2011. 5:193.

2.  Finley, S.D. and A.S. Popel, Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms. AAPS Journal, 2012. In press.

3.  Imoukhuede, P.I. and A.S. Popel, Quantification and cell-to-cell variation of vascular endothelial growth factor receptors. Experimental Cell Research, 2011. 317(7):955-965.