Wednesday, May 10, 2017

Mechanistic Modeling Quantifies The Influence Of Tumor Growth Kinetics On The Response To Anti-Angiogenic Treatment

Mechanistic Modeling Quantifies The Influence Of Tumor Growth Kinetics On The Response To Anti-Angiogenic Treatment

Thomas D. Gaddy, Stacey D. Finley

Abstract

Tumors exploit angiogenesis, the formation of new blood vessels from pre-existing vasculature, in order to obtain nutrients required for continued growth and proliferation. Targeting factors that regulate angiogenesis, including the potent promoter vascular endothelial growth factor (VEGF), is therefore an attractive strategy for inhibiting tumor growth. Systems biology modeling enables us to identify tumor-specific properties that influence the response to those anti-angiogenic strategies. Here, we build on our previous systems biology model of VEGF transport and kinetics in tumor-bearing mice to include a tumor compartment whose volume depends on the “angiogenic signal” produced when VEGF binds to its receptors on tumor endothelial cells. We trained and validated the model using in vivo measurements of xenograft tumor volume to produce a model that accurately predicts the tumor's response to anti-angiogenic treatment. We applied the model to investigate how tumor growth kinetics influence the response to anti-angiogenic treatment targeting VEGF. Based on multivariate regression analysis, we found that certain intrinsic kinetic parameters that characterize the growth of tumors could successfully predict response to anti-VEGF treatment. This model is a useful tool for predicting which tumors will respond to anti-VEGF treatment, complementing pre-clinical in vivo studies.