Quantitative Insight in Utilizing Circulating Angiogenic Factors as Biomarkers for Antiangiogenic Therapy: Systems Pharmacology Approach

Circulating angiogenic factors (CAF) like vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and sVEGFR2 have potential as biomarkers for antiangiogenic therapy. The interpretation of changes in CAF is complicated by the dynamic nature of the tumor and host cells emanating CAF in response to VEGF pathway inhibition. We developed a systems pharmacology model of anti-VEGF agents to investigate CAF modulation by tumor and host cells, and the relationship between overall CAF changes in response to sunitinib and antitumor efficacy. This model distinguishes between the tumor cells' contributions from tumor-independent response to therapy and total plasma CAF correlating with antitumor activity. Altered VEGF is more likely to serve as a useful biomarker reflecting tumor responses in cancer patients whose pretreatment VEGF is higher than baseline VEGF in healthy subjects. Our findings provide a mechanistic insight into tumor modulation of angiogenic molecules, and may explain the inconsistent results found in previous biomarker studies.