FIGURE 2.

(A) Relationships of therapeutic efficacy and modulation of VEGF and PlGF biomarkers to sunitinib doses. Percentage reduction in tumor volume (•) and fold change in PlGF (▴) and VEGF (▪) are shown at various doses of sunitinib at the end of study. At the dose of 40 mg/kg/day, ∼75% of tumor volume was reduced, with minimal upregulation of hypoxia-dependent CAF. Further dose escalation resulted in marginal therapeutic gain (<5%), but significant upregulation of CAF, which may indicate excessive anti-vascular effects. (B) Utilization of CAF biomarkers in the selection of biological dose of antiangiogenic drugs. The fold change in VEGF and PlGF may serve as a surrogate marker for excessive anti-vascular effects and, in turn, potential for emerging resistance. This illustrates how the biologically effective dose may be selected in a manner which does not invoke significant hypoxia and involves little stimulation of hypoxia-dependent CAF. Monitoring multiple CAFs will be advantageous, as each factor has a different dynamic range. PlGF has a wider dynamic range than VEGF, and results in higher fold change at the same dose. This provides an advantage over VEGF, because PlGF changes are more likely detectable even at lower doses.