Abstract
BackgroundSeveral proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-α and -β, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome.MethodsPatients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT).ResultsAt the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS.ConclusionsBaseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib.Trial registrationClinicalTrials.gov: NCT00247676
Highlights
Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis
High serum levels of vascular endothelial growth factor (VEGF)-A [7] and basic fibroblast growth factor [8] have been associated with poor clinical outcome in HCC [8], and vascular endothelial growth factor-A (VEGF-A) polymorphisms have been associated with prognosis [9]
The antiangiogenic activity of sunitinib likely results from inhibition of vascular endothelial growth factor receptors (VEGFRs) on endothelial cells and platelet-derived growth factor receptors (PDGFRs)-b on stromal cells
Summary
Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-a and -b, stem-cell factor receptor (KIT), and other tyrosine kinases. The hepatitis B virus X protein (HBx) is expressed in HBV-infected cells and enhances VEGF-A expression by stabilizing the transcription factor HIF-1a through inhibition of HIF-1a binding to VHL [10]. These and other findings strongly implicate angiogenesis in the pathophysiology of HCC (reviewed in [5]). The antiangiogenic activity of sunitinib likely results from inhibition of VEGFRs on endothelial cells and PDGFR-b on stromal cells
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