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Sunitinib-induced changes in circulating endothelial cell-related proteins in patients with metastatic renal cell
Astrid A M van der Veldt1, Laura Vroling, Richard R de Haas
1Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Abstract:
Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are effective agents in the treatment of metastatic renal cell cancer (mRCC). We here investigated whether inhibition of VEGFR signalin by sunitinib causes changes in plasma proteins associated with tumor endothelium. Forty-three patients with mRCC received sunitinib 50 mg/day in a 4-weeks on 2-weeks off schedule. Sequential plasma samples were obtained before treatment (C1D1), on C1D14, on C1D28, and on C2D1 before start of cycle 2. Plasma levels were assessed for VEGF, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), von Willebrand factor (vWF), circulating angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2). Total tumor burden was calculated at baseline and at first evaluation. Progression-free survival (PFS) and overall survival (OS) were determined. Tumor burden was positively associated with baseline circulating Ang-2 [Spearman's rho (ρ) = 0.378, p = 0.028] and vWF (ρ = 0.417, p = 0.008). During sunitinib treatment, circulating Ang-2 and sTie-2 significantly decreased (p < 0.001 for both), plasma levels of sVCAM-1 and VEGF significantly increased (p = 0.022 and p < 0.001), whereas those of sICAM-1 and vWF remained stable. These protein changes had recovered on C2D1. The reduction in circulating Ang-2 levels on C1D28 was positively correlated with the percentage decrease in tumor burden (ρ = 0.605; p = 0.002). Baseline protein levels and subsequent changes were not associated with PFS or OS. In conclusion, sunitinib-induced changes in Ang-2, sTie-2, sVCAM-1 and VEGF are related to the administration schedule, while reduction in Ang-2 is also associated with decrease in tumor burden.
Insights
Sunitinib treatment for metastatic renal cell cancer alters plasma proteins. Angiopoietin-2 reduction correlates with decreased tumor burden, but protein changes do not predict survival outcomes.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are established treatments for metastatic renal cell cancer (mRCC).
- Investigating the impact of sunitinib on plasma proteins linked to tumor endothelium is crucial for understanding treatment mechanisms.
Purpose of the Study:
- To examine how sunitinib treatment affects plasma protein levels associated with tumor endothelium in patients with mRCC.
- To correlate changes in these proteins with tumor burden, progression-free survival (PFS), and overall survival (OS).
Main Methods:
- Forty-three mRCC patients received sunitinib (50 mg/day, 4 weeks on/2 weeks off).
- Plasma samples were collected sequentially (baseline, C1D14, C1D28, C2D1) and analyzed for VEGF, sVCAM-1, sICAM-1, vWF, Ang-2, and sTie-2.
- Tumor burden, PFS, and OS were assessed.
Main Results:
- Baseline circulating Angiopoietin-2 (Ang-2) and von Willebrand factor (vWF) positively correlated with tumor burden.
- During treatment, Ang-2 and soluble Tie-2 (sTie-2) significantly decreased, while soluble vascular cell adhesion molecule-1 (sVCAM-1) and VEGF increased.
- The reduction in Ang-2 on C1D28 correlated with decreased tumor burden; protein levels returned to baseline by C2D1.
- No significant association was found between baseline protein levels or their changes and PFS or OS.
Conclusions:
- Sunitinib administration induces dynamic changes in plasma proteins (Ang-2, sTie-2, sVCAM-1, VEGF) that are dependent on the treatment schedule.
- The decrease in circulating Ang-2 levels during sunitinib therapy is linked to a reduction in tumor burden.
- These specific plasma protein alterations do not serve as predictive biomarkers for PFS or OS in mRCC patients treated with sunitinib.
