Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

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 (q) 5 0.378, p 5 0.028] and vWF (q 5 0.417, p 5 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 5 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 (q 5 0.605; p 5 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.

Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

“…As anticipated for bevacizumab, there was a pronounced decrease in unbound VEGF-A (À92.7%) to a near undetectable level in all patients indicating adequate VEGF-A inhibition. In contrast, increased VEGF-A levels can be expected during treatment with TKIs, as reported for sunitinib (29), sorafenib (30) and cediranib (31,32). We measured a reactive increase in sVEGFR2 levels on C2D1, in agreement with reports from small cohorts of patients during bevacizumab-based therapy (33)(34)(35), whereas decreased sVEGFR2 levels have been observed in patients receiving sorafenib (30) or cediranib (31,32).…”

“…For bevacizumab, we hypothesize that the increase in sVEGFR2 might result from shedding due to the near absence of VEGF-A to stimulate its receptor. The relative decrease in ANG2 (À18.1%) and sTIE2 (À10.5%) levels has also been described for sunitinib (29), sorafenib (30) and cediranib (31,32). It thus appears that blockade of the VEGF/VEGFR signaling route inhibits ANG2/TIE2 activation promoting tumor vessel normalization by ANG1 (37).…”

AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney

“…VCAM‐1 is highly expressed in endothelial cells, is up‐regulated in immune‐resistant RCC cell lines, and is also thought to be involved in immune escape 25. Levels of sVCAM‐1 have been shown to increase in RCC patients receiving sunitinib26 and in breast cancer patients receiving bevacizumab 27, 28. Further investigation will be required to establish clinical utility of these pharmacodynamic markers.…”

Vascular cell adhesion molecule‐1 (VCAM‐1)—An increasing insight into its role in tumorigenicity and metastasis

“…29,[149][150][151] Also in gastric and renal carcinoma, ovarian cancer, and in indolent non-Hodgkin lymphomas, an assessment of disease risk, cancer-free survival, or response to chemotherapy was feasible by VCAM-1 quantification. 106,[152][153][154][155][156] Taking alleviated VCAM-1 levels in cancer as a basis, Montes-Sanchez could identify three new glycosylated VCAM-1 isoforms resulting from HUVEC treatment with tumoral soluble factors. 157 These isoforms could perhaps be helpful in future to distinguish cancer from other diseases associated with augmented VCAM-1 levels.…”