Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins

J Transl Med. 2007 Jul 2;5:32. doi: 10.1186/1479-5876-5-32.

Abstract

Background: Sunitinib malate (SUTENT) is an oral, multitargeted tyrosine kinase inhibitor, approved multinationally for the treatment of advanced RCC and of imatinib-resistant or - intolerant GIST. The purpose of this study was to explore potential biomarkers of sunitinib pharmacological activity via serial assessment of plasma levels of four soluble proteins from patients in a phase II study of advanced RCC: VEGF, soluble VEGFR-2 (sVEGFR-2), placenta growth factor (PlGF), and a novel soluble variant of VEGFR-3 (sVEGFR-3).

Methods: Sunitinib was administered at 50 mg/day on a 4/2 schedule (4 weeks on treatment, 2 weeks off treatment) to 63 patients with metastatic RCC after failure of first-line cytokine therapy. Predose plasma samples were collected on days 1 and 28 of each cycle and analyzed via ELISA.

Results: At the end of cycle 1, VEGF and PlGF levels increased >3-fold (relative to baseline) in 24/54 (44%) and 22/55 (40%) cases, respectively (P < 0.001). sVEGFR-2 levels decreased >or= 30% in 50/55 (91%) cases and >or= 20% in all cases (P < 0.001) during cycle 1, while sVEGFR-3 levels were decreased >or= 30% in 48 of 55 cases (87%), and >or= 20% in all but 2 cases. These levels tended to return to near-baseline after 2 weeks off treatment, indicating that these effects were dependent on drug exposure. Overall, significantly larger changes in VEGF, sVEGFR-2, and sVEGFR-3 levels were observed in patients exhibiting objective tumor response compared with those exhibiting stable disease or disease progression (P < 0.05 for each analyte; analysis not done for PlGF).

Conclusion: Sunitinib treatment in advanced RCC patients leads to modulation of plasma levels of circulating proteins involved in VEGF signaling, including soluble forms of two VEGF receptors. This panel of proteins may be of value as biomarkers of the pharmacological and clinical activity of sunitinib in RCC, and of angiogenic processes in cancer and other diseases.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / blood*
  • Carcinoma, Renal Cell / blood*
  • Carcinoma, Renal Cell / drug therapy
  • Cluster Analysis
  • Humans
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Kidney Neoplasms / blood*
  • Kidney Neoplasms / drug therapy
  • Membrane Proteins / blood
  • Middle Aged
  • Neoplasm Proteins / blood*
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Pyrroles / therapeutic use
  • Solubility / drug effects
  • Sunitinib
  • Time Factors
  • Vascular Endothelial Growth Factor Receptor-2 / blood
  • Vascular Endothelial Growth Factor Receptor-3 / blood
  • Vascular Endothelial Growth Factors / blood*

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Indoles
  • Membrane Proteins
  • Neoplasm Proteins
  • PIGF protein, human
  • Pyrroles
  • Vascular Endothelial Growth Factors
  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-3
  • Sunitinib