The role of aberrant VHL/HIF pathway elements in predicting clinical outcome to pazopanib therapy in patients with metastatic clear-cell renal cell carcinoma

Clin Cancer Res. 2013 Sep 15;19(18):5218-26. doi: 10.1158/1078-0432.CCR-13-0491. Epub 2013 Jul 23.


Purpose: Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking.

Experimental design: We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent.

Results: The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib.

Conclusions: In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / mortality
  • DNA, Neoplasm / genetics
  • Follow-Up Studies
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunoenzyme Techniques
  • Indazoles
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / mortality
  • Mutation / genetics*
  • Neoplasm Staging
  • Polymerase Chain Reaction
  • Prognosis
  • Pyrimidines / therapeutic use*
  • Signal Transduction
  • Sulfonamides / therapeutic use*
  • Survival Rate
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*


  • Angiogenesis Inhibitors
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • DNA, Neoplasm
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indazoles
  • Pyrimidines
  • Sulfonamides
  • endothelial PAS domain-containing protein 1
  • pazopanib
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human

Supplementary concepts

  • Clear-cell metastatic renal cell carcinoma