Gene and protein expression markers of response to combined antiangiogenic and epidermal growth factor targeted therapy in renal cell carcinoma.

  • Tsavachidou-Fenner D
  • Tannir N
  • Tamboli P
 et al. 
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Abstract

BACKGROUND: Metastatic renal cell carcinoma (mRCC) patients treated with anti-vascular endothelial growth factor (VEGF) therapies demonstrate promising outcomes but not all patients benefit. Factors that predict response remain to be elucidated.

PATIENTS AND METHODS: Nephrectomy material from 37 patients with mRCC receiving bevacizumab +/- erlotinib was used for protein and gene expression assessment. Protein lysates were subjected to reverse-phase protein array profiling. RNA extracts were used to carry out gene expression microarray-based profiling. Normalized protein and gene expression data were correlated with overall survival (OS) and progression-free survival (PFS) using univariate Cox hazard model and linear regression. Immunoblotting was carried out to validate the results.

RESULTS: High protein levels of AMP-activated protein kinase and low levels of cyclin B1 (CCNB1) were associated with longer OS and PFS. Further validation revealed reduced expression and activation of phosphoinositide 3-kinase (PI3K) pathway components and cell cycle factors in patients with prolonged survival after therapy. Gene expression analysis revealed up-regulation of PI3K- and cell cycle-related pathways in patients with shorter PFS.

CONCLUSIONS: The OS and PFS of bevacizumab +/- erlotinib-treated patients with renal cell carcinoma were associated with changes in expression of protein and gene expression markers related to PI3K pathway and cell cycle signaling.

Author-supplied keywords

  • Angiogenesis Inhibitors
  • Angiogenesis Inhibitors: pharmacology
  • Angiogenesis Inhibitors: therapeutic use
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Monoclonal: pharmacology
  • Antibodies, Monoclonal: therapeutic use
  • Carcinoma, Renal Cell
  • Carcinoma, Renal Cell: blood supply
  • Carcinoma, Renal Cell: drug therapy
  • Carcinoma, Renal Cell: metabolism
  • Cell Cycle
  • Epidermal Growth Factor
  • Epidermal Growth Factor: antagonists & inhibitors
  • Gene Expression Profiling
  • Humans
  • Kidney Neoplasms
  • Kidney Neoplasms: blood supply
  • Kidney Neoplasms: drug therapy
  • Kidney Neoplasms: metabolism
  • Neoplasm Proteins
  • Neoplasm Proteins: metabolism
  • Oligonucleotide Array Sequence Analysis
  • Survival Analysis
  • Tumor Markers, Biological
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor A: antagonists

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Authors

  • D Tsavachidou-Fenner

  • N Tannir

  • P Tamboli

  • W Liu

  • D Petillo

  • B Teh

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