Reverse-phase protein array marker evaluation of protein expression patterns related to anti-angiogenesis treatment in renal cell carcinoma

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16016 Background: Renal carcinoma patients treated with anti-VEGF therapy (bevacizumab) typically exhibit 10–15% partial responses with detectable primary tumor shrinkage in 70% of the cases (Rini B.I., Clin Cancer Res, 2007). It is not well known which factors determine response or are modulated by therapy. In this study, primary tumors from patients treated with bevacizumab-erlotinib were screened for protein expression of markers representing a broad spectrum of signaling pathways, including AKT, MAPK, angiogenesis, cell growth and apoptosis pathways. Methods: 32 patients with metastatic clear-cell renal carcinoma received bevacizumab 10mg/kg IV Q14 days for a total of 4 infusions plus erlotinib 150mg PO daily for 8 weeks. Nephrectomies were performed 2 weeks after last dose of erlotinib, 4 weeks after last dose of bevacizumab. Tumor and matched normal renal tissue specimens were histologically confirmed and subjected to protein extraction. Lysates were serially diluted and spotted on protein array slides. The arrays were stained with 47 specific antibodies for protein detection. Data were normalized and analyzed according to unsupervised hierarchical clustering approaches, for detecting patterns of protein expression across samples. VHL status (deletions and mutations) was also assessed for each tumor. Results: The protein array method clearly separated normal renal tissue from tumor samples according to their protein expression patterns, as demonstrated by unsupervised hierarchical clustering. Furthermore, duplicate and replicate preparations clustered tightly with their tumor specimen of origin, demonstrating marked reproducibility of the technique, and limited intra-tumor heterogeneity of the biomarkers being analyzed. Treated primary tumors with more than or equal to 10% shrinkage grouped into a distinct protein expression cluster. This cluster was driven mainly by 8 factors (p<0.001) with PTEN being the most prominent (increased expression in the ≥10% shrinkage cluster, p<1.3*10-7). This response group correlated with VHL copy loss (p<0.02). Conclusions: Bevacizumab-erlotinib treated renal tumors reveal distinct protein expression signatures according to the degree of primary tumor response. No significant financial relationships to disclose.

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