Plasma angiopoietin-2 (ANG2) as an angiogenic biomarker in renal cell carcinoma (RCC).

Abstract

4630 Background: Several small molecules targeting angiogenic receptor tyrosine kinases (TKIs) are approved for treatment of advanced RCC. While many patients (pts) respond to TKIs, resistance develops in all. Ang2 is a secreted glycoprotein that is upregulated at sites of angiogenesis and has been implicated in cancer neovascularization. Ang2 is elevated in many cancer states, and higher levels are associated with poor prognosis. Recent studies have also suggested efficacy of combined angiopoietin and VEGFR inhibition as therapy in advanced RCC. Methods: Levels of circulating angiogenic cytokines, including Ang2, FGF, PlGF, sVEGFR, and VEGF, were measured in plasma collected from 34 pts with metastatic RCC. Plasma Ang2 concentration was measured by ELISA in duplicate samples collected at baseline, on treatment with sunitinib (median 34.5 days after starting sunitinib), and at resistance to sunitinib. Ang2 was also measured in plasma collected from 8 pts with stage I RCC prior to nephrectomy and 8 controls without RCC. Statistical significance was calculated by Wilcoxon sign rank test for paired data and Wilcoxon rank sum test for unpaired data. Results: Ang2 is significantly higher in pts with metastatic RCC (n=34) compared to controls (n=8) (median 3870 vs 1618 pg/ml; p<0.01) and pts with stage I RCC (n=8, median 2489 pg/ml; p=0.02). There is a trend toward higher Ang2 among pts with stage I disease vs controls (p=0.10). Among the 26 pts with metastatic RCC evaluated at baseline and on treatment with sunitinib, Ang2 decreased in 88% (23/26; p<0.01). Of the 20 pts who had progressed and had on treatment Ang2 levels at the time of analysis, Ang2 decreased with initiation of sunitinib in 90% (18/20; p<0.01), and then increased at resistance in 70% (14/20; p=0.08). Conclusions: Our data show that plasma Ang2 concentration is elevated in pts with RCC, and that this may correlate with disease burden. Ang2 decreases in pts treated with sunitinib and increases at the time of resistance to sunitinib. These data are consistent with the hypothesis that VEGFR inhibition leads to a loss of Ang2 expression, and that disease progression may be mediated at least in part by a rise in Ang2. Thus, Ang2 is a potential therapeutic target in TKI resistant RCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Pfizer Pfizer