1. Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies.
- Author
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Brauer MJ, Zhuang G, Schmidt M, Yao J, Wu X, Kaminker JS, Jurinka SS, Kolumam G, Chung AS, Jubb A, Modrusan Z, Ozawa T, James CD, Phillips H, Haley B, Tam RN, Clermont AC, Cheng JH, Yang SX, Swain SM, Chen D, Scherer SJ, Koeppen H, Yeh RF, Yue P, Stephan JP, Hegde P, Ferrara N, Singh M, and Bais C
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents pharmacology, Bevacizumab, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Disease Models, Animal, Drug Evaluation, Preclinical, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Neoplasms genetics, Neoplasms mortality, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Neuroendocrine Tumors drug therapy, Neuroendocrine Tumors genetics, Neuroendocrine Tumors metabolism, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Neoplasms metabolism, Signal Transduction drug effects, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism
- Abstract
Purpose: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients., Experimental Design: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy., Results: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies., Conclusions: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials., (©2013 AACR.)
- Published
- 2013
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