Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies

Matthew J. Brauer, Guanglei Zhuang, Maike Schmidt, Jenny Yao, Xiumin Wu, Joshua S. Kaminker, Stefanie S. Jurinka, Ganesh Kolumam, Alicia S. Chung, Adrian Jubb, Zora Modrusan, Tomoko Ozawa, C. David James, Heidi Phillips, Benjamin Haley, Rachel N W Tam, Anne C. Clermont, Jason H. Cheng, Sherry X. Yang, Sandra M. SwainDaniel Chen, Stefan J. Scherer, Hartmut Koeppen, Ru Fang Yeh, Peng Yue, Jean Philippe Stephan, Priti Hegde, Napoleone Ferrara, Mallika Singh*, Carlos Bais

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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 higherVDVexpression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies. Conclusions: In thiswork,weidentifiedsurrogatemarkers(VDVgenes) for in vivo VEGFsignaling intumors 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.

Original languageEnglish (US)
Pages (from-to)3681-3692
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number13
DOIs
StatePublished - Jul 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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