American Association for Cancer Research
10780432ccr123635-sup-fig2.pdf (707.4 kB)

Supplementary Figure 2 from Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies

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journal contribution
posted on 2023-03-31, 17:42 authored by 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. Swain, Daniel Chen, Stefan J. Scherer, Hartmut Koeppen, Ru-Fang Yeh, Peng Yue, Jean-Philippe Stephan, Priti Hegde, Napoleone Ferrara, Mallika Singh, Carlos Bais

PDF file - 708K, Fig S2A. Histological evidence for the in vivo activity of VEGF pathway inhibitors in MDA-MB-231 tumors. Fig S2B. In vivo VEGF blockade or VEGFR-2 downstream signaling inhibition induces consistent downregulation of proxVDV genes. Fig S2C. The proxVDV gene ESM1 is an in vivo VEGF target specifically expressed in tumor-associated vasculature



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. Clin Cancer Res; 19(13); 3681–92. ©2013 AACR.