title: Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94131, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brauer
authors.forename: Guanglei
authors.initials: G
authors.lastname: Zhuang
authors.forename: Maike
authors.initials: M
authors.lastname: Schmidt
authors.forename: Jenny
authors.initials: J
authors.lastname: Yao
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Kaminker
authors.forename: Stefanie S
authors.initials: SS
authors.lastname: Jurinka
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kolumam
authors.forename: Alicia S
authors.initials: AS
authors.lastname: Chung
authors.forename: Adrian
authors.initials: A
authors.lastname: Jubb
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozawa
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Heidi
authors.initials: H
authors.lastname: Phillips
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.forename: Rachel N W
authors.initials: RN
authors.lastname: Tam
authors.forename: Anne C
authors.initials: AC
authors.lastname: Clermont
authors.forename: Jason H
authors.initials: JH
authors.lastname: Cheng
authors.forename: Sherry X
authors.initials: SX
authors.lastname: Yang
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Swain
authors.forename: Daniel
authors.initials: D
authors.lastname: Chen
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Ru-Fang
authors.initials: RF
authors.lastname: Yeh
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Stephan
authors.forename: Priti
authors.initials: P
authors.lastname: Hegde
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Mallika
authors.initials: M
authors.lastname: Singh
authors.forename: Carlos
authors.initials: C
authors.lastname: Bais
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab