title: Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept.
abstract: OBJECTIVE
  VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma.
  
  
  METHODS
  In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients.
  
  
  RESULTS
  Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1(+) monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9.
  
  
  CONCLUSIONS
  These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis.
authors.affiliation: Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. jdegroot@mdanderson.org
authors.forename: John F
authors.initials: JF
authors.lastname: de Groot
authors.forename: Yuji
authors.initials: Y
authors.lastname: Piao
authors.forename: Hai
authors.initials: H
authors.lastname: Tran
authors.forename: Mark
authors.initials: M
authors.lastname: Gilbert
authors.forename: Hua-Kang
authors.initials: HK
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: B Nebiyou
authors.initials: BN
authors.lastname: Bekele
authors.forename: Tim
authors.initials: T
authors.lastname: Cloughesy
authors.forename: Minesh
authors.initials: M
authors.lastname: Mehta
authors.forename: H Ian
authors.initials: HI
authors.lastname: Robins
authors.forename: Andrew
authors.initials: A
authors.lastname: Lassman
authors.forename: Lisa
authors.initials: L
authors.lastname: DeAngelis
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.forename: W K A
authors.initials: WK
authors.lastname: Yung
authors.forename: Michael
authors.initials: M
authors.lastname: Prados
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000097:blood; D058990:Molecular Targeted Therapy; D009000:Monocytes / Q000378:metabolism; D011859:Radiography; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012008:Recurrence; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000652:urine; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016207:Cytokines; D008565:Membrane Proteins; C098069:PIGF protein, human; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1