title: Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome.
abstract: Integrins αvβ3 and αvβ5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-β pathway. The randomized phase III CENTRIC and phase II CORE trials explored the integrin inhibitor cilengitide in patients with newly diagnosed glioblastoma with versus without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. These trials failed to meet their primary endpoints.Immunohistochemistry was used to assess the levels of the target integrins of cilengitide, αvβ3 and αvβ5 integrins, of αvβ8 and of their putative target, phosphorylation of SMAD2, in tumor tissues from CENTRIC (n=274) and CORE (n=224).αvβ3 and αvβ5 expression correlated well in tumor and endothelial cells, but showed little association with αvβ8 or pSMAD2 levels. In CENTRIC, there was no interaction between the biomarkers and treatment for prediction of outcome. In CORE, higher αvβ3 levels in tumor cells were associated with improved progression-free survival by central review and with improved overall survival in patients treated with cilengitide.Integrins αvβ3, αvβ5 and αvβ8 are differentially expressed in glioblastoma. Integrin levels do not correlate with the activation level of the canonical TGF-β pathway. αvβ3 integrin expression may predict benefit from integrin inhibition in patients with glioblastoma lacking MGMT promoter methylation.
authors.affiliation: Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Louis Burt
authors.initials: LB
authors.lastname: Nabors
authors.affiliation: EORTC Data Centre, Brussels, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.affiliation: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Henning
authors.initials: H
authors.lastname: Leske
authors.affiliation: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rushing
authors.affiliation: Department of Education and Research, University of Lausanne, Lausanne, Switzerland.|SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.|Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bady
authors.affiliation: Department of Translational and Biomarkers Research, Oncology, Merck KGaA, Darmstadt, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hicking
authors.affiliation: Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Perry
authors.affiliation: The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Korea.
authors.forename: Yong-Kil
authors.initials: YK
authors.lastname: Hong
authors.affiliation: Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roth
authors.affiliation: Neurology Clinic, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Department of Translational and Biomarkers Research, Oncology, Merck KGaA, Darmstadt, Germany.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Goodman
authors.affiliation: Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
authors.affiliation: Department of Translational and Biomarkers Research, Oncology, Merck KGaA, Darmstadt, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Department of Translational and Biomarkers Research, Oncology, Merck KGaA, Darmstadt, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Straub
authors.affiliation: Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D019030:Receptors, Vitronectin / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism*; D012910:Snake Venoms / Q000627:therapeutic use*; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D039302:Integrin alphaVbeta3; D019030:Receptors, Vitronectin; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D012910:Snake Venoms; C064660:integrin alphaVbeta5; C422910:Cilengitide
keywords: TGF-β; biomarker; glioblastoma; integrin; pSmad