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Oncotarget. 2016 Mar 22;7(12):15018-32. doi: 10.18632/oncotarget.7588.

Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome.

Author information

1
Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
2
University of Alabama at Birmingham, Birmingham, AL, USA.
3
EORTC Data Centre, Brussels, Belgium.
4
Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
5
Department of Education and Research, University of Lausanne, Lausanne, Switzerland.
6
SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
7
Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland.
8
Department of Translational and Biomarkers Research, Oncology, Merck KGaA, Darmstadt, Germany.
9
Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
10
The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Korea.
11
Neurology Clinic, University of Heidelberg, Heidelberg, Germany.
12
Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
13
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
14
Department of Oncology, University Hospital Zurich, Zurich, Switzerland.

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.

KEYWORDS:

TGF-β; biomarker; glioblastoma; integrin; pSmad

PMID:
26918452
PMCID:
PMC4924768
DOI:
10.18632/oncotarget.7588
[Indexed for MEDLINE]
Free PMC Article

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