Oncotarget

Research Papers:

Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome

Michael Weller _, Louis Burt Nabors, Thierry Gorlia, Henning Leske, Elisabeth Rushing, Pierre Bady, Christine Hicking, James Perry, Yong-Kil Hong, Patrick Roth, Wolfgang Wick, Simon L. Goodman, Monika E. Hegi, Martin Picard, Holger Moch, Josef Straub and Roger Stupp

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Oncotarget. 2016; 7:15018-15032. https://doi.org/10.18632/oncotarget.7588

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Abstract

Michael Weller1, Louis Burt Nabors2, Thierry Gorlia3, Henning Leske4, Elisabeth Rushing4, Pierre Bady5,6,7, Christine Hicking8, James Perry9, Yong-Kil Hong10, Patrick Roth1, Wolfgang Wick11,12, Simon L. Goodman8, Monika E. Hegi7, Martin Picard8, Holger Moch13, Josef Straub8, Roger Stupp14

1Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland

2University of Alabama at Birmingham, Birmingham, AL, USA

3EORTC Data Centre, Brussels, Belgium

4Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland

5Department of Education and Research, University of Lausanne, Lausanne, Switzerland

6SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland

7Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland

8Department of Translational and Biomarkers Research, Oncology, Merck KGaA, Darmstadt, Germany

9Sunnybrook Health Sciences Centre, Toronto, ON, Canada

10The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea

11Neurology Clinic, University of Heidelberg, Heidelberg, Germany

12Clinical Cooperation Unit (CCU) Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

13Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland

14Department of Oncology, University Hospital Zurich, Zurich, Switzerland

Correspondence to:

Michael Weller, e-mail: [email protected]

Keywords: glioblastoma, integrin, pSmad, TGF-β, biomarker

Received: January 03, 2016    Accepted: January 29, 2016    Published: February 22, 2016

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.


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