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: 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, Roger Stupp
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 12 Pg. 15018-32 (Mar 22 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26918452 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Biomarkers, Tumor
• Integrin alphaVbeta3
• Receptors, Vitronectin
• SMAD2 protein, human
• Smad2 Protein
• Snake Venoms
• integrin alphaVbeta5
• Cilengitide

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (metabolism)
• Cohort Studies
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Integrin alphaVbeta3 (metabolism)
• Male
• Middle Aged
• Neoplasm Staging
• Prognosis
• Receptors, Vitronectin (metabolism)
• Smad2 Protein (metabolism)
• Snake Venoms (therapeutic use)
• Survival Rate
• Young Adult