Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome

Integrins alpha v beta 3 and alpha v beta 5 regulate angiogenesis and invasiveness in cancer, potentially by modulating activation of the transforming growth factor (TGF)-beta 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 O-6-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, alpha v beta 3 and alpha v beta 5 integrins, of alpha v beta 8 and of their putative target, phosphorylation of SMAD2, in tumor tissues from CENTRIC (n=274) and CORE (n=224). alpha v beta 3 and alpha v beta 5 expression correlated well in tumor and endothelial cells, but showed little association with alpha v beta 8 or pSMAD2 levels. In CENTRIC, there was no interaction between the biomarkers and treatment for prediction of outcome. In CORE, higher alpha v beta 3 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 alpha v beta 3, alpha v beta 5 and alpha v beta 8 are differentially expressed in glioblastoma. Integrin levels do not correlate with the activation level of the canonical TGF-beta pathway. alpha v beta 3 integrin expression may predict benefit from integrin inhibition in patients with =glioblastoma lacking MGMT promoter methylation.