Abstract
Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and its prognostic impact in a glioblastoma series of patients scheduled to undergo the Stupp protocol as first-line treatment for GBM. The integrin α5 protein expression level was estimated in each tumor by the mean fluorescence intensity (MFI) and allowed us to identify two subpopulations showing either a high or low expression level. The distribution of patients in both subpopulations was not significantly different according to age, gender, recursive partitioning analysis (RPA) prognostic score, molecular markers or surgical and medical treatment. A high integrin α5 protein expression level was associated with a high risk of recurrence (HR = 1.696, 95% CI 1.031–2.792, p = 0.0377) and reduced overall survival (OS), even more significant in patients who completed the Stupp protocol (median OS: 15.6 vs. 22.8 months; HR = 2.324; 95% CI 1.168–4.621, p = 0.0162). In multivariate analysis, a high integrin α5 protein expression level was confirmed as an independent prognostic factor in the subpopulation of patients who completed the temozolomide-based first-line treatment for predicting OS over age, extent of surgery, RPA score and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (p = 0.029). In summary, for the first time, our study validates that a high integrin α5 protein expression level is associated with poor prognosis in GBM and confirms its potential as a therapeutic target implicated in the Stupp protocol resistance.
Highlights
PFS: progression-free survival; OS: overall survival; HR: hazard ratio; 95% CI: 95% confidence interval; y: year; RPA: recursive partitioning analysis; MGMT: O-6-methylguanine-DNA methyltransferase. * log-rank test, p < 0.05 was considered as significant
PFS: progression-free survival; OS: overall survival; HR: hazard ratio; 95% CI: 95% confidence interval; y: year; RPA: recursive partitioning analysis; MGMT: O-6-methylguanine-DNA methyltransferase. * multivariate COX regression analysis, p < 0.05 was considered as significant
Several integrins are described as pertinent therapeutic targets in GBM, the first clinical trial with an αvβ3 integrin antagonist failed [14,35]
Summary
Pharmaceuticals 2021, 14, 882 sification of Tumors of the Central Nervous System (CNS) integrating both histological and molecular information. Glioblastoma (GBM), a grade IV diffuse glioma, belongs to the most refractory tumors to conventional or targeted therapies [1]. At the level of molecular biomarkers, GBMs are defined first by an IDH1 wild-type status. In these tumors, a marked overall genomic profile heterogeneity led to the definition of four molecular subclasses, mesenchymal, pro-neural, neural and classical forms of GBM, with the mesenchymal one being the most aggressive [3]. New treatments are urgently required, and the definition of GBM subpopulations is supposed to be better responders to the targeting of specific pathways
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