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Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome
Michael Weller1, Louis Burt Nabors2, Thierry Gorlia3
1Department of Neurology, University Hospital Zurich and University of 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.
Insights
Integrin αvβ3 levels may predict glioblastoma patient response to cilengitide treatment, particularly in those lacking O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Further research is needed to confirm these findings.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Integrins αvβ3 and αvβ5 are implicated in cancer angiogenesis and invasiveness, potentially through transforming growth factor (TGF)-β pathway modulation.
- The integrin inhibitor cilengitide was investigated in newly diagnosed glioblastoma patients in the CENTRIC and CORE trials.
- Both trials failed to meet their primary endpoints, necessitating further biomarker analysis.
Purpose of the Study:
- To investigate the expression of integrins αvβ3, αvβ5, αvβ8, and phosphorylated SMAD2 (pSMAD2) in glioblastoma tissues.
- To determine if these biomarkers correlate with treatment outcomes in patients receiving cilengitide.
- To explore the predictive value of integrin expression for cilengitide efficacy in glioblastoma.
Main Methods:
- Immunohistochemistry was employed to quantify integrin αvβ3, αvβ5, αvβ8, and pSMAD2 levels in tumor samples from the CENTRIC (n=274) and CORE (n=224) trials.
- Statistical analyses were performed to assess correlations between biomarker levels and clinical outcomes.
- Exploratory analyses investigated treatment-biomarker interactions for predicting patient outcomes.
Main Results:
- αvβ3 and αvβ5 expression showed strong correlation in tumor and endothelial cells but limited association with αvβ8 or pSMAD2.
- No significant treatment-biomarker interaction was observed in the CENTRIC trial for predicting outcomes.
- In the CORE trial, higher αvβ3 levels in tumor cells correlated with improved progression-free and overall survival in patients treated with cilengitide.
Conclusions:
- Integrins αvβ3, αvβ5, and αvβ8 exhibit differential expression patterns in glioblastoma.
- Integrin expression levels do not consistently correlate with the activation status of the canonical TGF-β pathway.
- αvβ3 integrin expression may serve as a predictive biomarker for response to integrin inhibition in glioblastoma patients without MGMT promoter methylation.
