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Published on: January 9, 2019
Cilengitide response in ultra-low passage glioblastoma cell lines: relation to molecular markers
Christina S Mullins1, Julia Schubert, Björn Schneider
1University Children's Hospital, University Medicine, Ernst-Heydemann-Straße 8, 18057 Rostock, Germany. christina.mullins@uni-rostock.de
Purpose:
In glioblastoma multiforme (GBM), a tumor still characterized by dismal prognosis, recent research focuses on novel-targeted compounds, in addition to standard temozolomide (TMZ) chemotherapy. One of these emerging compounds is cilengitide (CGT), which by binding to integrins (i.e., αvβ3 and αvβ5) may inhibit angiogenesis and also is directly cytotoxic to tumor cells by interfering with intracellular signaling pathways.
Methods:
A total of ten patient-derived ultra-low passage GBM cell lines were treated with increasing doses of CGT, TMZ, and a combination of both substances. Inhibitory concentrations of 50% (IC₅₀) were determined for the single agents and as a combination. Cell lines were stratified according to MGMT promoter methylation. The expression of relevant integrins was assessed by flow cytometry.
Results:
In monotherapy, all GBM cell lines showed higher sensitivity to CGT than to TMZ, as determined by IC₅₀ values in relation to clinically relevant patient plasma levels. MGMT promoter methylation correlated with a significantly higher TMZ response, but tended to be associated with a lower CGT response. Response to CGT was not correlated with cell surface integrin expression as measured by flow cytometry. Finally, addition of CGT to TMZ enhanced growth inhibition, but only in those cell lines with a methylated MGMT promoter.
Conclusions:
As suggested by this analysis, patients with MGMT promoter-methylated GBM may benefit from addition of CGT to the standard TMZ treatment, while patients with MGMT promoter-unmethylated GBM may better respond to CGT monotherapy.
Insights
Cilengitide (CGT) combined with temozolomide (TMZ) may improve glioblastoma treatment for patients with methylated MGMT promoters. Unmethylated tumors might respond better to CGT alone.
Area of Science:
- Neuro-oncology
- Molecular targeted therapy
- Cancer drug development
Background:
- Glioblastoma multiforme (GBM) has a poor prognosis, necessitating novel therapeutic strategies beyond standard temozolomide (TMZ).
- Cilengitide (CGT), an integrin-binding compound, shows potential by inhibiting angiogenesis and exerting direct cytotoxicity.
- Understanding treatment response based on tumor molecular characteristics, such as MGMT promoter methylation, is crucial.
Purpose of the Study:
- To evaluate the efficacy of cilengitide (CGT) and temozolomide (TMZ) in patient-derived glioblastoma (GBM) cell lines.
- To investigate the impact of MGMT promoter methylation status on treatment response to CGT and TMZ.
- To determine the optimal combination strategy for GBM treatment based on molecular profiles.
Main Methods:
- Ten patient-derived GBM cell lines were treated with varying doses of CGT, TMZ, and their combination.
- Inhibitory concentrations (IC₅₀) were determined for single agents and combinations.
- MGMT promoter methylation status was assessed, and integrin expression was measured via flow cytometry.
Main Results:
- GBM cell lines demonstrated greater sensitivity to CGT than TMZ as monotherapy.
- MGMT promoter methylation correlated with higher TMZ response but lower CGT response.
- CGT addition to TMZ enhanced growth inhibition specifically in MGMT-methylated cell lines.
Conclusions:
- Patients with MGMT promoter-methylated GBM may benefit from the addition of CGT to standard TMZ therapy.
- Patients with MGMT promoter-unmethylated GBM might respond more favorably to CGT monotherapy.
- Treatment stratification based on MGMT methylation status could personalize GBM therapy.
