Artikel
Effective therapy or driver of tumour aggression? Effects of long-term temozolomide treatment on stem-like GBM cells with different molecular profiles
Effektive Therapie oder treibende Kraft für aggressives Tumorwachstum? Auswirkungen der Langzeitbehandlung mit Temozolomid auf GBM-Stammzellen unterschiedlicher molekularer Charakteristika
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Autoren
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Jonas Feldheim
- University Hospital Essen, Department of Neurology, Division of Clinical Neurooncology, Essen, Deutschland; University of Würzburg, Department of Neurosurgery, Tumourbiology Laboratory, Würzburg, Deutschland
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Julia J. Feldheim
- University of Würzburg, Department of Neurosurgery, Tumourbiology Laboratory, Würzburg, Deutschland; University Hospital Essen, Department of Neurosurgery, Essen, Deutschland
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Ellina Schulz
- University of Würzburg, Department of Neurosurgery, Tumourbiology Laboratory, Würzburg, Deutschland
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Almuth Friederike Keßler
- University of Würzburg, Department of Neurosurgery, Tumourbiology Laboratory, Würzburg, Deutschland
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David Wend
- University of Würzburg, Department of Neurosurgery, Tumourbiology Laboratory, Würzburg, Deutschland
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Sebastian Brandner
- Queen Square, UCL Queen Square Institute of Neurology, Division of Neuropathology, London, Vereinigtes Königreich
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Ralf-Ingo Ernestus
- University of Würzburg, Department of Neurosurgery, Tumourbiology Laboratory, Würzburg, Deutschland
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Camelia Monoranu
- University of Würzburg, Institute of Pathology, Department of Neuropathology, Würzburg, Deutschland
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Mario Löhr
- University of Würzburg, Department of Neurosurgery, Tumourbiology Laboratory, Würzburg, Deutschland
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Carsten Hagemann
- University of Würzburg, Department of Neurosurgery, Tumourbiology Laboratory, Würzburg, Deutschland
| Veröffentlicht: | 4. Juni 2021 |
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Gliederung
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Objective: Glioblastoma multiforme (GBM) is one of the most aggressive cancers, with an overall survival of less than 2 years in over 60% of patients. Chemotherapy with temozolomide (TMZ) is the most commonly applied standard treatment. However, the effect of TMZ is counteracted by the cellular repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Its expression is regulated by the methylation of its promoter, making it a valuable prognostic and therapeutic biomarker. Previously, it has been shown that MGMT promoter methylation can change between primary tumour and recurrence and that TMZ might play a significant role in this phenomenon. However, these changes are not acknowledged by clinical guidelines yet, and their therapeutic implications are unclear.
Methods: We treated 3 patient-derived stem-like GBM cell lines with different molecular profiles with TMZ in an on/off scheme or continuously, reflecting the current therapeutic standard. We collected 144 samples to examine the MGMT promoter methylation of these cells by high resolution melting PCR, migration and proliferation by xCELLigence and TMZ-response by MTT assays 0, 4 and 8 weeks after treatment.
Results: We observed persistent and strong effects of TMZ treatment on MGMT promoter-methylated cells even after end of treatment. TMZ led to a decrease of MGMT promoter hypermethylation from 100% to 5-25% and a migratory rather than a proliferative phenotype. Cells without MGMT promoter methylation grew more aggressively after 6 weeks of long-term TMZ treatment (median doubling time with DMSO: 217h vs. TMZ: 63h, p<0.05). Isocitrate dehydrogenase mutated GBM cells and cells with initially low MGMT methylation showed varied response. There was a difference of 0.05 delta cell index/h in their migration rate in case the cells were treated with an on/off scheme (95% CI: 0.03-0.07, p<0.001), whereas cells did not change migration when treated with a continuous scheme (p>0.05).
Conclusion: Our results indicate that it might be useful to re-evaluate the current concept of TMZ chemotherapy and instead implement a therapeutic scheme based on molecular characteristics. Also, it may be interesting to determine additional pathogenic mutations that might occur during relapse due to TMZ treatment. Our observations are a starting point for further investigations, especially on co-interaction of TMZ and MGMT promoter methylation during recurrence development, based on molecular features of the primary tumour.
