Artikel
MicroRNAs as potential “tissue sensitisers” for the augmentation of glioblastoma immunotherapy
MicroRNAs als Therapeutika zur Verbesserung des Ansprechens von Glioblastomen auf Immuntherapie
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Autoren
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Friedrich Erhart
- Medizinische Universität Innsbruck, Universitätsklinik für Neurochirurgie, Wien, Austria
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Alexandra Lang
- Medizinische Universität Innsbruck, Universitätsklinik für Neurochirurgie, Wien, Austria
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Matthias Hackl
- TAmiRNA GmbH, Wien, Austria
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Barbara Kiesel
- Medizinische Universität Innsbruck, Universitätsklinik für Neurochirurgie, Wien, Austria
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Mario Mischkulnig
- Medizinische Universität Innsbruck, Universitätsklinik für Neurochirurgie, Wien, Austria
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Petra Andreea Mercea
- Medizinische Universität Innsbruck, Universitätsklinik für Neurochirurgie, Wien, Austria
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Sabine Spiegl-Kreinecker
- Johannes Kepler Universität Linz, Universitätsklinik für Neurochirurgie, Linz, Austria
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Daniela Lötsch-Gojo
- Medizinische Universität Innsbruck, Institut für Krebsforschung, Wien, Austria
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Adelheid Woehrer
- Medizinische Universität Innsbruck, Klinisches Institut für Neurologie, Wien, Austria
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Christine Marosi
- Medizinische Universität Innsbruck, Klinische Abteilung für Onkologie, Wien, Austria
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Karl Rössler
- Medizinische Universität Innsbruck, Universitätsklinik für Neurochirurgie, Wien, Austria
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Walter Berger
- Medizinische Universität Innsbruck, Institut für Krebsforschung, Wien, Austria
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Georg Widhalm
- Medizinische Universität Innsbruck, Universitätsklinik für Neurochirurgie, Wien, Austria
| Veröffentlicht: | 26. Juni 2020 |
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Gliederung
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Objective: Glioblastoma is the most frequent and most aggressive malignant brain tumor. Immunotherapies have so far not lived up to their promise. This is also true for a dendritic cell vaccination that was tested recently in a pan-Austrian phase II clinical trial. It failed to prolong survival. To better understand the reasons for treatment resistance and to explore novel therapeutic modalities, glioblastoma tissue from trial patients underwent a number of molecular and cellular analyses. In molecular biology, microRNAs (miRNAs) are increasingly recognized as potential master regulators of tissue phenotypes since one miRNA can regulate hundreds of messenger RNAs (mRNAs). was therefore also A microRNA sequencing approach was therefore also among the tissue investigation methods It led to the identification of miRNAs that seem to be survival-associated. The goal is now to develop these miRNAs towards a therapeutic usage in the context of immunotherapies.
Methods: In a first exploratory phase, glioblastoma tissue from 16 trial patients underwent miRNA sequencing. Then, in a validation phase, tissue from 38 trial patients underwent qRT-PCR, where miRNAs found in the exploratory phase were confirmed. In the current subsequent experiments, identified miRNAs are being characterized further. On the one hand, histopathology analyses (via in-situ hybridization) are being done to elucidate the cell type and the (sub)cellular location of the identified miRNAs. On the other hand, cell culture experiments are being carried out where miRNAs are artificially introduced into glioblastoma cells and the effects on gene expression, phenotype and function are evaluated.
Results: MiRNAs that were found to be apparently survival-associated included miR-216b, miR-216a, miR-708 and hsa-let-7i. They were more abundant in patients that survived relatively long under immunotherapy and could significantly separate Kaplan-Meier curves.
Conclusion: MiRNAs seem to be relevant players in glioblastoma immunotherapy research. In the future, they might serve as therapeutic "tissue sensitizers" to make glioblastoma more susceptible to immunotherapies. Further preclinical and clinical work will be necessary to achieve that goal.
Figure 1 [Fig. 1]
