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Molecular predictors for decitabine efficacy in meningiomas – a pilot study

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Abstract

Purpose

Effective chemotherapeutical agents for the treatment of meningiomas are still lacking. Previous in-vitro analyses revealed efficacy of decitabine (DCT), a DNA methyltransferase (DNMT) inhibitor established in the treatment of leukemia, in a yet undefined subgroup of meningiomas.

Methods

Effects of DCT on proliferation and viability was analyzed in primary meningioma cells by immunofluorescence and MTT assays, and cases were classified as drug responders and non-responders. Molecular preconditions for efficacy were analyzed using immunofluorescence for Ki67, DNMT1, and five oncogenes (TRIM58, FAM84B, ELOVL2, MAL2, LMO3) previously found to be differentially methylated after DCT exposition, as well as by genome-wide DNA methylation analyses.

Results

Efficacy of DCT (10µM) was found in eight (62%) of 13 meningioma cell lines 48 h after drug exposition (p < .05). DCT significantly reduced DNMT1 expression in all but two cell lines, and median ΔDNMT1 reduction 48 h after drug exposition was lower in DCT-resistant (-11.1%) than in DCT-sensitive (-50.5%, p = .030) cells. Rates of cell lines responsive to DCT exposition distinctly decreased to 25% after 72 h. No significant correlation of the patients´ age, sex, histological subtype, location of the paternal tumor, expression of Ki67, DNMT1 or the analyzed oncogenes with treatment response was found (p > .05, each). DCT efficacy was further independent of the methylation class and global DNA methylation of the paternal tumor.

Conclusion

Early effects of DCT in meningiomas are strongly related with DNMT1 expression, while clinical, histological, and molecular predictors for efficacy are sparse. Kinetics of drug efficacy might indicate necessity of repeated exposition and encourage further analyses.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Author notes

  1. Dorothee C. Spille1, Christian Thomas, Volker Senner and Benjamin Brokinkel contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, North Rhine-Westphalia, Germany

    Dorothee C. Spille, Julian Canisius, Eva Christine Bunk, Walter Stummer & Benjamin Brokinkel

  2. Institute of Neuropathology, University Hospital Münster, Münster, North Rhine-Westphalia, Germany

    Christian Thomas, Andrea Wagner, Werner Paulus, Volker Senner & Benjamin Brokinkel

  3. Department of Neurology, University of Münster, Münster, North Rhine-Westphalia, Germany

    Oliver Martin Grauer

  4. Department of Radiation Oncology, University Hospital Münster, Münster, North Rhine-Westphalia, Germany

    Hans T. Eich

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  1. Dorothee C. Spille
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Dorothee Cäcilia Spille, Volker Senner, Andrea Wagner, Julian Canisius, Christian Thomas and Eva Christine Bunk. Oliver Martin Grauer, Werner Paulus, Hans T. Eich and Walter Stummer provided scientific supervision. The first draft of the manuscript was written by Benjamin Brokinkel and Dorothee Cäcilia Spille, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Benjamin Brokinkel.

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Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the local Ethics Committee (Ethikkommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität Münster, 022-014-f-S).

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11060_2023_4379_MOESM1_ESM.tif

Suppl. Figure 1: Illustrative examples of the expression of the analyzed oncogenes in treatment-naïve meningioma cell lines. Immunofluorescence showed strong (MAL2, A, magnification 200-fold; ELOVL2, B, 100x; LMO3, C, magnification 200-fold) or moderate expression (TRIM58, D, 200x; FAM84B, E, magnification 100-fold) and therefore confirmed previous in-vivo findings.

Supplementary Material 2: Tables 1 and 2

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Spille, D.C., Thomas, C., Wagner, A. et al. Molecular predictors for decitabine efficacy in meningiomas – a pilot study. J Neurooncol 164, 97–105 (2023). https://doi.org/10.1007/s11060-023-04379-3

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