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      Sensitivity of human meningioma cells to the cyclin-dependent kinase inhibitor, TG02

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          Abstract

          Standards of care for meningioma include surgical resection and radiotherapy whereas pharmacotherapy plays almost no role in this disease. We generated primary cultures from surgically removed meningiomas to explore the activity of a novel cyclin-dependent kinase inhibitor, TG02, in meningioma cell cultures. Tumor and cell cultures were characterized by mutation profiling and DNA methylation profiling. DNA methylation data were used to allot each sample to one out of six previously established meningioma methylation classes: benign ( ben)-1, 2, 3, intermediate ( int)-A, B, and malignant ( mal). Four tumors assigned to the methylation class ben-2 showed the same class in culture whereas cultures from five non- ben-2 tumors showed a more malignant class in four patients. Cell cultures were uniformly sensitive to TG02 in the nanomolar range. Assignment of the cell cultures to a more malignant methylation class appeared to be more closely associated with TG02 sensitivity than assignment to a higher WHO grade of the primary tumors. Primary cell cultures from meningioma facilitate the investigation of the anti-meningioma activity of novel agents. TG02, an orally available cyclin-dependent kinase (CDK) inhibitor, warrants further exploration.

          Highlights

          • Standards of care for meningioma include surgical resection and radiotherapy whereas pharmacotherapy plays almost no role.

          • Primary cultures were established to explore the activity of a novel cyclin-dependent kinase inhibitor, TG02.

          • DNA methylation data were used to assign each sample to one out of six previously established methylation classes.

          • Cell cultures were uniformly sensitive to TG02 in the nanomolar range.

          • Methylation class of cell cultures was associated stronger with TG02 sensitivity than WHO grade of the primary tumor.

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          Most cited references12

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          Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

          We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
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            Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

            Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas 1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
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              Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets.

              With the number of prognostic and predictive genetic markers in neuro-oncology steadily growing, the need for comprehensive molecular analysis of neuropathology samples has vastly increased. We therefore developed a customized enrichment/hybrid-capture-based next-generation sequencing (NGS) gene panel comprising the entire coding and selected intronic and promoter regions of 130 genes recurrently altered in brain tumors, allowing for the detection of single nucleotide variations, fusions, and copy number aberrations. Optimization of probe design, library generation and sequencing conditions on 150 samples resulted in a 5-workday routine workflow from the formalin-fixed paraffin-embedded sample to neuropathological report. This protocol was applied to 79 retrospective cases with established molecular aberrations for validation and 71 prospective cases for discovery of potential therapeutic targets. Concordance of NGS compared to established, single biomarker methods was 98.0 %, with discrepancies resulting from one case where a TERT promoter mutation was not called by NGS and three ATRX mutations not being detected by Sanger sequencing. Importantly, in samples with low tumor cell content, NGS was able to identify mutant alleles that were not detectable by traditional methods. Information derived from NGS data identified potential targets for experimental therapy in 37/47 (79 %) glioblastomas, 9/10 (90 %) pilocytic astrocytomas, and 5/14 (36 %) medulloblastomas in the prospective target discovery cohort. In conclusion, we present the settings for high-throughput, adaptive next-generation sequencing in routine neuropathology diagnostics. Such an approach will likely become highly valuable in the near future for treatment decision making, as more therapeutic targets emerge and genetic information enters the classification of brain tumors.
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                Author and article information

                Contributors
                Journal
                Transl Oncol
                Transl Oncol
                Translational Oncology
                Neoplasia Press
                1936-5233
                08 September 2020
                December 2020
                08 September 2020
                : 13
                : 12
                : 100852
                Affiliations
                [a ]Department of Neurology, University Hospital Zurich, Zurich, Switzerland
                [b ]Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
                [c ]Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
                [d ]Department of Neuropathology, University of Heidelberg, Heidelberg, Germany
                [e ]Adastra Pharmaceuticals, San Diego, CA, United States of America
                [f ]Clinical Cooperation Unit Neuropathology, German Consortium for Transnational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
                [g ]Hopp Children's Cancer Center, Heidelberg, Germany
                Author notes
                [* ]Corresponding author at: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. michael.weller@ 123456usz.ch
                [1]

                Share first authorship.

                Article
                S1936-5233(20)30344-2 100852
                10.1016/j.tranon.2020.100852
                7490722
                07626e98-795d-4127-b3ab-be596553a8eb
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 24 June 2020
                : 29 June 2020
                Categories
                Original Research

                meningioma,tg02,mutation,methylation
                meningioma, tg02, mutation, methylation

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