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  • Kool, Marcel  (12)
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  • 1
    In: Neuro-Oncology, 2016, Vol. 18(suppl3), pp.iii110-iii110
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
  • 3
    Language: English
    In: Ecker, J., I. Oehme, R. Mazitschek, A. Korshunov, M. Kool, T. Hielscher, J. Kiss, et al. 2015. “Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma.” Acta Neuropathologica Communications 3 (1): 22. doi:10.1186/s40478-015-0201-7. http://dx.doi.org/10.1186/s40478-015-0201-7.
    Description: Introduction: Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Four subgroups with distinct genetic, epigenetic and clinical characteristics have been identified. Survival remains particularly poor in patients with Group 3 tumors harbouring a MYC amplification. We herein explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs. Material and Methods Expression of HDACs in primary MB subgroups was compared to normal brain tissue. A panel of MB cell lines, including Group 3 MYC amplified cell lines, were used as model systems. Cells were treated with HDAC inhibitors (HDACi) selectively targeting class I or IIa HDACs. Depletion of HDAC2 was performed. Intracellular HDAC activity, cellular viability, metabolic activity, caspase activity, cell cycle progression, RNA and protein expression were analyzed. Results: HDAC2 was found to be overexpressed in MB subgroups with poor prognosis (SHH, Group 3 and Group 4) compared to normal brain and the WNT subgroup. Inhibition of the enzymatic activity of the class I HDACs reduced metabolic activity, cell number, and viability in contrast to inhibition of class IIa HDACs. Increased sensitivity to HDACi was specifically observed in MYC amplified cells. Depletion of HDAC2 increased H4 acetylation and induced cell death. Simulation of clinical pharmacokinetics showed time-dependent on target activity that correlated with binding kinetics of HDACi compounds. Conclusions: We conclude that HDAC2 is a valid drug target in patients with MYC amplified MB. HDACi should cover HDAC2 in their inhibitory profile and timing and dosing regimen in clinical trials should take binding kinetics of compounds into consideration. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0201-7) contains supplementary material, which is available to authorized users.
    Keywords: Medulloblastoma ; Hdac ; Hdac Inhibitor ; Hdac2 ; Myc
    ISSN: 2051-5960
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  • 4
    In: Nature, 2018
    Description: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
    Keywords: DNA Methylation ; Tumors ; Standardization ; Data Processing ; Classification ; Methylation ; Brain Cancer ; Bioinformatics ; Cancer ; Generalized Linear Models ; DNA Methylation ; Diagnosis ; Tumors ; Genomes ; Classification ; Central Nervous System ; Central Nervous System ; Diagnosis ; Cancer ; Learning Algorithms ; Diagnostic Software ; Data Processing ; Tumors ; Central Nervous System ; Gene Expression ; Standardization ; Classification ; Cancer ; Classifiers ; Classification ; Clinical Trials ; Deoxyribonucleic Acid–DNA ; Probability ; Diagnostic Systems ; Nervous System ; Methylation ; Data Processing ; Tumors ; Data Processing ; Deoxyribonucleic Acid–DNA ; Deoxyribonucleic Acid–DNA ; World Health Organization;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 5
    In: Neuro-Oncology, 2017, Vol. 19(12), pp.1607-1617
    Description: BackgroundEmbryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the World Health Organization classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a preclinical drug screen in order to inform potentially more active clinical trial protocols. MethodsWe have carried out an in vitro and in vivo drug screen using the ETMR cell line BT183 and its xenograft model. Furthermore, we have generated the first patient-derived xenograft (PDX) model for ETMR and evaluated our top drug candidates in an in vitro drug screen using this model. ResultsBT183 cells are very sensitive to the topoisomerase inhibitors topotecan and doxorubicin, to the epigenetic agents decitabine and panobinostat, to actinomycin D, and to targeted drugs such as the polo-like kinase 1 (PLK1) inhibitor volasertib, the aurora kinase A inhibitor alisertib, and the mammalian target of rapamycin (mTOR) inhibitor MLN0128. In xenograft mice, monotherapy with topotecan, volasertib, and actinomycin D led to a temporary response in tumor growth and a significant increase in survival. Finally, using multi-agent treatment regimens of topotecan or doxorubicin combined with methotrexate and vincristine, the response in tumor growth and survival was further increased compared with mice receiving single treatments. ConclusionsWe have identified several promising candidates for combination therapies in future clinical trials for ETMR patients.
    Keywords: Actinomycin D ; Brain Tumor ; Etmr ; Topotecan ; Volasertib
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 6
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i155-i155
    Description: Identification of multiple distinct subtypes of pediatric brain tumors raises the need for more and better preclinical models reflecting these subtypes. Orthotopic patient-derived xenograft (PDX) models generated by injection of human tumor cells into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Extensive molecular characterization of PDX and matching primary tumor/blood are needed to see how well the PDX represents the original disease, to learn about targetable oncogenic drivers in each model, and to establish or confirm predictive biomarkers. In an ongoing world-wide effort we have generated and fully characterized thus far 130 PDX models reflecting 22 distinct molecular subtypes of pediatric brain tumors. PDX models always retain their molecular subtype as assessed by DNA methylation analysis and in the vast majority of cases also the mutations and copy number alterations when compared to their primary tumors. Most aggressive tumors, such as those having MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines are included. All models and corresponding molecular data will become available for the community for preclinical research. Our repertoire of PDX models and corresponding molecular characterizations allow researchers to find the right models for their specific scientific questions. It provides an unprecedented resource to study tumor biology and paves the way for improving treatment strategies for children with malignant brain tumors.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 7
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i130-i130
    Description: High-risk medulloblastoma (MB) is a deadly disease with poor overall survival. Survivors suffer from severe treatment-associated morbidity. Patients with Group 3 MB with an amplification of MYC show particularly poor outcome. Therefore novel therapies tailored to this subgroup are urgently needed. We have previously shown that MYC amplified MB cell lines are highly susceptible to inhibition of class I histone deacetylases (HDACs), including HDAC2. We here explore the functional interaction of HDAC2 and MYC.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 8
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i106-i106
    Description: The main challenge in the clinical management of pilocytic astrocytoma (PA) is its unpredictable growth behavior. PA cells are driven into oncogene-induced senescence (OIS) by aberrant MAPK activation. In other senescence models OIS was shown to be regulated and maintained by the senescence-associated secretory phenotype (SASP). In this study, the first patient-derived cell culture model DKFZ-BT66 was used to show presence of the SASP in PA and to analyze its impact on OIS. This model allows for shifting between proliferation and senescence via doxycycline-inducible inhibition of the OIS-relevant p53/RB pathway. Both states were studied using gene-expression profiling (GEP), Western blot, qPCR, ELISA, and automated trypan blue exclusion staining. The GEP shows significant upregulation of SASP factors during OIS in DKFZ-BT66 cells. Conditioned medium of senescent DKFZ-BT66 cells is sufficient to induce growth arrest of proliferating DKFZ-BT66 cells. Upregulation of the SASP factors IL-1B and IL-6 was validated on mRNA and protein levels and both pathways are active during OIS. Stimulation of the IL-1 pathway reduces growth of proliferating DKFZ-BT66 cells. While pharmacological inhibition of single cytokines is not sufficient to overcome growth arrest during OIS, treatment with the anti-inflammatory drug dexamethasone induces regrowth of senescent cells. Overall, the primary PA model provides evidence of the presence of OIS in PA and exhibits increased activity of the SASP during senescence. Our data suggest that the SASP has an important impact on the growth regulation of senescent PA cells. Alteration of SASP factors may result in spontaneous regrowth of senescent PA tumors.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 9
  • 10
    Language: English
    In: Acta Neuropathologica, 2016, Vol.131(6), pp.903-910
    Description: 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.
    Keywords: Medicine & Public Health ; Pathology ; Neurosciences ; Medicine;
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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