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  • EXPRESSION  (8)
  • DIFFERENTIATION  (4)
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  • 1
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; DRUG ; DIFFERENTIATION ; INDUCTION ; ACID ; NERVOUS-SYSTEM ; ASSAY ; CANCER-CELLS ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; p21(waf1) ; neuroblastoma ; INVITRO ; LEUKEMIA-CELLS ; ONCOLOGY ; CHILDHOOD ; RE ; medulloblastoma ; cell proliferation ; ASSAYS ; pharmacology ; USA ; anticancer drug ; childhood cancer ; HELMINTHOSPORIUM-CARBONUM (HC)-TOXIN ; HKI46F08
    Abstract: Embryonic childhood cancer such as neuroblastoma and medulloblastoma are still a therapeutic challenge requiring novel treatment approaches. Here, we investigated the antitumoral effects of HKI 46F08, a novel trifluoromethyl ketone histone deacetylase (HDAC) inhibitor with a nonhydroxamic acid type structure. HKI 46F08 inhibits in-vitro HDAC activity in cell-free assays with a half maximal inhibitory concentration of 0.6 mu mol/l and intracellular HDAC activity with a half maximal inhibitory concentration of 1.8 mu mol/l. The compound reduces viability of both cultured neuroblastoma and medulloblastoma cells with an EC50 of 0.1-4 mu mol/l. HKI 461708 efficiently arrests tumor cell proliferation, represses clonogenic growth and induces differentiation and apoptosis in both MYCN-amplified and nonamplified neuroblastoma cells. In summary, we identified HKI 48F08 as a structural novel, potent HDAC inhibitor with strong antitumoral activity against embryonic childhood cancer cells in the low micromolar range
    Type of Publication: Journal article published
    PubMed ID: 18765999
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CELLS ; GROWTH ; INHIBITOR ; tumor ; CELL ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; PATHWAY ; THERAPY ; DISEASE ; GENE ; GENES ; PROTEIN ; PROTEINS ; DRUG ; DIFFERENTIATION ; TUMORS ; NEUROBLASTOMA-CELLS ; ACTIVATION ; MECHANISM ; FAMILY ; prognosis ; mechanisms ; cell cycle ; CELL-CYCLE ; CYCLE ; MEMBERS ; SUSCEPTIBILITY ; ANTITUMOR-ACTIVITY ; MOUSE ; TRIAL ; TRIALS ; CELL-DEATH ; CLINICAL-TRIALS ; chemotherapy ; MOUSE MODEL ; TARGETS ; CHILDREN ; HDAC inhibitors ; HISTONE DEACETYLASE ; INTERFERON-ALPHA ; REPRESSION ; TRAIL-INDUCED APOPTOSIS ; neuroblastoma ; HDAC ; INHIBITORS ; ADULT ; review ; FAMILIES ; THERAPIES ; tumor suppressor gene ; EPIGENETICS ; CANCERS ; valproic acid ; Phase I ; SODIUM VALPROATE ; MALIGNANT PHENOTYPE ; NUCLEAR EXPORT ; drug targets ; DRUG-TARGET ; HDAC inhibitor
    Abstract: Histone deacetylases (HDACs) are an emerging class of novel anti-cancer drug targets. Recently, studies in adult cancers and in neuroblastoma have shown that individual HDAC family members are aberrantly expressed in tumors and correlate with disease stage and prognosis. In neuroblastoma, knockdown of individual HDAC family members causes distinct phenotypes ranging from differentiation to apoptosis. HDACs are involved in controlling MYCN function and are upregulated in chemotherapy-resistant neuroblastoma cells. Treatment with unselective pan-HDAC inhibitors causes cell cycle arrest, differentiation, apoptosis, and inhibition of clonogenic growth of neuroblastoma cells, and restores susceptibility to chemotherapy treatment. The molecular mechanisms mediating the anti-cancer effects of HDAC inhibitors on neuroblastoma cells are incompletely understood and involve targeting of aberrant epigenetic repression of tumor suppressor genes, activation of developmental differentiation pathways, as well as changing the acetylation level and function of non-histone proteins. In neuroblastoma mouse models, unselective HDAC inhibitors demonstrate antitumoral effects. First phase I clinical trials in children with refractory cancers using HDAC inhibitors depsipeptide and the recently approved vorinostat are underway. This review summarizes our current knowledge about classical HDAC family members as novel drug targets for neuroblastoma therapy and discusses the potential role of next generation, selective HDAC inhibitors
    Type of Publication: Journal article published
    PubMed ID: 19199971
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  • 3
    Keywords: EXPRESSION ; TUMORS ; ABERRATIONS ; METHYLATION ; EMBRYONIC STEM-CELLS ; MULTIFORME ; HIGH-GRADE GLIOMAS ; TELOMERES ; INTEGRATED GENOMIC ANALYSIS ; ATRX
    Abstract: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases(1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked)(5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres(6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 22286061
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  • 4
    Keywords: EXPRESSION ; SURVIVAL ; IDENTIFICATION ; PROGRESSION ; COMPARATIVE GENOMIC HYBRIDIZATION ; ABERRATIONS ; PROGNOSTIC-FACTORS ; CHROMOSOMAL IMBALANCES ; CANDIDATE GENES ; PEDIATRIC EPENDYMOMA
    Abstract: PURPOSE: The biologic behavior of intracranial ependymoma is unpredictable on the basis of current staging approaches. We aimed at the identification of recurrent genetic aberrations in ependymoma and evaluated their prognostic significance to develop a molecular staging system that could complement current classification criteria. PATIENTS AND METHODS: As a screening cohort, we studied a cohort of 122 patients with ependymoma before standardized therapy by using array-based comparative genomic hybridization. DNA copy-number aberrations identified as possible prognostic markers were validated in an independent cohort of 170 patients with ependymoma by fluorescence in situ hybridization analysis. Copy-number aberrations were correlated with clinical, histopathologic, and survival data. RESULTS: In the screening cohort, age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis. In contrast, gains of chromosomes 9, 15q, and 18 and loss of chromosome 6 were associated with excellent survival. On the basis of these findings, we developed a molecular staging system comprised of three genetic risk groups, which was then confirmed in the validation cohort. Likelihood ratio tests and multivariate Cox regression also demonstrated the clear improvement in predictive accuracy after the addition of these novel genetic markers. CONCLUSION: Genomic aberrations in ependymomas are powerful independent markers of disease progression and survival. By adding genetic markers to established clinical and histopathologic variables, outcome prediction can potentially be improved. Because the analyses can be conducted on routine paraffin-embedded material, it will now be possible to prospectively validate these markers in multicenter clinical trials on population-based cohorts.
    Type of Publication: Journal article published
    PubMed ID: 20516456
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  • 5
    Keywords: EXPRESSION ; COHORT ; DISEASE ; TISSUE ; IDENTIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; chemotherapy ; MUTATIONS ; ABNORMALITIES ; CHILDREN ; IMBALANCES ; PEDIATRIC EPENDYMOMA ; INTRACRANIAL EPENDYMOMA ; CLASS DISCOVERY
    Abstract: Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochennical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymonna tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients
    Type of Publication: Journal article published
    PubMed ID: 21840481
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  • 6
    Keywords: DIFFERENTIATION ; PROGNOSTIC-SIGNIFICANCE ; CENTRAL-NERVOUS-SYSTEM ; EMBRYONIC STEM-CELLS ; BRAIN-TUMORS ; intermediate filament protein ; CHILDHOOD EPENDYMOMAS ; PEDIATRIC INTRACRANIAL EPENDYMOMAS ; DIFFERENT TUMORS ; MARKER NESTIN
    Abstract: Ependymomas are primary brain tumors found throughout the central nervous system (CNS) in children and adults. Currently, many treatment protocols stratify grade I and II ependymomas as low-risk tumors, whereas grade III anaplastic ependymomas are considered high-risk tumors. The prognostic significance of World Health Organization (WHO) grade II or III, however, remains debated, and it is furthermore increasingly recognized that the pathologic differentiation between grades II and III is arbitrary in daily practice, thus resulting in imprecise risk stratification. Therefore, prognostic markers enabling more precise stratification to guide treatment decisions are urgently needed. An analysis of n = 379 tumor samples revealed that protein expression of nestin, a marker for neural stem and progenitor cells established as a routine staining in most neuropathology centers, is associated with poor outcome in intracranial ependymomas. Most importantly, nestin-positive grade II ependymomas have the same prognosis as grade III ependymomas. Multivariable analysis demonstrates that nestin positivity is an independent marker for poor progression-free survival (PFS) and overall survival (OS). Gene expression analysis for transcriptionally co-regulated genes revealed a strong association of developmental and epigenetic processes with nestin. In summary, our data implicate nestin as a useful novel marker for intracranial ependymoma risk stratification easily implementable in routine diagnostics.
    Type of Publication: Journal article published
    PubMed ID: 22568867
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  • 7
    Keywords: EXPRESSION ; GENE ; DIFFERENTIATION ; IDENTIFICATION ; EMBRYONIC STEM-CELLS ; HYPERMETHYLATION ; SUPPRESSOR ; methylome ; CANCER GENOME ; CPG ISLAND SHORES
    Abstract: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
    Type of Publication: Journal article published
    PubMed ID: 24847876
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  • 8
    Keywords: CANCER ; CELLS ; EXPRESSION ; GENE ; transcription ; CREB ; acetylation ; HISTONE DEACETYLASE INHIBITORS ; SOX4 ; COOPERATE
    Abstract: For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential. Selective targeting of individual HDAC isozymes in defined tumor entities may therefore be an attractive alternative treatment approach. We have previously identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. Using small-molecule inhibitors, we now demonstrate that selective inhibition of HDAC8 exhibits antineuroblastoma activity without toxicity in two xenograft mouse models of MYCN oncogene-amplified neuroblastoma. In contrast, the unselective HDAC inhibitor vorinostat was more toxic in the same models. HDAC8-selective inhibition induced cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation was significantly enhanced, as demonstrated by elongated neurofilament-positive neurites and upregulation of NTRK1. Additionally, MYCN oncogene expression was downregulated in vitro and tumor cell growth was markedly reduced in vivo. Mechanistic studies suggest that cAMP-response element-binding protein (CREB) links HDAC8- and retinoic acid-mediated gene transcription. In conclusion, HDAC-selective targeting can be effective in tumors exhibiting HDAC isozyme-dependent tumor growth in vivo and can be combined with differentiation-inducing agents.
    Type of Publication: Journal article published
    PubMed ID: 25695609
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  • 9
    Keywords: EXPRESSION ; ASTROCYTOMAS ; temozolomide ; HIGH-GRADE GLIOMAS ; SUBGROUPS ; IDH1 ; MGMT PROMOTER METHYLATION ; INTRINSIC PONTINE GLIOMA ; ACTIVATING ACVR1 MUTATIONS ; GENOMIC LANDSCAPE
    Abstract: Pediatric glioblastoma (pedGBM) is amongst the most common malignant brain tumors of childhood and carries a dismal prognosis. In contrast to adult GBM, few molecular prognostic markers for the pediatric counterpart have been established. We, therefore, investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1-18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations via direct sequencing or FISH. Unexpectedly, a subset of histologically diagnosed GBM (n = 40, 20 %) displayed methylation profiles similar to those of either low-grade gliomas or pleomorphic xanthoastrocytomas (PXA). These tumors showed a markedly better prognosis, with molecularly PXA-like tumors frequently harboring BRAF V600E mutations and 9p21 (CDKN2A) homozygous deletion. The remaining 162 tumors with pedGBM molecular signatures comprised four subgroups: H3.3 G34-mutant (15 %), H3.3/H3.1 K27-mutant (43 %), IDH1-mutant (6 %), and H3/IDH wild-type (wt) GBM (36 %). These subgroups were associated with specific cytogenetic aberrations, MGMT methylation patterns and clinical outcomes. Analysis of follow-up data identified a set of biomarkers feasible for use in risk stratification: pedGBM with any oncogene amplification and/or K27M mutation (n = 124) represents a particularly unfavorable group, with 3-year overall survival (OS) of 5 %, whereas tumors without these markers (n = 38) define a more favorable group (3-year OS similar to 70 %).Combined with the lower grade-like lesions, almost 40 % of pedGBM cases had distinct molecular features associated with a more favorable outcome. This refined prognostication method for pedGBM using a molecular risk algorithm may allow for improved therapeutic choices and better planning of clinical trial stratification for this otherwise devastating disease.
    Type of Publication: Journal article published
    PubMed ID: 25752754
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  • 10
    Keywords: EXPRESSION ; tumor ; INHIBITION ; PATHWAY ; TUMORS ; prognosis ; CLUSTER ; medulloblastoma ; SUBTYPES ; PROFILES ; hsa-miR-182 ; Metastatic dissemination ; POLYCISTRON ; SHH pathway
    Abstract: The contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MB patients, and is associated with a dismal prognosis. Using microRNA expression profiling, we demonstrate that the retinal miR-183-96-182 cluster on chromosome 7q32 is highly overexpressed in non-sonic hedgehog MBs (non-SHH-MBs). Expression of miR-182 and miR-183 is associated with cerebellar midline localization, and miR-182 is significantly overexpressed in metastatic MB as compared to non-metastatic tumors. Overexpression of miR-182 in non-SHH-MB increases and knockdown of miR-182 decreases cell migration in vitro. Xenografts overexpressing miR-182 invaded adjacent normal tissue and spread to the leptomeninges, phenotypically reminiscent of clinically highly aggressive large cell anaplastic MB. Hence, our study provides strong in vitro and in vivo evidence that miR-182 contributes to leptomeningeal metastatic dissemination in non-SHH-MB. We therefore reason that targeted inhibition of miR-182 may prevent leptomeningeal spread in patients with non-SHH-MB.
    Type of Publication: Journal article published
    PubMed ID: 22134538
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