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  • tumor  (6)
  • DIFFERENTIATION  (4)
Keywords
  • 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: CANCER ; CANCER CELLS ; CELLS ; INHIBITOR ; tumor ; CELL ; Germany ; PHASE-I ; THERAPY ; LUNG-CANCER ; DEATH ; DISEASE ; DISEASES ; GENE ; GENES ; DRUG ; TUMORS ; MICE ; MESSENGER-RNA EXPRESSION ; FAMILY ; MEMBERS ; BREAST-CANCER ; TRIAL ; TRIALS ; CLINICAL-TRIALS ; CANCER-CELLS ; TARGETS ; HDAC inhibitors ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; HDAC ; INHIBITORS ; SINGLE ; review ; FAMILIES ; IV ; CLASS-II ; development ; PHASE ; COMPOUND ; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA ; REFRACTORY SOLID TUMORS ; VIVO ANTITUMOR-ACTIVITY ; drug targets ; DRUG-TARGET ; HDAC inhibitor ; CONTROLS CHONDROCYTE HYPERTROPHY
    Abstract: Histone deacetylases comprise a family of 18 genes, which are grouped into classes I-IV based on their homology to their respective yeast orthologues. Classes I, II, and IV consist of 11 family members, which are referred to as "classical" HDACs, whereas the 7 class III members are called sirtuins. Classical HDACs are a promising novel class of anti-cancer drug targets. First HDAC inhibitors have been evaluated in clinical trials and show activity against several cancer diseases. However, these compounds act unselectively against several or all 11 HDAC family members. As a consequence, clinical phase 1 trials document a wide range of side effects. Therefore, the current challenge in the field is to define the cancer relevant HDAC family member(s) in a given tumor type and to design selective inhibitors, which target cancer cells but leave out normal cells. Knockout of single HDAC family members in mice produces a variety of phenotypes ranging from early embryonic death to viable animals with only discrete alterations, indicating that potential side effects of HDAC inhibitors depend on the selectivity of the compounds. Recently, several studies have shown that certain HDAC family members are aberrantly expressed in several tumors and have non-redundant function in controlling hallmarks of cancer cells. The aim of this review is to discuss individual HDAC family members as drug targets in cancer taking into consideration their function under physiological conditions and their oncogenic potential in malignant disease. (C) 2008 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18824292
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  • 4
    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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  • 5
    Keywords: GROWTH ; IN-VITRO ; tumor ; MODEL ; IDENTIFICATION ; STEM-CELLS ; ABNORMALITIES ; SUPRATENTORIAL ; CHILDHOOD EPENDYMOMAS ; PEDIATRIC INTRACRANIAL EPENDYMOMAS
    Abstract: PURPOSE OF REVIEW: Effective treatment options for ependymoma apart from radical surgery and radiotherapy remain scarce, and the understanding of the molecular basis of ependymoma biology is crucial to the development of novel therapies. Comprehensive work revealing molecular pathomechanisms of ependymoma has been done; however, the elucidation of the processes underlying the origins of various clearly distinguishable ependymoma subgroups has proved to be difficult. The future challenges will be to reach consensus about molecular subgroups, to translate these into a clinical setting, and to use available models for drug screening and preclinical testing. RECENT FINDINGS: Ependymoma subgroups with clearly distinct biology have been delineated and novel mouse models generated, and the first high-throughput drug screens were successfully conducted leading to the identification of subgroup-specific active regimens. SUMMARY: Coordinated efforts to advance novel therapies into the clinic have led to breakthrough insights into the molecular biology of ependymoma. The next step will be the translation of preclinical findings into the clinical setting, and international study groups are starting to implement the most recent advances into clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 23007011
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  • 6
    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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  • 7
    Keywords: tumor ; RISK ; DOWN-REGULATION ; chemotherapy ; p53 ; CHILDREN ; MULTICENTER TRIAL ; CHILDHOOD MEDULLOBLASTOMA ; BETA-CATENIN STATUS ; LI-FRAUMENI ; PEDIATRIC MEDULLOBLASTOMAS
    Abstract: PURPOSE The role of TP53 mutations in the tumorigenesis of sporadic medulloblastoma (MB) and the value of TP53 mutation status as a prognostic marker are not yet definitely elucidated. A recent report identified TP53 mutations in MB as an adverse prognostic marker. Hence, the current study was conducted to validate the prognostic role of TP53 mutation in MB and to understand its contribution to tumorigenesis. METHODS A comprehensive genetic analysis of 310 MB samples was performed by screening for TP53 mutations and further relating the TP53 mutation status to p53 immunostaining, cytogenetic aberrations, and clinical variables. Results Mutation analysis of TP53 revealed mutations in 21 (6.8%) of 310 samples. Germline TP53 mutations were found in two patients with a history suggestive of a hereditary cancer syndrome. TP53 mutation status was not associated with unfavorable prognosis (P = .63) and was not linked to 17p allelic loss but was over-represented in the prognostically favorable WNT subgroup of MB as defined by CTNNB1 mutation (seven of 35 TP53-mutated tumors v 14 of 271 TP53 wild-type tumors; P = .005) and in tumors carrying high-level MYCN amplification (seven of 21 TP53-mutated tumors v 14 of 282 TP53 wild-type tumors; P = .001). CONCLUSION The contradictory results in the recent literature concerning the prognostic value of TP53 mutation might be explained by different frequencies of WNT MBs, different frequencies of patients with Li-Fraumeni syndrome, and different cumulative doses of alkylating drugs applied in these studies.
    Type of Publication: Journal article published
    PubMed ID: 21060032
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  • 8
    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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