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Berlin Brandenburg

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  • 11
    Language: English
    In: CNS oncology, July 2013, Vol.2(4), pp.359-76
    Description: Histone deacetylase inhibitors (HDACis) have fascinated researchers in almost all fields of oncology for many years owing to their pleiotropic effects on nearly every aspect of cancer biology. Since the approval of the first HDACi vorinostat for the treatment of cutaneous T-cell leukemia in 2006, more than a hundred clinical trials have been initiated with a HDACi as a single agent or in combination therapy. Although a number of epigenetic and nonepigenetic molecular mechanisms of action have been proposed, biomarkers for response prediction and patient selection are still lacking. One of the inherent problems in the field of HDACis is their 'reverse' history of drug development: these compounds reached clinical application at an early stage, before the biology of their targets, HDAC1-11, was sufficiently understood. This review summarizes the current knowledge on the human family of HDACs as drug targets in pediatric and adult brain tumors, the efficacy and molecular action of HDACis in preclinical models, as well as the current status of the clinical development of these compounds in the field of neuro-oncology.
    Keywords: Brain Neoplasms -- Drug Therapy ; Histone Deacetylase Inhibitors -- Therapeutic Use ; Histone Deacetylases -- Metabolism
    ISSN: 20450907
    E-ISSN: 2045-0915
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  • 12
    Language: English
    In: Cancer Research, 04/15/2011, Vol.71(8 Supplement), pp.4724-4724
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 13
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 01 November 2011, Vol.81(3), pp.e7-e13
    Description: To investigate treatment outcome and prognostic factors after radiation therapy in patients with medulloblastomas (MB). Sixty-six patients with histologically confirmed MB were treated at the University Hospital of Heidelberg between 1985 and 2009. Forty-two patients (64%) were pediatric (≤18 years), and 24 patients (36%) were adults. Tumor resection was performed in all patients and was complete in 47%. All patients underwent postoperative craniospinal irradiation (CSI) delivering a median craniospinal dose of 35.5 Gy with additional boosts to the posterior fossa up to 54.0 Gy. Forty-seven patients received chemotherapy, including 21 in whom chemotherapy was administered before CSI. Statistical analysis was performed using the log-rank test and the Kaplan-Meier method. Median follow-up was 93 months. Overall survival (OS) and local and distant progression-free survival (LPFS and DPFS) were 73%, 62%, and 77% at 60 months. Both local and distant recurrence predisposed for significantly reduced OS. Macroscopic complete tumor resection, desmoplastic histology and early initiation of postoperative radiation therapy within 28 days were associated with improved outcome. The addition of chemotherapy did not improve survival rates. Toxicity was moderate. Complete resection of MB followed by CSI yields long survival rates in both children and adults. Delayed initiation of CSI is associated with poor outcome. Desmoplastic histology is associated with improved survival. The role of chemotherapy, especially in the adult population, must be further investigated in clinical studies.
    Keywords: Medulloblastoma ; Radiochemotherapy ; Craniospinal Irradiation ; Prognostic Factors ; Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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  • 14
    Language: English
    In: International Journal of Cancer, 01 September 2010, Vol.127(5), pp.1230-1239
    Description: Despite multimodal therapeutic concepts, advanced localized and high‐risk neuroblastoma remains a therapeutic challenge with a long‐term survival rate below 50%. Consequently, new modalities for the treatment of neuroblastoma, ., oncolytic virotherapy are urgently required. H‐1PV is a rodent parvovirus devoid of relevant pathogenic effects in infected adult animals. In contrast, the virus has oncolytic properties and is particularly cytotoxic for transformed or tumor‐derived cells of various species including cells of human origin. Here, a preclinical assessment of the application of oncolytic H‐1PV for the treatment of neuroblastoma cells was performed. Infection efficiency, viral replication and lytic activity of H‐1PV were analyzed in 11 neuroblastoma cell lines with different MYCN status. Oncoselectivity of the virus was confirmed by the infection of short term cultures of nonmalignant infant cells of different origin. In these nontransformed cells, no effect of H‐1PV on viability or morphology of the cells was observed. In contrast, a lytic infection was induced in all neuroblastoma cell lines examined at MOIs between 0.001 and 10 pfu/cell. H‐1PV actively replicated with virus titres increasing up to 5,000‐fold within 48–96 hr after infection. The lytic effect of H‐1PV was observed independent of MYCN oncogene amplification or differentiation status. Moreover, a significant G2‐arrest and induction of apoptosis could be demonstrated. Infection efficiency, rapid virus replication and exhaustive lytic effects on neuroblastoma cells together with the low toxicity of H‐1PV for nontransformed cells, render this parvovirus a promising candidate for oncolytic virotherapy of neuroblastoma.
    Keywords: Neuroblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Apoptosis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 15
    In: Nature, 2014, Vol.510(7506), p.537
    Description: 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.
    Keywords: Gene Expression Regulation, Neoplastic ; Gene Silencing ; DNA Methylation -- Genetics ; Medulloblastoma -- Genetics ; Sequence Analysis, DNA -- Methods;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 16
  • 17
    In: Nature, 2012, Vol.482(7384), p.226
    Description: 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.
    Keywords: Gene Mutation -- Research ; Dna -- Research ; Dna -- Physiological Aspects ; Glioblastomas -- Genetic Aspects ; Glioblastomas -- Research ; Tumor Proteins -- Physiological Aspects ; Tumor Proteins -- Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 18
  • 19
    Language: English
    In: Cancer Research, 04/15/2011, Vol.71(8 Supplement), pp.3458-3458
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 20
    Language: English
    In: Journal of medicinal chemistry, 28 December 2017, Vol.60(24), pp.10188-10204
    Description: Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic acids as potent and selective HDAC8 inhibitors. Docking studies using available crystal structures have been used for structure-based optimization of this series of compounds. Within this study, we have investigated the role of HDAC8 in the proliferation of cancer cells and optimized hits for potency and selectivity, both in vitro and in cell culture. The combination of structure-based design, synthesis, and in vitro screening to cellular testing resulted in potent and selective HDAC8 inhibitors that showed anti-neuroblastoma activity in cellular testing.
    Keywords: Antineoplastic Agents–Chemistry ; Biomarkers, Tumor–Pharmacology ; Cell Line, Tumor–Genetics ; Drug Design–Drug Effects ; Drug Screening Assays, Antitumor–Chemistry ; Gene Expression Regulation, Neoplastic–Pharmacology ; Hek293 Cells–Chemistry ; Histone Deacetylase Inhibitors–Metabolism ; Histone Deacetylases–Chemistry ; Humans–Drug Therapy ; Hydroxamic Acids–Genetics ; Molecular Docking Simulation–Pathology ; Neuroblastoma–Antagonists & Inhibitors ; Repressor Proteins–Chemistry ; Structure-Activity Relationship–Metabolism ; Antineoplastic Agents ; Biomarkers, Tumor ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Repressor Proteins ; Hdac8 Protein, Human ; Histone Deacetylases ; Benzohydroxamic Acid;
    ISSN: 00222623
    E-ISSN: 1520-4804
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