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Berlin Brandenburg

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  • Cancer
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  • 1
    Language: English
    In: The Journal of clinical investigation, April 2011, Vol.121(4), pp.1344-8
    Description: Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.
    Keywords: Astrocytoma -- Etiology ; Brain Neoplasms -- Etiology ; Proto-Oncogene Proteins B-Raf -- Genetics
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 2
    Language: English
    In: International Journal of Cancer, 01 May 2013, Vol.132(9), pp.2200-2208
    Description: Inhibition of histone deacetylase (HDAC) activity as stand‐alone or combination therapy represents a promising therapeutic approach in oncology. The pan‐ or class I HDAC inhibitors (HDACi) currently approved or in clinical studies for oncology give rise to dose‐limiting toxicities, presumably because of the inhibition of several HDACs. This could potentially be overcome by selective blockade of single HDAC family members. Here we report that HDAC11, the most recently identified zinc‐dependent HDAC, is overexpressed in several carcinomas as compared to corresponding healthy tissues. HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in HCT‐116 colon, PC‐3 prostate, MCF‐7 breast and SK‐OV‐3 ovarian cancer cell lines. The antitumoral effect induced can be mimicked by enforced expression of a catalytically impaired HDAC11 variant, suggesting that inhibition of the enzymatic activity of HDAC11 by small molecules could trigger the desired phenotypic changes. HDAC11 depletion in normal cells causes no changes in metabolic activity and viability, strongly suggesting that tumor‐selective effects can be achieved. Altogether, our data show that HDAC11 plays a critical role in cancer cell survival and may represent a novel drug target in oncology. What's new? Histone deacetylase (HDAC) enzymes influence the regulation of numerous cellular processes, and their inhibition by small molecules has been shown to provide benefits against multiple cancer types. Here, HDAC11, a recently identified member of the HDAC family, was found to play an important role in the control of proliferation and survival pathways in several carcinoma cell lines. The high incidence of the tumors represented suggests that HDAC11 could be a valuable drug target in oncology.
    Keywords: Chromatin Modulation ; Targeted Therapy ; Histone Deacetylase ; Colon Cancer ; Prostate Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: Cells, 01 April 2015, Vol.4(2), pp.135-168
    Description: The exploitation of autophagy by some cancer entities to support survival and dodge death has been well-described. Though its role as a constitutive process is important in normal, healthy cells, in the milieu of malignantly transformed and...
    Keywords: Histone Deacetylase Inhibitor ; Cancer ; Hdac6 ; Hdac10 ; Autophagic Flux ; Targeted Therapy ; Biology
    E-ISSN: 2073-4409
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  • 4
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
    Language: English
    In: Nature, July 2018, Vol.559(7714), pp.E10
    Description: In this Article, author Benedikt Brors was erroneously associated with affiliation number '8' (Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA); the author's two other affiliations (affiliations '3' and '7', both at the German Cancer Research Center (DKFZ)) were correct. This has been corrected online.
    Keywords: Cancer ; Medical Schools;
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 6
    Language: English
    In: Cancer Letters, 2009, Vol.277(1), pp.8-21
    Description: 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 I 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.
    Keywords: Histone Deacetylase ; Hdac ; Hdac Inhibitor ; Cancer ; Development ; Therapy ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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  • 7
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 July 2011, Vol.17(14), pp.4650-60
    Description: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA. We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes. Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic β-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation. OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients.
    Keywords: Astrocytoma -- Genetics ; Brain Neoplasms -- Genetics ; MAP Kinase Signaling System -- Genetics ; Oncogene Proteins -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 8
    Language: English
    In: European Journal of Cancer, July 2016, Vol.62, pp.124-131
    Description: An urgent need remains for new paediatric oncology drugs to cure children who die from cancer and to reduce drug-related sequelae in survivors. In 2007, the European Paediatric Regulation came into law requiring industry to create paediatric drug (all types of medicinal products) development programmes alongside those for adults. Unfortunately, paediatric drug development is still largely centred on adult conditions and not a mechanism of action (MoA)-based model, even though this would be more logical for childhood tumours as these have much fewer non-synonymous coding mutations than adult malignancies. Recent large-scale sequencing by International Genome Consortium and Paediatric Cancer Genome Project has further shown that the genetic and epigenetic repertoire of driver mutations in specific childhood malignancies differs from more common adult-type malignancies. To bring about much needed change, a Paediatric Platform, ACCELERATE, was proposed in 2013 by the Cancer Drug Development Forum, Innovative Therapies for Children with Cancer, the European Network for Cancer Research in Children and Adolescents and the European Society for Paediatric Oncology. The Platform, comprising multiple stakeholders in paediatric oncology, has three working groups, one with responsibility for promoting and developing high-quality MoA-informed paediatric drug development programmes, including specific measures for adolescents. Key is the establishment of a freely accessible aggregated database of paediatric biological tumour drug targets to be aligned with an aggregated pipeline of drugs. This will enable prioritisation and conduct of early phase clinical paediatric trials to evaluate these drugs against promising therapeutic targets and to generate clinical paediatric efficacy and safety data in an accelerated time frame. Through this work, the Platform seeks to ensure that potentially effective drugs, where the MoA is known and thought to be relevant to paediatric malignancies, are evaluated in early phase clinical trials, and that this approach to generate pre-clinical and clinical data is systematically pursued by academia, sponsors, industry, and regulatory bodies to bring new paediatric oncology drugs to front-line therapy more rapidly.
    Keywords: Paediatric Oncology ; Mechanism of Action ; Targeted Cancer Drug Development ; Medicine
    ISSN: 0959-8049
    E-ISSN: 1879-0852
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  • 9
    In: Nature, 2018
    Description: Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 10
    Language: English
    In: Future medicinal chemistry, September 2016, Vol.8(13), pp.1609-34
    Description: Histone deacetylase 8 (HDAC8), a unique class I zinc-dependent HDAC, is an emerging target in cancer and other diseases. Its substrate repertoire extends beyond histones to many nonhistone proteins. Besides being a deacetylase, HDAC8 also mediates signaling via scaffolding functions. Aberrant expression or deregulated interactions with transcription factors are critical in HDAC8-dependent cancers. Many potent HDAC8-selective inhibitors with cellular activity and anticancer effects have been reported. We present HDAC8 as a druggable target and discuss inhibitors of different chemical scaffolds with cellular effects. Furthermore, we review HDAC8 activators that revert activity of mutant enzymes. Isotype-selective HDAC8 targeting in patients with HDAC8-relevant cancers is challenging, however, is promising to avoid adverse side effects as observed with pan-HDAC inhibitors.
    Keywords: Hdac8 ; Smc3 ; T-Cell ; Cancer ; Druggable ; Hydroxamic Acid ; Inhibitor ; Stem Cell ; Therapy ; Antineoplastic Agents -- Pharmacology ; Neoplasms -- Drug Therapy ; Neurodegenerative Diseases -- Drug Therapy ; Neuroprotective Agents -- Pharmacology ; Repressor Proteins -- Antagonists & Inhibitors
    ISSN: 17568919
    E-ISSN: 1756-8927
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