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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i40-i40
    Description: Astroblastomas are rare brain tumours which predominate in children and young adults, and have a controversial claim as a distinct entity, with no established WHO grade. Reports suggest a better outcome than high grade gliomas, though they frequently recur. Recently, they have been described to overlap with a newly-discovered group of tumours described as ‘high grade neuroepithelial tumour with MN1 alteration’ (CNS HGNET-MN1), defined by global methylation patterns and strongly associated with gene fusions targeting MN1 . We have studied a rare case of astroblastoma arising in a 6 year-old girl, with multiple recurrences over a period of 10 years, with the pathognomonic MN1:BEND2 fusion. Exome sequencing of eleven surgical interventions allowed for a phylogenetic reconstruction of tumour evolution, which when integrated with clinical, pathological and radiological data provide for a detailed understanding of disease progression, with initial treatment driving tumour dissemination along four distinct trajectories. Infiltration of distant sites was associated with gains of chromosomal arms and later genome doubling. There was evidence of convergent evolution of different lesions acquiring distinct alterations targeting the NF-kB pathway, supported by strong immunohistochemical staining of RELA, and high levels of target gene expression, such as IL8. These data represent an unique opportunity to understand the evolutionary history of a highly recurrent childhood brain tumour, and provide novel therapeutic targets for astroblastoma / CNS HGNET-MN1.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Nature Genetics, 2014, Vol.46(5), p.457
    Description: Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors (1). We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21 % of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) (2) and have been shown to constitutively activate the BMP-TGF-b signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.
    Keywords: Gliomas – Genetic Aspects ; Gene Mutation – Health Aspects ; Activins – Genetic Aspects ; Activins – Physiological Aspects ; Cell Receptors – Genetic Aspects ; Cell Receptors – Physiological Aspects;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 3
    Language: English
    In: Molecular cancer therapeutics, December 2012, Vol.11(12), pp.2654-63
    Description: Medulloblastoma is the most common malignant brain tumor of childhood. Novel therapeutic strategies are urgently needed to overcome cytotoxic resistance. We hypothesized that antiapoptotic signals contribute to resistance and that treatment with proapoptotic agents could increase the efficacy of conventional therapies. A PCR array was used to assess the status of the apoptotic signaling pathway in medulloblastoma cells after treatment with cytotoxic chemotherapy. Treatment with cisplatin led to the upregulation of antiapoptotic signals, including inhibitor of apoptosis proteins (IAP), in medulloblastoma cells. We subsequently investigated the synergistic effect of a small-molecule IAP inhibitor, LBW242, in combination with cisplatin and/or radiotherapy in three human medulloblastoma cell lines and 5 short term primary patient medulloblastoma cultures. The addition of LBW242 to chemotherapy resulted in significantly increased antitumor activity with a similar effect observed in combination with radiotherapy. Measurement of caspase-8 and -9 activity indicated that the synergy resulted from induction of both the intrinsic and extrinsic apoptotic pathways. Apoptosis was confirmed by Annexin V staining and activation of caspases 3/7. Xenograft models were used to evaluate the mechanism of action and efficacy in vivo. The combination therapy significantly reduced the tumor burden in a medulloblastoma xenograft model and TUNEL analysis in a medulloblastoma orthograft confirmed in vivo induction of apoptosis. These findings support the strategy of targeting IAPs in combination with cytotoxic therapy as a novel treatment strategy for patients with medulloblastoma.
    Keywords: Antineoplastic Combined Chemotherapy Protocols -- Pharmacology ; Cerebellar Neoplasms -- Drug Therapy ; Inhibitor of Apoptosis Proteins -- Antagonists & Inhibitors ; Medulloblastoma -- Drug Therapy
    E-ISSN: 1538-8514
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  • 4
    Language: English
    In: Nature medicine, August 2018, Vol.24(8), pp.1204-1215
    Description: The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in 〈1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.
    Keywords: Brain Stem Neoplasms -- Pathology ; Glioblastoma -- Pathology
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 5
    In: Oncogene, 2002, Vol.21(53), p.8196
    Description: Sonic Hedgehog is a secreted morphogen involved in patterning a wide range of structures in the developing embryo. Disruption of the Hedgehog signalling cascade leads to a number of developmental disorders and plays a key role in the formation of a range of human cancers. The identification of genes regulated by Hedgehog is crucial to understanding how disruption of this pathway leads to neoplastic transformation. We have used a Sonic Hedgehog (Shh) responsive mouse cell line, C3H/10T1/2, to provide a model system for hedgehog target gene discovery. Following activation of cell cultures with Shh, RNA was used to interrogate microarrays to investigate downstream transcriptional consequences of hedgehog stimulation. As a result 11 target genes have been identified, seven of which are induced (Thrombomodulin, GILZ, BF-2, Nr4a1, IGF2, PMP22, LASP1) and four of which are repressed (SFRP-1, SFRP-2, Mip1-[gamma], Amh) by Shh. These targets have a diverse range of putative functions and include transcriptional regulators and molecules known to be involved in regulating cell growth or apoptosis. The corroboration of genes previously implicated in hedgehog signalling, along with the finding of novel targets, demonstrates both the validity and power of the C3H/10T1/2 system for Shh target gene discovery. Oncogene(2002) 21,8196-8205.doi: 10.1038/sj.onc.1205975 Keywords: Sonic Hedgehog, downstream target genes, C3H/10T1/2, microarray
    Keywords: Cancer Genetics -- Research ; Embryonic Development -- Physiological Aspects ; Embryonic Development -- Genetic Aspects ; Embryonic Development -- Research ; Gene Expression -- Research ; Stem Cells -- Identification And Classification ; Stem Cells -- Health Aspects ; Stem Cells -- Research;
    ISSN: 0950-9232
    E-ISSN: 14765594
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  • 6
    Language: English
    In: Scientific Reports, 01 January 2018, Vol.8(1), pp.1-10
    Description: Abstract Astroblastomas are rare brain tumours which predominate in children and young adults, and have a controversial claim as a distinct entity, with no established WHO grade. Reports suggest a better outcome than high grade gliomas, though they frequently recur. Recently, they have been...
    Keywords: Biology
    E-ISSN: 2045-2322
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  • 7
    Language: English
    In: Acta Neuropathologica Communications, Oct 10, 2013, Vol.1(1)
    Description: Background Medulloblastoma is the most common malignant brain tumor in children. Genetic profiling has identified four principle tumor subgroups; each subgroup is characterized by different initiating mutations, genetic and clinical profiles, and prognoses. The two most well-defined subgroups are caused by overactive signaling in the WNT and SHH mitogenic pathways; less is understood about Groups 3 and 4 medulloblastoma. Identification of tumor subgroup using molecular classification is set to become an important component of medulloblastoma diagnosis and staging, and will likely guide therapeutic options. However, thus far, few druggable targets have emerged. G-protein coupled receptors (GPCRs) possess characteristics that make them ideal targets for molecular imaging and therapeutics; drugs targeting GPCRs account for 30-40% of all current pharmaceuticals. While expression patterns of many proteins in human medulloblastoma subgroups have been discerned, the expression pattern of GPCRs in medulloblastoma has not been investigated. We hypothesized that analysis of GPCR expression would identify clear subsets of medulloblastoma and suggest distinct GPCRs that might serve as molecular targets for both imaging and therapy. Results Our study found that medulloblastoma tumors fall into distinct clusters based solely on GPCR expression patterns. Normal cerebellum clustered separately from the tumor samples. Further, two of the tumor clusters correspond with high fidelity to the WNT and SHH subgroups of medulloblastoma. Distinct over-expressed GPCRs emerge; for example, LGR5 and GPR64 are significantly and uniquely over-expressed in the WNT subgroup of tumors, while PTGER4 is over-expressed in the SHH subgroup. Uniquely under-expressed GPCRs were also observed. Our key findings were independently validated using a large international dataset. Conclusions Our results identify GPCRs with potential to act as imaging and therapeutic targets. Elucidating tumorigenic pathways is a secondary benefit to identifying differential GPCR expression patterns in medulloblastoma tumors. Keywords: Medulloblastoma subgroups, G-protein coupled receptors, Therapeutic targets, Imaging targets
    Keywords: Therapeutics – Health Aspects ; Proteins – Health Aspects ; Medulloblastoma – Genetic Aspects ; Medulloblastoma – Care and Treatment ; Medulloblastoma – Health Aspects ; Cell Receptors – Health Aspects ; Carcinogenesis – Genetic Aspects ; Carcinogenesis – Care and Treatment ; Carcinogenesis – Health Aspects
    ISSN: 2051-5960
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  • 8
    Language: English
    In: Experimental Hematology & Oncology, Oct 4, 2013, Vol.2(1)
    Description: Background Resistance to radiation treatment remains a major clinical problem for patients with brain cancer. Medulloblastoma is the most common malignant brain tumor of childhood, and occurs in the cerebellum. Though radiation treatment has been critical in increasing survival rates in recent decades, the presence of resistant cells in a substantial number of medulloblastoma patients leads to relapse and death. Methods Using the established medulloblastoma cell lines UW228 and Daoy, we developed a novel model system to enrich for and study radiation tolerant cells early after radiation exposure. Using fluorescence-activated cell sorting, dead cells and cells that had initiated apoptosis were removed, allowing surviving cells to be investigated before extensive proliferation took place. Results Isolated surviving cells were tumorigenic in vivo and displayed elevated levels of ABCG2, an ABC transporter linked to stem cell behavior and drug resistance. Further investigation showed another family member, ABCA1, was also elevated in surviving cells in these lines, as well as in early passage cultures from pediatric medulloblastoma patients. We discovered that the multi-ABC transporter inhibitors verapamil and reserpine sensitized cells from particular patients to radiation, suggesting that ABC transporters have a functional role in cellular radiation protection. Additionally, verapamil had an intrinsic anti-proliferative effect, with transient exposure in vitro slowing subsequent in vivo tumor formation. When expression of key ABC transporter genes was assessed in medulloblastoma tissue from 34 patients, levels were frequently elevated compared with normal cerebellum. Analysis of microarray data from independent cohorts (n = 428 patients) showed expression of a number of ABC transporters to be strongly correlated with certain medulloblastoma subtypes, which in turn are associated with clinical outcome. Conclusions ABC transporter inhibitors are already being trialed clinically, with the aim of decreasing chemotherapy resistance. Our findings suggest that the inhibition of ABC transporters could also increase the efficacy of radiation treatment for medulloblastoma patients. Additionally, the finding that certain family members are associated with particular molecular subtypes (most notably high ABCA8 and ABCB4 expression in Sonic Hedgehog pathway driven tumors), along with cell membrane location, suggests ABC transporters are worthy of consideration for the diagnostic classification of medulloblastoma. Keywords: Medulloblastoma, Radiation resistance, ABC transporter, ABCG2, ABCA1, Stem, Brain tumor, Verapamil, Reserpine, Sonic hedgehog
    Keywords: Drug Resistance – Analysis ; Medical Research – Analysis ; Reserpine – Analysis ; Radiotherapy – Analysis ; Stem Cells – Analysis ; Chemotherapy – Analysis ; Radiation (Physics) – Analysis ; Childhood Cancer – Care and Treatment ; Childhood Cancer – Analysis ; Medulloblastoma – Care and Treatment ; Medulloblastoma – Analysis ; Drug Resistance – Care and Treatment ; Transport Proteins – Analysis
    ISSN: 2162-3619
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  • 9
  • 10
    Language: English
    In: Oncotarget, 10 June 2015, Vol.6(16), pp.14584-95
    Description: Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in a separate cohort of medulloblastoma tissue samples to identify the most robust proteogenomic differences. Interestingly, highly expressed proteins associated with MYC-amplified tumors were significantly related to glycolytic metabolic pathways via alternative splicing of pyruvate kinase (PKM) by heterogeneous ribonucleoproteins (HNRNPs). Furthermore, when maintained under hypoxic conditions, these MYC-amplified tumors demonstrated increased viability compared to non-amplified tumors within the same subgroup. Taken together, these findings highlight the power of proteomics as an integrative platform to help prioritize genetic and molecular drivers of cancer biology and behavior.
    Keywords: Cmyc ; Cancer ; Glycolysis ; Medulloblastoma ; Proteomics ; Biomarkers, Tumor -- Genetics ; Cerebellar Neoplasms -- Genetics ; Medulloblastoma -- Genetics ; Proteomics -- Methods
    E-ISSN: 1949-2553
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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