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  • Reifenberger, Guido  (29)
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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i131-i131
    Description: Medulloblastoma is the most common malignant pediatric brain tumor and comprises at least four distinct biological subgroups. MYC-driven tumorigenesis constitutes a hallmark feature underlying Group 3 biology and metastatic dissemination at diagnosis or recurrence constitutes a major clinical problem in this highly aggressive subgroup. Employing our institutional drug screening platform, we evaluated an in-house library of over 200 histone deacetylase inhibitors (HDACi) in various brain tumor cell lines and patient-derived primary cultures including glioblastoma (n=8), medulloblastoma (n=10) and atypical teratoid/rhabdoid tumors (n=11). Thereby, we identified CI-994, a clinically established class I specific HDAC inhibitor, which selectively inhibited proliferation of MYC-driven medulloblastoma in our primary and secondary screen. We confirmed the MYC-dependent response in medulloblastoma cell lines with CRISPR/CAS9-based MYC overexpression compared to their isogenic controls with low MYC expression. Notably, inhibitor treatment resulted in significantly reduced MYC mRNA and protein expression levels, decreased cell viability and induction of apoptosis. Additionally, a screen for synergism with a clinical inhibitor library (clinical phase III/IV and approved chemotherapeutics) revealed favorable interaction with NFκB inhibition. Furthermore, integrated proteogenomics using RNA sequencing and proteomic profiling corroborated NFκB pathway activation upon CI-994 treatment. Finally, we demonstrated a significantly prolonged survival, a decrease in tumor growth and spinal metastasis in two orthotopic xenograft mouse models of MYC-driven medulloblastoma. In conclusion, our results suggest a MYC-dependent response to class I HDAC inhibition in medulloblastoma and provide compelling rationale for further development of a novel, potentially highly effective therapeutic strategy against the primary site and, importantly, the metastatic compartment.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    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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  • 3
  • 4
    In: Nature, 2012, Vol.488(7409), p.100
    Description: Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
    Keywords: Cerebellar Neoplasms -- Genetics ; Genome, Human -- Genetics ; Medulloblastoma -- Genetics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
    Language: English
    In: Cancer Research, 04/15/2010, Vol.70(8 Supplement), pp.4349-4349
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i112-i112
    Description: Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Aberrant MAPK signaling, typically mediated by BRAF alterations, drives PA formation. While five-year overall survival rates exceed 95%, incompletely resected tumors recur frequently despite treatment. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach utilizes RNA sequencing and LC/MS-based proteomic profiling and Similarity Fusion Network (SNF) analysis reveals the biological heterogeneity of PA. Integrative genomics dissects aberrant pathway activation in biological subgroups. Lastly, we utilize a drug screening pipeline to evaluate selective therapeutic activity of conventional anti-cancer and phase III/IV clinical trial drugs in PA culture models. PAs segregate into three groups with distinct clinical and molecular features. Age and tumor location are significantly associated with the SNF groups. BRAF fusions were predominantly observed in Groups 1 and 2, while Group 3 PA largely harbored other alterations leading to MAPK activation. Pathway enrichment analyses reveals genesets involved in primary ciliogenesis in Group 3, while immune response signatures, many SYK-related, are associated with Group 1. Confirming this analysis, the SYK inhibitor R788 was specifically active in Group 1, and less active in other brain tumors models (n=27). In summary, our proteogenomic approach reveals important biological heterogeneity with novel therapeutic targets emerging in PA. These biological insights may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of progressive disease.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 7
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i80-i80
    Description: Ependymoma is the third most common brain tumor in children. Subsets of ependymomas, in particular RELA fusion-positive supratentorial ependymomas and posterior fossa type A ependymomas, are associated with frequent recurrence and dismal outcome. Neurosurgical resection and radiotherapy are the main therapeutic options, while response to conventional chemotherapy is limited. We aimed to establish a high-throughput drug screening (HTS) pipeline for comprehensive individualized testing of patient-derived primary cultures to identify novel therapeutic targets for ependymomas. Ependymoma primary cultures (n=6) were established following tumor resection and underwent HTS in 1536-well plates to allow large-scale drug screening despite limited cell numbers. We generated dose-response data with 9 dilution steps (dose range 32.5nM to 25µM) for a clinical inhibitor library (n=196) comprising established chemotherapeutic agents and novel anti-cancer compounds currently in phase III and IV studies. The Infinium MethylationEPIC Array was used to characterize primary tumors and matched primary cultures genomically and epigenetically. DNA methylation and copy number profiles revealed that short-term primary cultures faithfully recapitulate the genomic and epigenetic landscape of the corresponding primary tumors. Comparison of drug response data from ependymomas, other pediatric brain tumors (n=25) and controls (i.e. non-neoplastic neural progenitor cells) confirmed extraordinary chemoresistance of ependymomas but also revealed promising selectively active drugs, such as neratinib, an irreversible ERBB2 inhibitor. Thus, our data demonstrate the feasibility of HTS in primary cultures derived from pediatric brain tumors and provide preclinical evidence suggesting inhibition of ERBB2 as a promising therapeutic option in a subset of otherwise highly chemoresistant ependymomas.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 8
    Language: English
    In: Acta Neuropathologica, 2013, Vol.125(6), pp.913-916
    Description: It is now clear that medulloblastoma (MB), one of the most clinically challenging paediatric brain tumours, is not a single disease entity. Rather, it comprises four distinct molecular subgroups (Wnt pathway activated (WNT), Sonic hedgehog pathway activated (SHH), and the less well-characterised Group 3 and Group 4) [7, 15], which are highly divergent in terms of their patient demographics, underlying biology, and survival outcomes [4, 6]. These subgroups are becoming increasingly important, not only for refining the discovery of prognostic markers or therapeutic targets, but also for the design of prospective clinical trials. Patients with WNT subgroup tumours, for example, generally have a favourable prognosis, and may benefit from a reduction or omission of radiotherapy or chemotherapy to spare neurological side-effects or other toxicities, as is now being prospectively tested in upcoming trials both in North America and Europe. In contrast, patients with poor prognosis Group 3 tumo ...
    Keywords: Medicine;
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 9
    Language: English
    In: The Journal of clinical investigation, May 2008, Vol.118(5), pp.1739-49
    Description: The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.
    Keywords: Gene Duplication ; Astrocytoma -- Enzymology ; Brain Neoplasms -- Enzymology ; MAP Kinase Signaling System -- Physiology ; Mitogen-Activated Protein Kinases -- Metabolism ; Proto-Oncogene Proteins B-Raf -- Metabolism
    ISSN: 0021-9738
    E-ISSN: 15588238
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  • 10
    Language: English
    In: Cell, 25 February 2016, Vol.164(5), pp.1060-1072
    Description: Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with activation (CNS NB- ),” “CNS Ewing sarcoma family tumor with alteration (CNS EFT- ),” “CNS high-grade neuroepithelial tumor with alteration (CNS HGNET- ),” and “CNS high-grade neuroepithelial tumor with alteration (CNS HGNET- ),” will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. Highly malignant primitive neuroectodermal tumors of the CNS (CNS-PNETs) have been challenging to diagnose and distinguish from other kinds of brain tumors, but molecular profiling now reveals that these cancers can be readily classified into some known tumor types and four new entities with distinct histopathological and clinical features, paving the way for meaningful clinical trials.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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