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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2015, Vol. 17(suppl3), pp.iii33-iii33
    Description: Brain tumors are the leading cause of cancer-related mortality in childhood. Based on the many recent genomic studies, we know now that multiple molecular subtypes of brain cancers exist that are not only biologically but also clinically highly distinct. These findings may lead to novel treatment strategies. For this we need better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NOD scid gamma (NSG) mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations are needed to learn about targetable oncogenic drivers in each model. Therefore, we aim to generate a large repertoire of PDX models reflecting the many different molecular subtypes of pediatric brain cancer. For each established PDX model, we perform DNA methylation profiling, gene expression profiling, low-coverage whole genome sequencing and whole exome sequencing and compare these data with the matching primary tumor. Thus far, as a collaborative effort between different laboratories, we have established and fully characterized 34 PDX models from 1 atypical teratoid rhabdoid tumor (ATRT), 4 ependymoma, 9 glioblastoma, 18 medulloblastoma, and 2 primitive neuroectodermal tumors (PNET). Molecular analysis of all available PDX models identified a clear overrepresentation of most aggressive tumors such as models characterized by MYC- or MYCN amplification. Other, less aggressive cancers, like Wnt medulloblastoma, are underrepresented. For in vivo imaging during treatment of PDX models we created luciferase labeled PDX sublines. Our data demonstrate that PDX models retain characteristics of the primary human tumors from which they were derived. These reagents provide an unprecedented resource to study tumor biology and pave the way for improving treatment strategies of malignant pediatric brain tumors.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 15 January 2013, Vol.110(3), pp.1041-1046
    Description: The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, wholetranscriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU. 1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.
    Keywords: Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Cytology ; Health sciences -- Medical conditions -- Diseases ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Physiology ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Genetics ; Health sciences -- Medical conditions -- Diseases ; Biological sciences -- Biology -- Cytology
    ISSN: 00278424
    E-ISSN: 10916490
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  • 3
  • 4
    Language: English
    In: Cancer Cell, 08 December 2014, Vol.26(6), pp.940-940.e1
    Description: Medulloblastoma (MB) is the most common malignant brain tumor in children, where one-third of patients succumb to their disease. This SnapShot describes the classification of MB subgroups, historically by histopathology and currently based on genomic information. Genomics-based classification has identified four major subgroups and provides greater opportunity for developing targeted therapies more successful than current conventional therapy.
    Keywords: Medicine
    ISSN: 1535-6108
    E-ISSN: 1878-3686
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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 17 December 2018
    Description: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anti-cancer small molecule in clinical trials for high grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201. The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in 〉1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. Immunohistochemistry staining of DRD2/DRD5 was performed in tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies. DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a de novo Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from recurrent glioblastoma patients treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes. These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 6
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i155-i155
    Description: Identification of multiple distinct subtypes of pediatric brain tumors raises the need for more and better preclinical models reflecting these subtypes. Orthotopic patient-derived xenograft (PDX) models generated by injection of human tumor cells into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Extensive molecular characterization of PDX and matching primary tumor/blood are needed to see how well the PDX represents the original disease, to learn about targetable oncogenic drivers in each model, and to establish or confirm predictive biomarkers. In an ongoing world-wide effort we have generated and fully characterized thus far 130 PDX models reflecting 22 distinct molecular subtypes of pediatric brain tumors. PDX models always retain their molecular subtype as assessed by DNA methylation analysis and in the vast majority of cases also the mutations and copy number alterations when compared to their primary tumors. Most aggressive tumors, such as those having MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines are included. All models and corresponding molecular data will become available for the community for preclinical research. Our repertoire of PDX models and corresponding molecular characterizations allow researchers to find the right models for their specific scientific questions. It provides an unprecedented resource to study tumor biology and paves the way for improving treatment strategies for children with malignant brain tumors.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 7
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i142-i142
    Description: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Even with an intensive therapeutic regimen of surgery, radiation and chemotherapy, one-third of patients still succumb to their disease and survivors suffer devastating side effects from the therapy. Thus, more effective and less toxic therapies are desperately needed. Genomic analyses have identified four major subgroups of MB – WNT, SHH, Group 3 and Group 4 – that differ in terms of mutations, gene expression and patient outcomes. Despite this heterogeneity, all MB patients currently receive similar therapies. To identify novel therapies for each subgroup of MB, we have assembled a panel of patient-derived xenograft (PDX) lines established by orthotopic transplantation of tumor cells obtained from surgery. We used these PDXs to perform high-throughput drug screening, and integrated drug response data with mutational, transcriptional, and epigenetic profiles. These studies revealed significant heterogeneity in drug responses among MB patients, and identified the RNA synthesis inhibitor Actinomycin D as a potent inhibitor of Group 3 MB, the most aggressive form of the disease. Based on these studies, we hope to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are likely to be more effective against their tumor.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 8
    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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  • 9
    Language: English
    In: Oncotarget, 06/10/2015, Vol.6(16)
    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.
    ISSN: Oncotarget
    E-ISSN: 1949-2553
    Source: CrossRef
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  • 10
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