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  • Cell Proliferation
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  • 1
    In: Neuro-Oncology, 2014, Vol. 16(suppl5), pp.v214-v214
    Description: Aggressive cancer cells are characterized by high rates glycolysis and lactate production, a metabolic reprogramming event known as the Warburg effect. This ultimately provides tumor cells including GBM the most malignant and common primary brain tumor with intermediate metabolites for anabolic processes, cell proliferation and invasion. However, these biological processes generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss of function screen in pre-disposed but non-transformed astrocytes, we demonstrate that PTEN Induced Kinase 1 (PINK1), a mitochondrial kinase is a crucial regulator of the Warburg effect. Mechanistically, loss of PINK1 mediates metabolic reprogramming in normal human astrocytes through ROS dependent hypoxia-inducible factor-1α (HIF1α) stabilization, a transcription factor that controls expression of several aerobic glycolysis genes. Overexpression of PINK1 in GBM cells suppresses ROS, HIF1a and the Warburg effect in vitro and in vivo. Surprisingly, loss of PINK1 in GBM cells that retain PINK1 expression increases oxidative stress and reduces cell viability suggesting ROS balance and maintenance is critical in tumor cells and can be therapeutically exploited. PINK1 loss was observed in GBM and correlated with poor patient survival. Collectively, we demonstrate that PINK1 is a negative regulator of the Warburg effect.
    Keywords: Detoxification ; Glioblastoma ; Astrocytes ; Pten-Induced Putative Kinase ; Mitochondria ; Oncology ; Metabolites ; Pten Protein ; Tumor Cells ; Cancer ; Brain Tumors ; Reactive Oxygen Species ; Oxidative Stress ; Transcription Factors ; Lactic Acid ; Cell Proliferation ; Glycolysis ; Neurobiology;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Nature Medicine, 2014, Vol.20(12), p.1378
    Description: Despite advances in chemotherapy and radiation over the past 40 years, the outcome for children with diffuse intrinsic pontine gliomas (DIPGs) remains almost uniformly fatal, with survival of less than 12 months despite numerous trials of chemotherapy, targeted agents and radiation therapy. Recently, large genome-sequencing studies of pediatric high-grade gliomas have been carried out and have consistently identified a lysine to methionine (K27M) substitution in histones H3.1 and H3.3 in over 80% of midline high-grade gliomas and DIPGs2.
    Keywords: Tumors ; Chemotherapy ; Radiation Therapy ; Medical Research ; Epigenetics;
    ISSN: 1078-8956
    E-ISSN: 1546170X
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  • 3
    In: Oncogene, 2016, Vol.35(32), p.4256-4268
    Description: Post-natal proliferation of cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for the SHH-associated subgroup of medulloblastoma (MB), is driven by Sonic Hedgehog (Shh) and Insulin-like Growth Factor (IGF) in the developing cerebellum. Shh induces the oncogene Yes-associated protein (YAP), which drives IGF2 expression in CGNPs and mouse Shh-associated medulloblastomas. To determine how IGF2 expression is regulated downstream of YAP, we carried out an unbiased screen for transcriptional regulators bound to IGF2 promoters. We report that Y-box binding protein-1 (YB-1), an onco-protein regulating transcription and translation, binds to IGF2 promoter P3. We observed that YB-1 is up-regulated across human medulloblastoma subclasses as well as in other varieties of pediatric brain tumors. Utilizing the cerebellar progenitor model for the Shh-subgroup of MB in mice, we show for the first time that YB-1 is induced by Shh in CGNPs. Its expression is YAP-dependent and it is required for IGF2 expression in CGNPs. Finally, both gain-of function and loss-of-function experiments reveal that YB-1 activity is required for sustaining CGNP and medulloblastoma cell (MBC) proliferation. Collectively, our findings describe a novel role for YB-1 in driving proliferation in the developing cerebellum and medulloblastoma cells and they identify the SHH:YAP:YB1:IGF2 axis as a powerful target for therapeutic intervention in medulloblastomas.
    Keywords: Article ; Medulloblastoma ; Sonic Hedgehog ; Hippo ; Yb1 ; Yap ; Igf2 ; Cerebellum ; Cell Cycle
    ISSN: 0950-9232
    E-ISSN: 1476-5594
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  • 4
    Language: English
    In: Journal of medicinal chemistry, 13 July 2017, Vol.60(13), pp.5334-5348
    Description: The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC values in the low μM and sub-μM range. 1g-i revealed low nM IC values for HDAC6 with up to 15-fold preference over HDAC1, 〉3500-fold selectivity over HDAC4, and 〉100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1g-i significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g-i interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR.
    Keywords: Antineoplastic Agents -- Pharmacology ; Cisplatin -- Pharmacology ; Histone Deacetylase Inhibitors -- Pharmacology ; Histone Deacetylases -- Metabolism ; Urea -- Pharmacology
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 June 2010, Vol.16(12), pp.3240-52
    Description: Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth. Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells. HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability. HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets.
    Keywords: Biomarkers, Tumor -- Metabolism ; Brain Neoplasms -- Metabolism ; Histone Deacetylases -- Metabolism ; Medulloblastoma -- Metabolism ; Repressor Proteins -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 6
    Language: English
    In: Cancer research, 01 January 2015, Vol.75(1), pp.134-46
    Description: Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)-driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma.
    Keywords: Anilides -- Pharmacology ; Cerebellar Neoplasms -- Drug Therapy ; Hedgehog Proteins -- Metabolism ; Medulloblastoma -- Drug Therapy ; Quinolines -- Pharmacology
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 7
    Language: English
    In: Child's Nervous System, 2013, Vol.29(8), pp.1253-1262
    Description: Byline: Marc Remke (1,2,3), Esther Hering (4), Nicolas U. Gerber (5), Marcel Kool (2), Dominik Sturm (2), Christian H. Rickert (6), Joachim Gerss (7), Stefan Schulz (8), Thomas Hielscher (9), Martin Hasselblatt (10), Astrid Jeibmann (10), Volkmar Hans (11), Vijay Ramaswamy (1), Michael D. Taylor (1), Torsten Pietsch (12), Stefan Rutkowski (13), Andrey Korshunov (14,15), Carmelia-Maria Monoranu (16), Michael C. Fruhwald (4,17,18) Keywords: Somatostatin receptor 2 (sst.sub.2); Medulloblastoma; CNS-PNET; Glioma; Molecular targeting; Diagnostic imaging; Children Abstract: Introduction Neuroectodermal tumors in general demonstrate high and dense expression of the somatostatin receptor subtype 2 (sst.sub.2). It controls proliferation of both normal and neoplastic cells. sst.sub.2 has thus been suggested as a therapeutic target and prognostic marker for certain malignancies. Methods To assess global expression patterns of sst .sub.2 mRNA, we evaluated normal (n=353) and tumor tissues (n=340) derived from previously published gene expression profiling studies. These analyses demonstrated specific upregulation of sst .sub.2 mRNA in medulloblastoma (p〈0.001). sst.sub.2 protein was investigated by immunohistochemistry in two independent cohorts. Results Correlation of sst.sub.2 protein expression with clinicopathological variables revealed significantly higher levels in medulloblastoma (p〈0.05) compared with CNS-PNET, ependymoma, or pilocytic astrocytoma. The non-SHH medulloblastoma subgroup tumors showed particularly high expression of sst.sub.2, when compared to other tumors and normal tissues. Furthermore, we detected a significant survival benefit in children with tumors exhibiting high sst.sub.2 expression (p=0.02) in this screening set. A similar trend was observed in a validation cohort including 240 independent medulloblastoma samples. Conclusion sst.sub.2 is highly expressed in medulloblastoma and deserves further evaluation in the setting of prospective trials, given its potential utility as a prognostic marker and a therapeutic target. Author Affiliation: (1) Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (2) Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany (3) Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany (4) Department of Pediatric Hematology and Oncology, University Children's Hospital Munster, Munster, Germany (5) Department of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland (6) Institute of Neuropathology and Paidopathology, Vivantes Hospitals, Friedrichshain and Neukolln, Berlin, Germany (7) Department of Medical Informatics and Biomathematics, University of Muenster, Munster, Germany (8) Institute of Pharmacology and Toxicology Friedrich-Schiller-Universitat Jena, University Hospitals of Jena, Jena, Germany (9) Division Biostatistics (C060), DKFZ, Heidelberg, Germany (10) Institute of Neuropathology, University Hospital, Munster, Germany (11) Institute of Neuropathology, Bethel, Germany (12) Institute of Neuropathology, University Hospitals Bonn, Bonn, Germany (13) Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, Germany (14) Department of Neuropathology, University of Heidelberg, Heidelberg, Germany (15) Clinical Cooperation Unit Neuropathology, DKFZ, Heidelberg, Germany (16) Department of Neuropathology, Institute of Pathology, University of Wurzburg, Wurzburg, Germany (17) Childrens' Hospital Augsburg, Augsburg, Germany (18) Klinikum Augsburg, I, Kinderklinik, Stenglinstr. 2, 86156, Augsburg, Germany Article History: Registration Date: 01/05/2013 Received Date: 25/03/2013 Accepted Date: 30/04/2013 Online Date: 16/05/2013 Article note: Marc Remke, Esther Hering, and Nicolas U. Gerber contributed equally to this work Electronic supplementary material The online version of this article (doi: 10.1007/s00381-013-2142-4) contains supplementary material, which is available to authorized users.
    Keywords: Somatostatin receptor 2 (sst) ; Medulloblastoma ; CNS-PNET ; Glioma ; Molecular targeting ; Diagnostic imaging ; Children
    ISSN: 0256-7040
    E-ISSN: 1433-0350
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  • 8
    In: Brain, 2018, Vol. 141(5), pp.1300-1319
    Description: The molecular events underlying dissemination of group 3 medulloblastoma remain elusive. Ferrucci et al. show that PRUNE1 overexpression enhances the canonical TGF-β cascade, upregulates OTX2 and SNAIL, and inhibits the tumour suppressor PTEN. They describe anti-metastatic properties of an anti-PRUNE1 drug, and identify further deleterious gene variants as therapeutic targets. Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL ( SNAI1 ) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3. 10.1093/brain/awy039_video1 awy039media1 5742053534001
    Keywords: Medulloblastoma ; Metastatic Cns Tumour ; Molecular Genetics ; Genetic Network ; Oncology
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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  • 9
    Language: English
    In: Acta neuropathologica communications, 24 January 2014, Vol.2, pp.10
    Description: Medulloblastoma is the most common intracranial childhood malignancy and a genetically heterogeneous disease. Despite recent advances, current therapeutic approaches are still associated with high morbidity and mortality. Recent molecular profiling has suggested the stratification of medulloblastoma from one single disease into four distinct subgroups namely: WNT Group (best prognosis), SHH Group (intermediate prognosis), Group 3 (worst prognosis) and Group 4 (intermediate prognosis). BMI1 is a Polycomb group repressor complex gene overexpressed across medulloblastoma subgroups but most significantly in Group 4 tumours. Bone morphogenetic proteins are morphogens belonging to TGF-β superfamily of growth factors, known to inhibit medulloblastoma cell proliferation and induce apoptosis. Here we demonstrate that human medulloblastoma of Group 4 characterised by the greatest overexpression of BMI1, also display deregulation of cell adhesion molecules. We show that BMI1 controls intraparenchymal invasion in a novel xenograft model of human MB of Group 4, while in vitro assays highlight that cell adhesion and motility are controlled by BMI1 in a BMP dependent manner. BMI1 controls MB cell migration and invasion through repression of the BMP pathway, raising the possibility that BMI1 could be used as a biomarker to identify groups of patients who may benefit from a treatment with BMP agonists.
    Keywords: Bone Morphogenetic Proteins -- Metabolism ; Cell Adhesion -- Physiology ; Cerebellar Neoplasms -- Genetics ; Medulloblastoma -- Genetics ; Polycomb Repressive Complex 1 -- Genetics
    E-ISSN: 2051-5960
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  • 10
    Language: English
    In: Oncotarget, 15 May 2014, Vol.5(9), pp.2355-71
    Description: Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo.
    Keywords: Cell Proliferation ; Cerebellar Neoplasms -- Prevention & Control ; Medulloblastoma -- Prevention & Control ; Neoplastic Stem Cells -- Pathology ; Nuclear Proteins -- Antagonists & Inhibitors ; Proto-Oncogene Proteins C-Myc -- Metabolism ; Transcription Factors -- Antagonists & Inhibitors
    E-ISSN: 1949-2553
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