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Berlin Brandenburg

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  • 1
    In: International Journal of Cancer, 01 February 2014, Vol.134(3), pp.703-716
    Description: Based on extensive pre‐clinical studies, the oncolytic parvovirus H‐1 (H‐1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high‐risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H‐1PV on MB cells and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non‐transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H‐1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H‐1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H‐1PV. H‐1PV induced down‐regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H‐1PV infection. H‐1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. What's new? Medulloblastoma, the most frequent pediatric brain cancer, causes death in about 60 percent of high‐risk patients, and so there is a major need for novel, highly effective therapies. One therapy of interest is parvovirus H‐1 (H‐1PV), which was found in this study to produce marked cytotoxic effects in six medulloblastoma cell lines. Gene expression profiling revealed that H‐1PV infection causes down‐regulation of key regulatory genes involved in early neurogenesis, with significant repression of . The master regulators affected may represent putative direct or indirect H‐1PV target genes.
    Keywords: Medulloblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Cellular Targets ; Myc ; Master Regulators Of Neurogenesis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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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: International Journal of Cancer, 01 September 2010, Vol.127(5), pp.1230-1239
    Description: Despite multimodal therapeutic concepts, advanced localized and high‐risk neuroblastoma remains a therapeutic challenge with a long‐term survival rate below 50%. Consequently, new modalities for the treatment of neuroblastoma, ., oncolytic virotherapy are urgently required. H‐1PV is a rodent parvovirus devoid of relevant pathogenic effects in infected adult animals. In contrast, the virus has oncolytic properties and is particularly cytotoxic for transformed or tumor‐derived cells of various species including cells of human origin. Here, a preclinical assessment of the application of oncolytic H‐1PV for the treatment of neuroblastoma cells was performed. Infection efficiency, viral replication and lytic activity of H‐1PV were analyzed in 11 neuroblastoma cell lines with different MYCN status. Oncoselectivity of the virus was confirmed by the infection of short term cultures of nonmalignant infant cells of different origin. In these nontransformed cells, no effect of H‐1PV on viability or morphology of the cells was observed. In contrast, a lytic infection was induced in all neuroblastoma cell lines examined at MOIs between 0.001 and 10 pfu/cell. H‐1PV actively replicated with virus titres increasing up to 5,000‐fold within 48–96 hr after infection. The lytic effect of H‐1PV was observed independent of MYCN oncogene amplification or differentiation status. Moreover, a significant G2‐arrest and induction of apoptosis could be demonstrated. Infection efficiency, rapid virus replication and exhaustive lytic effects on neuroblastoma cells together with the low toxicity of H‐1PV for nontransformed cells, render this parvovirus a promising candidate for oncolytic virotherapy of neuroblastoma.
    Keywords: Neuroblastoma ; Oncolytic Virus ; Parvovirus H‐1pv ; Apoptosis
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 4
    Language: English
    In: International Journal of Cancer, 15 April 2008, Vol.122(8), pp.1891-1900
    Description: The survival rate of children with advanced neuroblastoma (NB) is dismal despite intensive multimodal therapy. The limited efficacy and the frequent and serious side effects of currently used therapeutic regimens necessitate the development of new, less toxic treatment strategies. This study shows that the histone deacetylase inhibitor (HC)‐toxin suppresses the malignant phenotype of both established NB cell lines and primary NB cells with and without amplified at dosages lower than 20 nM. HC‐toxin induces cell cycle arrest and apoptosis as well as neuronal differentiation and diminishes both colony formation and invasive growth. These cellular changes are accompanied by the transcriptional repression of cell cycle regulators of the retinoblastoma (RB) tumor suppressor network found at high levels in NBs with poor prognosis, like E2F‐1 and its targets Skp2, N‐myc, Mad2 and survivin. The levels of the hypophosphorylated active form of RB, and of cyclin‐dependent kinase inhibitors including p15, p16, p21 and p27 are increased. In conclusion, nanomolar doses of the HDACI HC‐toxin cause a shift to a differentiated and benign phenotype of NB cells that is associated with an activation of the RB tumor suppressor network. © 2007 Wiley‐Liss, Inc.
    Keywords: Epigenetic Therapy ; Cell Cycle Arrest ; Differentiation ; E2f‐1 Regulated Genes ; Rb Tumor Suppressor Network
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 5
    Language: English
    In: International journal of cancer, 15 October 2019
    Description: Reports on pediatric low-grade glioma (LGG) of the caudal brainstem are retrospective with heterogeneous cohorts, variable treatments and inconsistent outcome-data. We analyzed their natural history and asked whether brainstem location proved unfavorable for survival within the framework of the comprehensive SIOP-LGG 2004 management strategy. Within the prospectively registered, population-based German SIOP-LGG 2004 cohort 116 patients (age 0.2-16.5 years, 10% Neurofibromatosis NF1) were diagnosed with LGG of the pons (27%) and medulla oblongata (73%). Following biopsy (23%), variable resection (63%), or radiologic diagnosis only (14%), 59 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemo- (n = 39) or radiotherapy (n = 18). Following further progression (28/57) salvage treatments included multiple treatment lines for 12/28 patients. Five-years event-free survival dropped to 0.40, while 5-years overall survival was 0.95 (median observation time 6.8 years). Higher extent of resection yielded lower progression-rate (p = 0.001), but at a cost of 21/100 patients suffering from new postsurgical complications including respiratory insufficiency. Central review confirmed pilocytic astrocytoma (56%), diffuse astrocytoma (8%) or glioneuronal histology (16%), (others 4%, no histology 17%). Malignant evolution was documented in 5 patients associated with Histone3-mutation in 2/5. Our treatment algorithm conveyed high overall survival for pediatric brainstem LGG. Extensive neurosurgical resection did increase additional postoperative neurologic deficits but not overall survival in this often-chronic disease. More than half of all patients can be safely followed by observation, while multimodal adjuvant treatment can control progressive tumors. Molecular assessment should confirm low-grade diagnosis and may detect patterns prognostic for malignant evolution. This article is protected by copyright. All rights reserved.
    Keywords: Brainstem Low Grade Glioma ; Chemotherapy ; Child ; Radiotherapy ; Surgery;
    E-ISSN: 1097-0215
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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