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  • 1
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; DRUG ; DIFFERENTIATION ; INDUCTION ; ACID ; NERVOUS-SYSTEM ; ASSAY ; CANCER-CELLS ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; p21(waf1) ; neuroblastoma ; INVITRO ; LEUKEMIA-CELLS ; ONCOLOGY ; CHILDHOOD ; RE ; medulloblastoma ; cell proliferation ; ASSAYS ; pharmacology ; USA ; anticancer drug ; childhood cancer ; HELMINTHOSPORIUM-CARBONUM (HC)-TOXIN ; HKI46F08
    Abstract: Embryonic childhood cancer such as neuroblastoma and medulloblastoma are still a therapeutic challenge requiring novel treatment approaches. Here, we investigated the antitumoral effects of HKI 46F08, a novel trifluoromethyl ketone histone deacetylase (HDAC) inhibitor with a nonhydroxamic acid type structure. HKI 46F08 inhibits in-vitro HDAC activity in cell-free assays with a half maximal inhibitory concentration of 0.6 mu mol/l and intracellular HDAC activity with a half maximal inhibitory concentration of 1.8 mu mol/l. The compound reduces viability of both cultured neuroblastoma and medulloblastoma cells with an EC50 of 0.1-4 mu mol/l. HKI 461708 efficiently arrests tumor cell proliferation, represses clonogenic growth and induces differentiation and apoptosis in both MYCN-amplified and nonamplified neuroblastoma cells. In summary, we identified HKI 48F08 as a structural novel, potent HDAC inhibitor with strong antitumoral activity against embryonic childhood cancer cells in the low micromolar range
    Type of Publication: Journal article published
    PubMed ID: 18765999
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  • 2
    Keywords: GROWTH ; IN-VITRO ; tumor ; MODEL ; IDENTIFICATION ; STEM-CELLS ; ABNORMALITIES ; SUPRATENTORIAL ; CHILDHOOD EPENDYMOMAS ; PEDIATRIC INTRACRANIAL EPENDYMOMAS
    Abstract: PURPOSE OF REVIEW: Effective treatment options for ependymoma apart from radical surgery and radiotherapy remain scarce, and the understanding of the molecular basis of ependymoma biology is crucial to the development of novel therapies. Comprehensive work revealing molecular pathomechanisms of ependymoma has been done; however, the elucidation of the processes underlying the origins of various clearly distinguishable ependymoma subgroups has proved to be difficult. The future challenges will be to reach consensus about molecular subgroups, to translate these into a clinical setting, and to use available models for drug screening and preclinical testing. RECENT FINDINGS: Ependymoma subgroups with clearly distinct biology have been delineated and novel mouse models generated, and the first high-throughput drug screens were successfully conducted leading to the identification of subgroup-specific active regimens. SUMMARY: Coordinated efforts to advance novel therapies into the clinic have led to breakthrough insights into the molecular biology of ependymoma. The next step will be the translation of preclinical findings into the clinical setting, and international study groups are starting to implement the most recent advances into clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 23007011
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  • 3
    Keywords: IN-VITRO ; PHASE-I ; NERVOUS-SYSTEM ; INDUCED APOPTOSIS ; POOR-PROGNOSIS ; COLON-CANCER CELLS ; SOLID TUMORS ; valproic acid ; HDAC inhibitor ; GENETIC PROFILES
    Abstract: Medulloblastomas are the most common malignant brain tumors in childhood. Emerging evidence suggests that medulloblastoma comprises at least four distinct diseases (WNT, SHH, Group 3 and 4) with different biology, clinical presentation, and outcome, with especially poor prognosis in Group 3. The tight connection of biology and clinical behavior in patients emphasizes the need for subgroup-specific preclinical models in order to develop treatments tailored to each subgroup. Herein we report on the novel cell line HD-MB03, isolated from tumor material of a patient with metastasized Group 3 medulloblastoma, and preclinical testing of different histone deacetylase inhibitors (HDACis) in this model. HD-MB03 cells grow long term in vitro and form metastatic tumors in vivo upon orthotopic transplantation. HD-MB03 cells reflect the original Group 3 medulloblastoma at the histological and molecular level, showing large cell morphology, similar expression patterns for markers Ki67, p53, and glial fibrillary acidic protein (GFAP), a gene expression profile most closely matching Group 3 medulloblastomas, and persistence of typical molecular alterations, i.e., isochromosome 17q [i(17q)] and MYC amplification. Protein expression analysis of HDACs 2, 5, 8, and 9 as well as the predictive marker HR23B showed intermediate to strong expression, suggesting sensitivity to HDACis. Indeed, treatment with HDACis Helminthosporium carbonum (HC)-toxin, vorinostat, and panobinostat revealed high sensitivity to this novel drug class, as well as a radiation-sensitizing effect with significantly increased cell death upon concomitant treatment. In summary, our data indicate that HD-MB03 is a suitable preclinical model for Group 3 medulloblastoma, and HDACis could represent a therapeutic option for this subgroup.
    Type of Publication: Journal article published
    PubMed ID: 23054560
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  • 4
    Keywords: CANCER ; IN-VITRO ; histone deacetylase inhibitor ; neuroblastoma ; CHILDHOOD ; medulloblastoma ; HELMINTHOSPORIUM-CARBONUM (HC)-TOXIN ; SUBEROYLANILIDE HYDROXAMIC ACID ; INDUCE CELL-DEATH ; PEDIATRIC-ONCOLOGY
    Abstract: Members of the histone deacetylase (HDAC) family exhibit great promise as potential drug targets in pediatric tumors including neuroblastoma, medulloblastoma, ependymoma and Ewing's sarcoma. HDAC inhibitors of various structural classes have shown anti-tumoral effects in pre-clinical pediatric tumor models as single agents or in combination treatments. Suberoylanilidehydroxamic acid (SAHA=vorinostat) is the most clinical advanced compound of the class and was approved by the US FDA in October 2006 for the treatment of refractory cutaneous T-cell lymphoma. In this phase I/II trial, pediatric patients with relapsed solid tumors, lymphoma or leukemias are treated according to an individualized dose escalation concept ensuring each individual patient to receive his optimal dose with respect to toxicity and efficacy. The study is accompanied by an extensive pharmacokinetic, pharmacodynamic and biomarker program.
    Type of Publication: Journal article published
    PubMed ID: 22915450
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