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HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment

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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.

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Acknowledgments

We thank Jasmin Wünschel, Markus Sohn, Christina Xanthopoulos, Diana Rieker, Peter van Sluis, and Richard Volckmann for excellent technical assistance. Work was supported by a grant from the University of Heidelberg through the OLYMPIA MORATA program to H.E.D., and a grant from the Interdisciplinary Research Program (NCT-IFP) of the National Center of Tumor Diseases, Heidelberg, Germany, to T.M. and S.M.P. The experiments comply with the current laws of the country in which they were performed. The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Till Milde, Marco Lodrini, André S. L. M. Antunes, Ina Oehme, Olaf Witt & Hedwig E. Deubzer

  2. Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany

    Till Milde, Stefan M. Pfister, Andreas E. Kulozik, Olaf Witt & Hedwig E. Deubzer

  3. Tumor Genetics (B030), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Larissa Savelyeva & Lena M. Brueckner

  4. Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany

    Andrey Korshunov

  5. Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Andrey Korshunov

  6. Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Marcel Kool & Stefan M. Pfister

  7. Department of Infectious Diseases, King’s College London School of Medicine, London, UK

    André S. L. M. Antunes

  8. Pediatric Oncology, Prof. Hess Children’s Hospital, Bremen, Germany

    Arnulf Pekrun

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  1. Till Milde
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  2. Marco Lodrini
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  3. Larissa Savelyeva
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Correspondence to Till Milde.

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Milde, T., Lodrini, M., Savelyeva, L. et al. HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J Neurooncol 110, 335–348 (2012). https://doi.org/10.1007/s11060-012-0978-1

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