Klin Padiatr 2013; 225 - A30
DOI: 10.1055/s-0033-1343647

Dysregulated expression of histone deacetylases in medulloblastoma – potential targets for selective inhibitor treatment

J Ecker 1, I Oehme 1, A Schomburg 2, R Mazitschek 3, A Korshunov 4, 5, M Kool 6, HE Deubzer 1, 7, A von Deimling 4, 5, AE Kulozik 7, S Pfister 6, 7, O Witt 1, 7, T Milde 1, 7
  • 1Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg
  • 2Proteros Biostructures GmbH, Martinsried
  • 3Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
  • 4Department of Neuropathology, University Hospital Heidelberg, Heidelberg
  • 5Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), Heidelberg
  • 6Division of Pediatric Neurooncology (B062), German Cancer Research Center (DKFZ), Heidelberg
  • 7Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany

Introduction: Medulloblastoma is the most common malignant brain tumor in childhood comprising 4 molecular subgroups. Survival rates remain particularly poor for patients with subgroup 3 tumors despite multimodal treatment. Therefore targeted therapies are urgently needed. Broad-spectrum inhibition of histone deacetylases (HDACs) has previously been shown to be a promising approach in cancer therapy. We here explore the possibility of isoenzyme-selective HDAC isozyme inhibition for treatment of MB.

Methods: Gene expression profiles and tissue microarrays of medulloblastomas were analyzed for differential expression of HDACs. Medulloblastoma cells lines were treated with pan-HDACi, inhibitors selective for class IIa HDACs and inhibitors with increased HDAC2 residence time, respectively. The phenotypes were characterized in cell culture.

Results: HDAC2 is overexpressed in MB compared to other brain tumors and normal brain tissue. In contrast to SHH group cell lines, group3 cMYC amplified cell lines demonstrate increased susceptibility towards pan-HDAC inhibition. Preliminary results indicate that inhibitors with increased HDAC2 residence time reduce metabolic activity.

Conclusion: HDAC inhibition presents a promising strategy for targeted therapies in patients with cMYC-amplified MB. In this context, HDACis with increased residence times for HDAC2 are attractive candidates for the development of novel medulloblastoma chemotherapies.