Klin Padiatr 2013; 225 - A28
DOI: 10.1055/s-0033-1343645

Selective inhibition of Histone Deacetylase 8 as a novel therapeutic strategy for the treatment of high-risk neuroblastoma

I Wiegand 1, T Milde 1, 2, HE Deubzer 1, 2, S Balasubramanian 3, O Witt 1, 2, I Oehme 1
  • 1CCU Pediatric Oncology, DKFZ, Heidelberg, Germany
  • 2Dpt of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Germany
  • 3Pharmacyclics, Inc., Sunnyvale, California, USA

Aims: Expression studies of primary neuroblastoma samples from the German Neuroblastoma Trial revealed histone deacetylase 8 (HDAC8) to be upregulated in stage 4 patients, associated with a significantly worse prognosis. Here, we investigated the anti-neuroblastoma activity of HDAC8-selective inhibitors (HDAC8i) in vitro and in vivo.

Methods: Treatment of neuroblastoma cell lines and mouse xenografts were used to evaluate the therapeutic potential of HDAC8i. Selectivity for HDAC8 was verified by absence of off-target acetylation in Western Blot at the relevant in vitro and in vivo administration of HDAC8i. In vivo maximal tolerable doses (MTDs) were determined by toxicity studies.

Results: HDAC8i treatment in vitro induced the expression of TrkA, neurofilament and CDK-inhibitor p21Waf-1/Cip-1 and clearly decreased cell population growth. Long term treatment resulted in tumor cell death. Treatment of BE(2)-C xenografted animals with HDAC8i significantly retarded tumor growth compared to control groups (p < 0.001).

Conclusion: Our data show that the selective inhibition of HDAC8 with small molecule compounds provides a novel therapeutic strategy to be effective on NB in vivo.