Klin Padiatr 2011; 223 - A7
DOI: 10.1055/s-0030-1270300

Targeting HDACs in Pediatric Oncology

O Witt 1, H Deubzer 1, I Oehme 1, T Milde 1
  • 1CCU Pediatric Oncology, German Cancer Research Center, Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Germany.

The analysis of the human acetylome has revealed that about 2000 proteins are regulated through reversible acetylation in a given cell, suggesting that this post-translational modification system may be equally important as protein phosphorylation. The acetylome is at least partially controlled by the human histone deacetylase (HDAC) family consisting of 11 members. It is now becoming clear that this family of enzymes regulate the acetylation status of numerous cellular proteins beyond histones and the term protein/lysine deacetylases has recently been introduced. The contribution of individual HDACs to cancer biology in general and in pediatric malignancies in particular is largely unknown, although it has been shown in numerous tumor models that their unselective inhibition results in anti-cancer effects. We have discovered that high expression of distinct and so far poorly studied HDAC family members is associated with unfavorable clinical outcome in neuroblastoma, medulloblastoma, and ependymoma tumors. Functionally, these HDACs suppress differentiation and apoptosis, and promote clonogenic survival and proliferation in cultured cells. Of note, cancer stem cells isolated from a patient with chemotherapy-resistant anaplastic ependymoma showed sensitivity to HDACs targeting. Selective targeting of individual HDACs through novel small molecule compounds recapitulate the anti-cancer phenotype observed with siRNA mediated knockdown. Translation of these findings in an early phase I/II clinical trial in pediatric oncology is currently underway.