Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiation

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2008; 105(28):9751-6. DOI: 10.1073/pnas.0710413105
Source: PubMed


The discovery of new small molecules and their testing in rational combination poses an ongoing problem for rare diseases, in particular, for pediatric cancers such as neuroblastoma. Despite maximal cytotoxic therapy with double autologous stem cell transplantation, outcome remains poor for children with high-stage disease. Because differentiation is aberrant in this malignancy, compounds that modulate transcription, such as histone deacetylase (HDAC) inhibitors, are of particular interest. However, as single agents, HDAC inhibitors have had limited efficacy. In the present study, we use an HDAC inhibitor as an enhancer to screen a small-molecule library for compounds inducing neuroblastoma maturation. To quantify differentiation, we use an enabling gene expression-based screening strategy. The top hit identified in the screen was all-trans-retinoic acid. Secondary assays confirmed greater neuroblastoma differentiation with the combination of an HDAC inhibitor and a retinoid versus either alone. Furthermore, effects of combination therapy were synergistic with respect to inhibition of cellular viability and induction of apoptosis. In a xenograft model of neuroblastoma, animals treated with combination therapy had the longest survival. This work suggests that testing of an HDAC inhibitor and retinoid in combination is warranted for children with neuroblastoma and demonstrates the success of a signature-based screening approach to prioritize compound combinations for testing in rare diseases.

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    • "Inducing NB cells to differentiate is an important therapeutic approach that seems to be particularly promising for NBs [44]. Administration of VPA to NB cells such as Neuro2a, SHSY-5Y and BE (2)-C in vitro leads to proliferative arrest and neuronal differentiation [20], [45], [46]. Very recently, a whole-genome sequence analysis of 87 neuroblastomas reveals novel molecular defects in neurite genesis genes including a series of regulators of the Rac/Rho pathway, which frequently occur in high-risk tumours [47]. "
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