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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: 9.81). 08/2008; 105(28):9751-6. DOI: 10.1073/pnas.0710413105
Source: PubMed

ABSTRACT 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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Available from: Renee D. Wright-Michaud, Jul 29, 2015
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    • "Efforts to establish a consensus on what constitutes the RA-induced differentiation has recently led to recognition of a set of 10 genes as a potential signature and a more general yet reliable predictor of differentiation in NBs (Hahn et al., 2008). Moreover, a gene-expression high-throughput screening of small molecule libraries revealed a synergistic action of RA (all trans RA and 13-cis RA) and histone deacetylase inhibitors towards induction of NB differentiation, both in culture and in vivo (Hahn et al., 2008). "
    Neuroblastoma - Present and Future, 02/2012; , ISBN: 978-953-307-016-2
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    • "We studied the effect of VPA on MAO A and its molecular mechanisms in a human neuronal BE(2)C cell line, which expresses MAO A (Chen et al., 2005) and well responds to VPA in terms of the activation of known VPA downstream target genes (Hahn et al., 2008). "
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    • "In another example, neuroblastoma cells differentiate in response to RA (Sidell et al., 1983; Turano et al., 2006; Muley et al., 2008); and, after completion of chemoradiotherapy, differentiation therapy with RA significantly improves survival in high risk neuroblastoma patients (Reynolds et al., 2003). More recently, differentiation therapy with RA plus histone deacetylase inhibitors, drugs which modify the epigenetic state of cells, was shown to be a powerful combination for neuroblastoma treatment (Hahn et al., 2008). An interaction of the zinc-finger protein Zfp423 (Gene ID: 94187) with the RXRα/RARα complex at RAREs was recently shown to be required for RA to induce cell proliferation arrest and differentiation of neuroblastoma cells (Huang et al., 2009). "
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