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Updated: Jul 3, 2026
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for
Cynthia K Hahn1, Kenneth N Ross, Ian M Warrington
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
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.
Insights
Combining histone deacetylase (HDAC) inhibitors with retinoids effectively promotes neuroblastoma maturation and survival in preclinical models. This combination therapy shows synergistic effects, offering new hope for treating high-stage neuroblastoma in children.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pediatric cancers like neuroblastoma have poor outcomes despite intensive therapy.
- Histone deacetylase (HDAC) inhibitors show limited efficacy as single agents in neuroblastoma.
- Aberrant differentiation in neuroblastoma necessitates novel therapeutic strategies.
Purpose of the Study:
- To identify compounds that enhance neuroblastoma differentiation when combined with an HDAC inhibitor.
- To evaluate the efficacy of combination therapy in preclinical models of neuroblastoma.
- To demonstrate the utility of a gene expression-based screening approach for rare disease drug discovery.
Main Methods:
- A small-molecule library was screened using an HDAC inhibitor as an enhancer to identify compounds inducing neuroblastoma maturation.
- A gene expression-based strategy was employed to quantify cellular differentiation.
- Combination therapy effects were assessed in vitro for cellular viability and apoptosis, and in vivo using a neuroblastoma xenograft model.
Main Results:
- All-trans-retinoic acid was identified as the top hit, enhancing neuroblastoma differentiation with an HDAC inhibitor.
- Combination therapy with an HDAC inhibitor and a retinoid demonstrated synergistic effects on inhibiting cellular viability and inducing apoptosis.
- Combination therapy significantly prolonged survival in a neuroblastoma xenograft model.
Conclusions:
- Combination therapy of HDAC inhibitors and retinoids warrants clinical investigation for neuroblastoma treatment.
- A signature-based screening approach is effective for prioritizing compound combinations for rare diseases.
- This study highlights a promising therapeutic strategy for high-stage pediatric neuroblastoma.
