title: Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiation.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Cynthia K
authors.initials: CK
authors.lastname: Hahn
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.forename: Ian M
authors.initials: IM
authors.lastname: Warrington
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Kanegai
authors.forename: Renee D
authors.initials: RD
authors.lastname: Wright
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D012176:Retinoids / Q000494:pharmacology* / Q000627:therapeutic use; D054852:Small Molecule Libraries; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012176:Retinoids; D054852:Small Molecule Libraries