No citation available. Published: 2008.07.14
Cynthia K. Hahn, Kenneth N. Ross, Ian Warrington, Ralph Mazitschek, Cindy M. Kanegai, Renee D. Wright, Andrew L. Kung, Todd R. Golub, and Kimberly Stegmaier
The discovery of new small molecules and their testing in rational combination poses an ongoing problem for rare diseases, particularly 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 deactylase (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 bioactive small molecule library for compounds inducing neuroblastoma maturation. In order 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 compound 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.
|Plain text file describing available supplementary information||README.NB|
|Neuroblastoma microarray data||NeuroCellLines_060628_ams.res|
|CEL files for neuroblastoma data||Neuroblastoma_CelFiles_070924.zip|