Abstract
Neuroblastoma is a pediatric malignancy of the sympathetic nervous system with diverse clinical behaviors. Genomic amplification of MYCN oncogene has been shown to drive neuroblastoma pathogenesis and correlate with aggressive disease, but the survival rates for those high-risk tumors carrying no MYCN amplification remain equally dismal. The paucity of mutations and molecular heterogeneity has hindered the development of targeted therapies for most advanced neuroblastomas. We use an alternative method to identify potential drugs that target nononcogene dependencies in high-risk neuroblastoma. By using a gene expression-based integrative approach, we identified prognostic signatures and potentially effective single agents and drug combinations for high-risk neuroblastoma. Among these predictions, we validated in vitro efficacies of some investigational and marketed drugs, of which niclosamide, an anthelmintic drug approved by the FDA, was further investigated in vivo. We also quantified the proteomic changes during niclosamide treatment to pinpoint nucleoside diphosphate kinase 3 (NME3) downregulation as a potential mechanism for its antitumor activity. Our results establish a gene expression-based strategy to interrogate cancer biology and inform drug discovery and repositioning for high-risk neuroblastoma.
Highlights
Neuroblastoma is a childhood cancer of the peripheral sympathetic nervous system
We quantified the proteomic changes during niclosamide treatment to pinpoint nucleoside diphosphate kinase 3 (NME3) downregulation as a potential mechanism for its antitumor activity
To investigate which genes are associated with a poor clinical course in high-risk neuroblastoma, we performed an integrated transcriptomic analysis for 4 comparative categories based on patient risk groups: (i) "MNA," representing HR-MNA (i.e., MYCN-amplified, stage 4, >18 months; n 1⁄4 67) versus HRnonMNA; (ii) "HR-MNA," representing HR-MNA versus LR (i.e., MYCN-nonamplified, stage 1 or 2,
Summary
Neuroblastoma is a childhood cancer of the peripheral sympathetic nervous system. Several clinical and biological variables, including age at initial diagnosis, stage of disease, and amplification of the MYCN oncogene, are used to stratify patients into neuroblastoma risk groups [1]. The survival rates from neuroblastoma have been improved substantially in recent decades, children bearing high-risk tumors, regardless of the presence of amplified MYCN, still have poor outcomes [2, 3]. Owing to the lack of recurrent mutations and heterogeneity of mutational spectrum in neuroblastoma [4], current treatment approach for high-risk diseases is largely based on intensive combination chemotherapy, radiotherapy, stem cell transplant, immunotherapy, and differentiation therapy [1,2,3]. MYCN has a well-established role in neuroblastoma development, pharmaceutical targeting of this oncogenic transcription factor remains
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