Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma

Chen-Tsung Huang, Chiao-Hui Hsieh, Wen-Chi Lee, Yen-Lin Liu, Tsai-Shan Yang, Wen-Ming Hsu, Yen-Jen Oyang, Hsuan-Cheng Huang, Hsueh-Fen Juan

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Abstract

Purpose: 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.Experimental Design: By using a gene expression-based integrative approach, we identified prognostic signatures and potentially effective single agents and drug combinations for high-risk neuroblastoma.Results: 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.Conclusions: Our results establish a gene expression-based strategy to interrogate cancer biology and inform drug discovery and repositioning for high-risk neuroblastoma.

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Neuroblastoma
Niclosamide
NM23 Nucleoside Diphosphate Kinases
Therapeutics
Drug Repositioning
Investigational Drugs
Gene Expression
Neoplasms
Anthelmintics
Sympathetic Nervous System
Drug Combinations
Drug Discovery
Oncogenes
Pharmaceutical Preparations
Proteomics
Research Design
Down-Regulation
Pediatrics
Mutation

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Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma. / Huang, Chen-Tsung; Hsieh, Chiao-Hui; Lee, Wen-Chi; Liu, Yen-Lin; Yang, Tsai-Shan; Hsu, Wen-Ming; Oyang, Yen-Jen; Huang, Hsuan-Cheng; Juan, Hsueh-Fen.

In: Clinical cancer research : an official journal of the American Association for Cancer Research, 05.04.2019.

Research output: Contribution to journalArticle

Huang, Chen-Tsung ; Hsieh, Chiao-Hui ; Lee, Wen-Chi ; Liu, Yen-Lin ; Yang, Tsai-Shan ; Hsu, Wen-Ming ; Oyang, Yen-Jen ; Huang, Hsuan-Cheng ; Juan, Hsueh-Fen. / Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma. In: Clinical cancer research : an official journal of the American Association for Cancer Research. 2019.
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title = "Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma",
abstract = "Purpose: 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.Experimental Design: By using a gene expression-based integrative approach, we identified prognostic signatures and potentially effective single agents and drug combinations for high-risk neuroblastoma.Results: 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.Conclusions: Our results establish a gene expression-based strategy to interrogate cancer biology and inform drug discovery and repositioning for high-risk neuroblastoma.",
author = "Chen-Tsung Huang and Chiao-Hui Hsieh and Wen-Chi Lee and Yen-Lin Liu and Tsai-Shan Yang and Wen-Ming Hsu and Yen-Jen Oyang and Hsuan-Cheng Huang and Hsueh-Fen Juan",
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AU - Huang, Chen-Tsung

AU - Hsieh, Chiao-Hui

AU - Lee, Wen-Chi

AU - Liu, Yen-Lin

AU - Yang, Tsai-Shan

AU - Hsu, Wen-Ming

AU - Oyang, Yen-Jen

AU - Huang, Hsuan-Cheng

AU - Juan, Hsueh-Fen

N1 - ©2019 American Association for Cancer Research.

PY - 2019/4/5

Y1 - 2019/4/5

N2 - Purpose: 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.Experimental Design: By using a gene expression-based integrative approach, we identified prognostic signatures and potentially effective single agents and drug combinations for high-risk neuroblastoma.Results: 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.Conclusions: Our results establish a gene expression-based strategy to interrogate cancer biology and inform drug discovery and repositioning for high-risk neuroblastoma.

AB - Purpose: 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.Experimental Design: By using a gene expression-based integrative approach, we identified prognostic signatures and potentially effective single agents and drug combinations for high-risk neuroblastoma.Results: 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.Conclusions: Our results establish a gene expression-based strategy to interrogate cancer biology and inform drug discovery and repositioning for high-risk neuroblastoma.

U2 - 10.1158/1078-0432.CCR-18-4117

DO - 10.1158/1078-0432.CCR-18-4117

M3 - Article

C2 - 30952635

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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