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Therapeutic Targeting of Non-Oncogene Dependencies In Published OnlineFirst April 5, 2019; DOI: 10.1158/1078-0432.CCR-18-4117 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Therapeutic Targeting of Non-oncogene Dependencies in High-risk Neuroblastoma Chen-Tsung Huang1, Chiao-Hui Hsieh2,Wen-Chi Lee2,Yen-Lin Liu3,Tsai-Shan Yang4, Wen-Ming Hsu4, Yen-Jen Oyang1, Hsuan-Cheng Huang5, and Hsueh-Fen Juan1,2,6 Abstract Purpose: Neuroblastoma is a pediatric malignancy of the potentially effective single agents and drug combinations for sympathetic nervous system with diverse clinical behaviors. high-risk neuroblastoma. Genomic amplification of MYCN oncogene has been shown to Results: Among these predictions, we validated in vitro drive neuroblastoma pathogenesis and correlate with aggres- efficacies of some investigational and marketed drugs, sive disease, but the survival rates for those high-risk tumors of which niclosamide, an anthelmintic drug approved carrying no MYCN amplification remain equally dismal. The by the FDA, was further investigated in vivo.Wealso paucity of mutations and molecular heterogeneity has hin- quantified the proteomic changes during niclosamide dered the development of targeted therapies for most treatment to pinpoint nucleoside diphosphate kinase 3 advanced neuroblastomas. We use an alternative method to (NME3) downregulation as a potential mechanism for its identify potential drugs that target nononcogene dependen- antitumor activity. cies in high-risk neuroblastoma. Conclusions: Our results establish a gene expression–based Experimental Design: By using a gene expression–based strategy to interrogate cancer biology and inform drug discov- integrative approach, we identified prognostic signatures and ery and repositioning for high-risk neuroblastoma. Introduction challenging (5). However, alternative strategies that target the MYCN-mediated transcriptional program (6, 7), the regulators of Neuroblastoma is a childhood cancer of the peripheral sym- MYCN protein stability (8), or the downstream effects of MYCN pathetic nervous system. Several clinical and biological variables, amplification (9, 10) have shown clinical promise. In addition to including age at initial diagnosis, stage of disease, and amplifi- MYCN (amplified in 20% of neuroblastomas), several genomic cation of the MYCN oncogene, are used to stratify patients into alterations, for example, ALK-activating mutation (10%; ref. 11), neuroblastoma risk groups (1). Although the survival rates from ATRX-inactivating mutation or deletion (10%; ref. 12), and TERT neuroblastoma have been improved substantially in recent dec- promoter rearrangement (25%; ref. 13, 14), have been described in ades, children bearing high-risk tumors, regardless of the presence aggressive neuroblastoma, among which ALK is currently the only of amplified MYCN, still have poor outcomes (2, 3). Owing to the tractable oncogene for targeted therapy (15). Relapsed neuroblas- lack of recurrent mutations and heterogeneity of mutational toma, by contrast, was found to harbor more druggable mutations, spectrum in neuroblastoma (4), current treatment approach for most of which converged on the activation of the RAS–MAPK high-risk diseases is largely based on intensive combination pathway (16, 17). Despite tremendous advances in understanding chemotherapy, radiotherapy, stem cell transplant, immunother- the cancer genome, new therapeutic approaches to effectively treat apy, and differentiation therapy (1–3). Although MYCN has a this heterogeneous, aggressive disease are in high demand. well-established role in neuroblastoma development, pharma- Paralleling the dedicated efforts of researchers to identify driver ceutical targeting of this oncogenic transcription factor remains mutations that confer selective growth advantage, the importance of acquired dependencies of cancer cells on the activities of certain 1Graduate Institute of Biomedical Electronics and Bioinformatics, National nonmutated genes has been increasingly recognized (18, 19). This Taiwan University, Taipei, Taiwan. 2Institute of Molecular and Cellular Biology, cancer's addiction to both oncogenes and nononcogenes is National Taiwan University, Taipei, Taiwan. 3Department of Pediatrics, Taipei required to sustain the hallmark capabilities and tumorigenic 4 Medical University Hospital, Taipei, Taiwan. Department of Surgery, National state (20). In particular, leveraging the nononcogene addiction for 5 Taiwan University Hospital, Taipei, Taiwan. Institute of Biomedical Informatics, therapeutic intervention has thus far proved beneficial in cancer National Yang-Ming University, Taipei, Taiwan. 6Department of Life Science, National Taiwan University, Taipei, Taiwan. treatment (18, 19, 21, 22). Here, we used a gene expression–based approach to identify the Note: Supplementary data for this article are available at Clinical Cancer cancer-related transcriptional signatures and inform potential Research Online (http://clincancerres.aacrjournals.org/). therapeutics for treating high-risk neuroblastoma. This was Corresponding Authors: Hsueh-Fen Juan, National Taiwan University, 1, Sec. 4, achieved by correlating gene expression signatures between Roosevelt Rd., Taipei, 106, Taiwan. Phone: 8862-3366-4536; Fax: 8862-2367- high-risk neuroblastoma and small-molecule perturbations 3374; E-mail: [email protected]; and Hsuan-Cheng Huang, fi [email protected] (23). In this study, we rst performed integrative analysis of the transcriptomes of primary neuroblastoma tumors obtained from Clin Cancer Res 2019;25:4063–78 multiple Gene Expression Omnibus (GEO) datasets. This process doi: 10.1158/1078-0432.CCR-18-4117 led to the identification of gene signatures that were prognostic for Ó2019 American Association for Cancer Research. patient survival in an independent cohort, especially for children www.aacrjournals.org 4063 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst April 5, 2019; DOI: 10.1158/1078-0432.CCR-18-4117 Huang et al. combined gene expression matrix (11,939 by 1,065) was taken by Translational Relevance the model as input with hyperparameters set as follows: NUM High-risk neuroblastoma has few recurrent somatic muta- (number of topics) ¼ 2; GAMMAPARAM (scale b for the gamma tions and is still associated with poor outcomes despite inten- distribution) ¼ 4; BETA (beta for the Dirichlet distribution) ¼ 10; sive treatment. The lack of druggable oncogenes continues to and number of interactions ¼ 100. After this cross-platform restrict the development of targeted therapies for high-risk normalization, the resultant matrix was then quantile-normalized neuroblastoma. Here, we use an alternative, gene expression– again to ensure that the gene expression distributions of all based approach to identify potential drugs that target the samples were identical. nononcogene dependencies in high-risk neuroblastoma. To assess the quality of data after PLIDA transformation, we Among the top predicted drugs by this approach, our work computed the following measures: (i) sample-wise principal then investigates an FDA-approved anthelmintic drug, niclo- component analysis (Supplementary Fig. S1A); (ii) a Spearman samide, as an effective treatment for neuroblastoma through correlation coefficient (SCC) between a given gene vector the regulation of nucleotide biosynthesis and nucleoside beforePLIDAandthesamegenevectorafterPLIDAforeach diphosphate kinase 3 (NME3) protein. dataset category (within individual or across all GEO datasets; Supplementary Fig. S1B); (iii) SCCs between a gene and any other genes before and after PLIDA for each dataset category (Supplementary Fig. S1C); and (iv) gene expression values before and after PLIDA for each dataset category, for which a with advanced-stage, MYCN-nonamplified tumors. We used the 1-way ANOVA or KruskalÀWallis test was applied to determine high-risk neuroblastoma gene signature to predict effective drugs whether the mean or median expression values of a gene were or their combinations and validated some of these predictions in equivalent across all dataset categories, respectively (Supple- vitro. The in vivo efficacy of niclosamide, an anthelmintic drug mentary Fig. S1D). approved by the FDA to treat tapeworm infections, was confirmed in neuroblastoma xenograft models. By further investigating the Clustering patients with high-risk neuroblastoma without neuroblastoma proteome following niclosamide treatment, we MYCN amplification identified downregulation of nucleoside diphosphate kinase 3 We used a gene expression intensity-based similarity met- (NME3), an enzyme involved in the nucleotide biosynthesis, as a ric (26) to compute pairwise similarities among the patients with potential molecular mechanism of the drug's effects. Given the high-risk, MYCN-nonamplified neuroblastoma (HR-nonMNA) rarity of actionable mutations, our data present an alternative for clustering analysis (Supplementary Fig. S2A). This intensity- solution to target-based drug screening in this deadly pediatric based similarity metric has proved superior to other commonly neoplasm. used metrics derived from the Pearson correlation or Euclidean distance in a clustering task of drugs with diverse mechanisms of Materials and Methods action (MoA). In brief, for each HR-nonMNA sample (MYCN-nonamplified, Data source, cross-platform normalization, and quality stage 4, >18 months; n ¼ 156), we subtracted the median measures expression vector of all low-risk (LR) samples (MYCN- Six gene expression
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