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Nat Commun. 2020 Jan 3;11(1):71. doi: 10.1038/s41467-019-13817-8.

Integrative discovery of treatments for high-risk neuroblastoma.

Author information

1
Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85, Uppsala, Sweden.
2
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, SE-17176, Stockholm, Sweden.
3
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
4
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, SE-223 81, Lund, Sweden.
5
Department of Medicine, Integrated Cardio-Metabolic Centre Single Cell Facility, Karolinska Institutet, SE-17177, Stockholm, Sweden.
6
Mathematical Sciences, Chalmers University of Technology, Gothenburg, SE-41296, Sweden.
7
Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85, Uppsala, Sweden. sven.nelander@igp.uu.se.

Abstract

Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

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