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Nat Commun. 2019 Aug 2;10(1):3476. doi: 10.1038/s41467-019-10744-6.

A genome-wide positioning systems network algorithm for in silico drug repurposing.

Cheng F1,2,3, Lu W4, Liu C5, Fang J1, Hou Y1, Handy DE6, Wang R6, Zhao Y7,8, Yang Y7,8, Huang J7, Hill DE9,10, Vidal M9,10, Eng C1,2,3,11,12, Loscalzo J13.

Author information

1
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
2
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.
3
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
4
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
5
Alibaba Research Center for Complexity Sciences, Hangzhou Normal University, 311121, Hangzhou, China.
6
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
7
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China.
8
Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 200237, Shanghai, China.
9
Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
10
Department of Genetics, Blavatnik Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA.
11
Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
12
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
13
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. jloscalzo@rics.bwh.harvard.edu.

Abstract

Recent advances in DNA/RNA sequencing have made it possible to identify new targets rapidly and to repurpose approved drugs for treating heterogeneous diseases by the 'precise' targeting of individualized disease modules. In this study, we develop a Genome-wide Positioning Systems network (GPSnet) algorithm for drug repurposing by specifically targeting disease modules derived from individual patient's DNA and RNA sequencing profiles mapped to the human protein-protein interactome network. We investigate whole-exome sequencing and transcriptome profiles from ~5,000 patients across 15 cancer types from The Cancer Genome Atlas. We show that GPSnet-predicted disease modules can predict drug responses and prioritize new indications for 140 approved drugs. Importantly, we experimentally validate that an approved cardiac arrhythmia and heart failure drug, ouabain, shows potential antitumor activities in lung adenocarcinoma by uniquely targeting a HIF1α/LEO1-mediated cell metabolism pathway. In summary, GPSnet offers a network-based, in silico drug repurposing framework for more efficacious therapeutic selections.

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