文献类型：期刊文献

英文题名：A genome-wide positioning systems network algorithm for in silico drug repurposing

作者：Cheng, Feixiong[1,2,3];Lu, Weiqiang[4,5];Liu, Chuang[6];Fang, Jiansong[1];Hou, Yuan[1];Handy, Diane E.[7];Wang, Ruisheng[7];Zhao, Yuzheng[8,9];Yang, Yi[8,9];Huang, Jin[8];Hill, David E.[10,11];Vidal, Marc[10,11];Eng, Charis[1,2,3,12,13];Loscalzo, Joseph[7]

机构：[1]Cleveland Clin, Lerner Res Inst, Genom Med Inst, Cleveland, OH 44195 USA;[2]Case Western Reserve Univ, Dept Mol Med, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA;[3]Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA;[4]East China Normal Univ, Shanghai Key Lab Regulatory Biol, Inst Biomed Sci, Shanghai 200241, Peoples R China;[5]East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China;[6]Hangzhou Normal Univ, Alibaba Res Ctr Complex Sci, Hangzhou 311121, Zhejiang, Peoples R China;[7]Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA;[8]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[9]Shanghai Collaborat Innovat Ctr Biomfg Technol, Synthet Biol & Biotechnol Lab, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[10]Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA;[11]Harvard Med Sch, Blavatnik Inst, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA;[12]Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44195 USA;[13]Case Western Reserve Univ, Dept Genet & Genome Sci, Sch Med, Cleveland, OH 44106 USA

年份：2019

卷号：10

外文期刊名：NATURE COMMUNICATIONS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000478576500008)】；

基金：We thank Stephanie Tribuna for expert technical assistance. We thank Albert-Laszlo Barabasi, Marc Santolini, Tong Hao, Yadi Zhou, and Michael Calderwood for useful discussion on the manuscript. This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) under Award Number K99HL138272 and R00HL138272 to F.C., and NHGRI grants HG001715 to D.E.H. and M.V. and HG004233 to M.V., and NIH grants HG007690, HL119145, and GM107618, and American Heart Association grant #D700382 to J.L.

语种：英文

摘要：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 similar to 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 HIF1 alpha/LEO1-mediated cell metabolism pathway. In summary, GPSnet offers a network-based, in silico drug repurposing framework for more efficacious therapeutic selections.