Functional Module Connectivity Map (FMCM): A framework for searching repurposed drug compounds for systems treatment of cancer and an application to colorectal adenocarcinoma

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Title:	Functional Module Connectivity Map (FMCM): A framework for searching repurposed drug compounds for systems treatment of cancer and an application to colorectal adenocarcinoma
Authors:	馬念涵;Chung, Feng-Hsiang;Chiang, Yun-Ru;Tseng, Ai-Lun;Sung, Yung-Chuan;Lu, Jean;Huang, Min-Chang;Ma, Nianhan;Lee, Hoong-Chien
Contributors:	生醫理工學院生醫科學與工程學系
Keywords:	Acids;Adenocarcinoma;Adenocarcinoma - drug therapy;Algorithms;Alzheimer's disease;Anopheles;Anticancer properties;Bioinformatics;Biology;Biomarkers;Brain cancer;Cancer;Cancer prevention;Carcinogens;Cell cycle;Colorectal cancer;Colorectal Neoplasms - drug therapy;Development and progression;DNA microarrays;Drug development;Drug discovery;Drug Repositioning - methods;Drugs;Epistasis, Genetic - genetics;Ethacrynic Acid;FDA approval;Gene expression;Gene Regulatory Networks - genetics;Genes;Genomics;Geospatial data;Ginkgo;Ginkgo biloba;Ginkgolides;Health services;Humans;Imipenem;Immune system;Immunosuppressive agents;Indoles;Lactones;Leukemia;Medical screening;Medical treatment;Medicine;Microarray Analysis;Modules;Ovarian cancer;Phenoxybenzamine;Physics;R&D;Reproducibility;Research & development;Sensitivity and Specificity;Side effects;Studies;Suppressors;Thymine - analogs & derivatives
Date:	2014-01-27
Issue Date:	2026-04-23 11:16:09 (UTC+8)
Publisher:	Public Library of Science;United States: Public Library of Science
Abstract:	摘要： Drug repurposing has become an increasingly attractive approach to drug development owing to the ever-growing cost of new drug discovery and frequent withdrawal of successful drugs caused by side effect issues. Here, we devised Functional Module Connectivity Map (FMCM) for the discovery of repurposed drug compounds for systems treatment of complex diseases, and applied it to colorectal adenocarcinoma. FMCM used multiple functional gene modules to query the Connectivity Map (CMap). The functional modules were built around hub genes identified, through a gene selection by trend-of-disease-progression (GSToP) procedure, from condition-specific gene-gene interaction networks constructed from sets of cohort gene expression microarrays. The candidate drug compounds were restricted to drugs exhibiting predicted minimal intracellular harmful side effects. We tested FMCM against the common practice of selecting drugs using a genomic signature represented by a single set of individual genes to query CMap (IGCM), and found FMCM to have higher robustness, accuracy, specificity, and reproducibility in identifying known anti-cancer agents. Among the 46 drug candidates selected by FMCM for colorectal adenocarcinoma treatment, 65% had literature support for association with anti-cancer activities, and 60% of the drugs predicted to have harmful effects on cancer had been reported to be associated with carcinogens/immune suppressors. Compounds were formed from the selected drug candidates where in each compound the component drugs collectively were beneficial to all the functional modules while no single component drug was harmful to any of the modules. In cell viability tests, we identified four candidate drugs: GW-8510, etacrynic acid, ginkgolide A, and 6-azathymine, as having high inhibitory activities against cancer cells. Through microarray experiments we confirmed the novel functional links predicted for three candidate drugs: phenoxybenzamine (broad effects), GW-8510 (cell cycle), and imipenem (immune system). We believe FMCM can be usefully applied to repurposed drug discovery for systems treatment of other types of cancer and other complex diseases. 其他題名： PLoS One 出版者： United States: Public Library of Science 出版日期： 2014-01-27 出處： PloS one, 2014-01, Vol.9 (1), p.e86299 資源來源： Agricultural & Environmental Science Collection 版權： COPYRIGHT 2014 Public Library of Science 版權： 2014 Chung et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 版權： 2014 Chung et al 2014 Chung et al 識別號： ISSN: 1932-6203 識別號： EISSN: 1932-6203 識別號： DOI: 10.1371/journal.pone.0086299 識別號： PMID: 24475102
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