Functional Module Connectivity Map (FMCM): a framework for searching repurposed drug compounds for systems treatment of cancer and an application to colorectal adenocarcinoma.
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.
Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, Taiwan ; Center for Dynamical Biomarkers and Translational Medicine, National Central University, Zhongli, Taiwan.
Feng-Hsiang
FH
Chung
Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, Taiwan.
Yun-Ru
YR
Chiang
Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, Taiwan.
Ai-Lun
AL
Tseng
Division of Hematology and Oncology, Cathay General Hospital, Taipei, Taiwan.
Yung-Chuan
YC
Sung
Institute of Biomedical Science, Academia Sinica, Nangang, Taipei, Taiwan.
Jean
J
Lu
Department of Physics, Chung Yuan Christian University, Zhongli, Taiwan.
Min-Chang
MC
Huang
Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, Taiwan.
Nianhan
N
Ma
Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, Taiwan ; Center for Dynamical Biomarkers and Translational Medicine, National Central University, Zhongli, Taiwan ; Department of Physics, Chung Yuan Christian University, Zhongli, Taiwan ; Cathay Medical Research Institute, Cathay General Hospital, Taipei, Taiwan ; Physics Division, National Center for Theoretical Sciences, Hsinchu, Taiwan.
Hoong-Chien
HC
Lee
D000230:Adenocarcinoma / Q000188:drug therapy*; D000465:Algorithms; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D058492:Drug Repositioning / Q000379:methods*; D004843:Epistasis, Genetic / Q000235:genetics*; D004976:Ethacrynic Acid; D053263:Gene Regulatory Networks / Q000235:genetics*; D046934:Ginkgolides; D006801:Humans; D015378:Imipenem; D007211:Indoles; D007783:Lactones; D046228:Microarray Analysis; D010643:Phenoxybenzamine; D012680:Sensitivity and Specificity; D013941:Thymine / Q000031:analogs & derivatives
C500810:GW8510; D046934:Ginkgolides; D007211:Indoles; D007783:Lactones; D010643:Phenoxybenzamine; D015378:Imipenem; D004976:Ethacrynic Acid; D013941:Thymine; C477042:ginkgolide A; C039857:6-azathymine