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.