Abstract
The decreasing cost of genomic technologies has enabled the molecular characterization of large-scale clinical disease samples and of molecular changes upon drug treatment in various disease models. Exploring methods to relate diseases to potentially efficacious drugs through various molecular features is critically important in the discovery of new therapeutics. Here we show that the potency of a drug to reverse cancer-associated gene expression changes positively correlates with that drug’s efficacy in preclinical models of breast, liver and colon cancers. Using a systems-based approach, we predict four compounds showing high potency to reverse gene expression in liver cancer and validate that all four compounds are effective in five liver cancer cell lines. The in vivo efficacy of pyrvinium pamoate is further confirmed in a subcutaneous xenograft model. In conclusion, this systems-based approach may be complementary to the traditional target-based approach in connecting diseases to potentially efficacious drugs.
Highlights
The decreasing cost of genomic technologies has enabled the molecular characterization of large-scale clinical disease samples and of molecular changes upon drug treatment in various disease models
We collected 66,612 compound gene expression profiles consisting of 12,442 distinct compounds profiled in 71 cell lines, using data downloaded from Library of Integrated Networkbased Cellular Signatures (LINCS)
The recent mixed results from the SHIVA trial, which selected therapies primarily based on actionable mutations, indicate that innovative approaches are going to be needed to increase the success of personalized medicine[41]
Summary
The decreasing cost of genomic technologies has enabled the molecular characterization of large-scale clinical disease samples and of molecular changes upon drug treatment in various disease models. As a proof of principle, four compounds with significant RGES were newly identified as having efficacy against liver cancer, and each was successfully validated to exert antiproliferative effects against five liver cancer cell lines in vitro Of these four compounds, pyrvinium pamoate, which had the lowest IC50, was further validated to significantly reduce the growth of subcutaneous liver cancer cell xenografts in nude mice. Pyrvinium pamoate, which had the lowest IC50, was further validated to significantly reduce the growth of subcutaneous liver cancer cell xenografts in nude mice This large-scale computational analysis demonstrates the feasibility and potential of investigating the potency to reverse disease gene expression as a tool for hypothesis generation in the drug discovery process
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