Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets

Nat Commun. 2017 Jul 12;8:16022. doi: 10.1038/ncomms16022.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Validation Study

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Female
  • Gene Expression / drug effects*
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism*
  • Mice
  • Mice, Nude
  • Pyrvinium Compounds / pharmacology
  • Pyrvinium Compounds / therapeutic use*
  • Systems Biology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Pyrvinium Compounds
  • pyrvinium