ANTENNA, a Multi-Rank, Multi-Layered Recommender System for Inferring Reliable Drug-Gene-Disease Associations: Repurposing Diazoxide as a Targeted Anti-Cancer Therapy [article]

Annie Wang, Hansaim Lim, Shu-Yuan Cheng, Lei Xie
2017 bioRxiv   pre-print
Existing drug discovery process follows a reductionist model of 'one-drug-one-gene-one-disease,' which is not adequate to tackle complex diseases that involve multiple malfunctioned genes. The availability of big omics data offers new opportunities to transform the drug discovery process into a new paradigm of systems pharmacology that focuses on designing drugs to target molecular interaction networks instead of a single gene. Here, we develop a reliable multi-rank, multi-layered recommender
more » ... stem ANTENNA to mine large-scale chemical genomics and disease association data for the prediction of novel drug-gene-disease associations. ANTENNA integrates a novel tri-factorization based dual-regularized weighted and imputed One Class Collaborative Filtering (OCCF) algorithm tREMAP with a statistical framework that is based on Random Walk with Restart and can assess the reliability of a specific prediction. In the benchmark study, tREMAP clearly outperforms the single rank OCCF. We apply ANTENNA to a real-world problem: repurposing old drugs for new clinical indications that have yet had an effective treatment. We discover that FDA-approved drug diazoxide can inhibit multiple kinase genes whose malfunction is responsible for many diseases including cancer, and kill triple negative breast cancer (TNBC) cells effectively at a low concentration (IC50 = 0.87 μM). The TNBC is a deadly disease that currently does not have effective targeted therapies. Our finding demonstrates the power of big data analytics in drug discovery, and has a great potential toward developing a targeted therapy for the effective treatment of TNBC.
doi:10.1101/192385 fatcat:3fmr4f2p3vcplfv6qie46fsz6m