Prediction of Novel Drugs for Hepatocellular Carcinoma Based on Multi-Source Random Walk.

Abstract

Computational approaches for predicting drug-disease associations by integrating gene expression and biological network provide great insights to the complex relationships among drugs, targets, disease genes, and diseases at a system level. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high rate of morbidity and mortality. We provide an integrative framework to predict novel d rugs for HCC based on multi-source random walk (PD-MRW). Firstly, based on gene expression and protein interaction network, we construct a gene-gene weighted i nteraction network (GWIN). Then, based on multi-source random walk in GWIN, we build a drug-drug similarity network. Finally, based on the known drugs for HCC, we score all drugs in the drug-drug similarity network. The robustness of our predictions, their overlap with those reported in Comparative Toxicogenomics Database (CTD) and literatures, and their enriched KEGG pathway demonstrate our approach can effectively identify new drug indications. Specifically, regorafenib (Rank = 9 in top-20 list) is proven to be effective in Phase I and II clinical trials of HCC, and the Phase III trial is ongoing. And, it has 11 overlapping pathways with HCC with lower p-values. Focusing on a particular disease, we believe our approach is more accurate and possesses better scalability.