Abstract
Purpose: Most prostate cancers (PCs) initially respond to androgen deprivation therapy (ADT), but eventually many PC patients develop castration resistant PC (CRPC). Currently, available drugs that have been approved for the treatment of CRPC patients are limited. Computational drug repositioning methods using public databases represent a promising and efficient tool for discovering new uses for existing drugs. The purpose of the present study is to predict drug candidates that can treat CRPC using a computational method that integrates publicly available gene expression data of tumors from CRPC patients, drug-induced gene expression data and drug response activity data.Methods: Gene expression data from tumoral and normal or benign prostate tissue samples in CRPC patients were downloaded from the Gene Expression Omnibus (GEO) and differentially expressed genes (DEGs) in CRPC were determined with a meta-signature analysis by a metaDE R package. Additionally, drug activity data were downloaded from the ChEMBL database. Furthermore, the drug-induced gene expression data were downloaded from the LINCS database. The reversal relationship between the CRPC and drug gene expression signatures as the Reverse Gene Expression Scores (RGES) were computed. Drug candidates to treat CRPC were predicted using summarized scores (sRGES). Additionally, synergic effects of drug combinations were predicted with a Target Inhibition interaction using the Minimization and Maximization Averaging (TIMMA) algorithm.Results: The drug candidates of sorafenib, olaparib, elesclomol, tanespimycin, and ponatinib were predicted to be active for the treatment of CRPC. Meanwhile, CRPC-related genes, in this case MYL9, E2F2, APOE, and ZFP36, were identified as having gene expression data that can be reversed by these drugs. Additionally, lenalidomide in combination with pazopanib was predicted to be most potent for CRPC.Conclusion: These findings support the use of a computational reversal gene expression approach to identify new drug and drug combination candidates that can be used to treat CRPC.
Highlights
Drug repurposing or repositioning is a strategy for identifying new indications for approved or investigational drugs that are outside the scope of the original medical indication [1]
Drug development strategies based on gene expression levels are advantageous in that they do not require a large amount of a priori knowledge pertaining to particular diseases or drugs [6, 7]
The four datasets of GSE3325, GSE35988, GSE70768, and GSE80609 were selected for further analysis after a MetaQC analysis (Supplementary Table S1)
Summary
Drug repurposing or repositioning is a strategy for identifying new indications for approved or investigational drugs that are outside the scope of the original medical indication [1]. Drug development strategies based on gene expression levels are advantageous in that they do not require a large amount of a priori knowledge pertaining to particular diseases or drugs [6, 7]. The reverse gene expression scores (RGES) computation method was developed as a one of the powerful drug repositioning tools to predict drug candidates [13]. The RGES computation method was applied to find drug candidates for CRPC in this study
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