Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer

Abstract

The strategy of using existing drugs originally developed for one disease to treat other indications has found success across medical fields. Such drug repurposing promises faster access of drugs to patients while reducing costs in the long and difficult process of drug development. However, the number of existing drugs and diseases, together with the heterogeneity of patients and diseases, notably including cancers, can make repurposing time consuming and inefficient. The key question we address is how to efficiently repurpose an existing drug to treat a given indication. As drug efficacy remains the main bottleneck for overall success, we discuss the need for machine-learning computational methods in combination with specific phenotypic studies along with mechanistic studies, chemical genetics and omics assays to successfully predict disease-drug pairs. Such a pipeline could be particularly important to cancer patients who face heterogeneous, recurrent and metastatic disease and need fast and personalized treatments. Here we focus on drug repurposing for colorectal cancer and describe selected therapeutics already repositioned for its prevention and/or treatment as well as potential candidates. We consider this review as a selective compilation of approaches and methodologies, and argue how, taken together, they could bring drug repurposing to the next level.

Keywords: Colorectal cancer; Computational approaches; Drug repositioning; Mechanism of action; Omics; On/off-target effects; Phenotypes; Polypharmacology; Repurposing in oncology; Side effects; Signaling pathways.

Scheme 1

Drug development scheme. A. Traditional drug development. B. Drug candidates with good clinical safety profiles can be repurposed relatively easily when the same, delivery route is used. C. Drug candidates repurposed using different routes than in the original indication require safety clinical testing. D. Repurposed drug combinations, depending on on-target/off-target characterization, might or might not (therefore the question mark) require a clinical safety step to reach clinical efficacy test.

Scheme 2

Classical drug development pathway and drug repurposing options.