Drug Repurposing for Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.

Keywords: cancer stem cells; clinical trials; computational methods; drug repurposing; personalized medicine; triple-negative breast cancer.

Figure 1

Comparison between de novo drug development and drug repurposing. Adapted from Ashburn and Thor [22].

Figure 2

Diagram of the main computational approaches and software for drug repurposing.

Figure 3

Overview of the different pathways investigated by drug repurposing. Repurposed inhibitors under investigation are shown in red. Created with BioRender.com.

Figure 4

Overview of the different pathways investigated by drug repurposing to target breast cancer stem cells (BCSCs) and their potential inhibitors/modulators. Repurposed inhibitors under investigation are shown in red. Hypothesized inhibitors are shown in yellow. Created with BioRender.com.