Advances in the discovery of microRNA-based anticancer therapeutics: latest tools and developments

ABSTRACT

Introduction: MicroRNAs (miRNAs) are small endogenous non-coding RNAs that repress the expression of their target genes by reducing mRNA stability and/or inhibiting translation. miRNAs are known to be aberrantly regulated in cancers. Modulators of miRNA (mimics and antagonists) have emerged as novel therapeutic tools for cancer treatment.

Areas covered: This review summarizes the various strategies that have been applied to correct the dysregulated miRNA in cancer cells. The authors also discuss the recent advances in the technical development and preclinical/clinical evaluation of miRNA-based therapeutic agents.

Expert opinion: Application of miRNA-based therapeutics for cancer treatment is appealing because they are able to modulate multiple dysregulated genes and/or signaling pathways in cancer cells. Major obstacles hindering their clinical development include drug delivery, off-target effects, efficacious dose determination, and safety. Tumor site-specific delivery of novel miRNA therapeutics may help to minimize off-target effects and toxicity. Combination of miRNA therapeutics with other anticancer treatment modalities could provide a synergistic effect, thus allowing the use of lower dose, minimizing off-target effects, and improving the overall safety profile in cancer patients. It is critical to identify individual miRNAs with cancer type-specific and context-specific regulation of oncogenes and tumor-suppressor genes in order to facilitate the precise use of miRNA anticancer therapeutics.

KEYWORDS:

• Antisense oligonucleotide
• artificial ribonucleases
• CRISPR/Cas9 gene editing
• extracellular vesicles
• microRNA masking oligonucleotides
• microRNA mimic
• microRNA sponges
• N-acetylgalactosamine
• small RNA zippers

Article highlights

• Correction of miRNA dysregulation in cancer cells represents a novel anticancer strategy.

• Various miRNA therapeutics for cancer treatment has been designed to inhibit oncogenic miRNAs (e.g., antisense oligonucleotides, miRNA sponges, miRNA-masking oligonucleotides, artificial ribonucleases) or restore tumor-suppressor miRNAs (e.g., mimics).

• A few miRNA-based anticancer therapeutics are currently investigated in Phase I/II clinical trials with promising results.

• Clinical application of miRNA therapeutics is hindered by the lack of site-specific delivery, insufficient target specificity, possible off-target effects, and toxicity.

• miRNA therapeutics have been combined with chemo-, radio-, targeted, or immuno-therapy to provide a more pronounced anticancer effect.

• Novel delivery systems with tumor site targeting capability have been designed to facilitate the co-delivery of miRNA-based therapeutics with other anticancer treatment modalities.This box summarizes the key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported in part by a grant from the Medicine Panel of the Chinese University of Hong Kong (4054497) to Kenneth K.W. To.