RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

Abstract

RNA-based therapeutic technologies represent a rapidly expanding class of therapeutic opportunities with the power to modulate cellular biology in ways never before possible. With RNA-targeted therapeutics, inhibitors of previously undruggable proteins, gene expression modulators, and even therapeutic proteins can be rationally designed based on sequence information alone, something that is not possible with other therapeutic modalities. The most advanced RNA therapeutic modalities are antisense oligonucleotides (ASOs) and small interfering RNAs. Particularly with ASOs, recent clinical data have demonstrated proof of mechanism and clinical benefit with these approaches across several nononcology disease areas by multiple routes of administration. In cancer, next-generation ASOs have recently demonstrated single-agent activity in patients with highly refractory cancers. Here we discuss advances in RNA therapeutics for the treatment of cancer and the challenges that remain to solidify these as mainstay therapeutic modalities to bridge the pharmacogenomic divide that remains in cancer drug discovery.

MicroRNAs as Potential Targets for Therapeutic Intervention With Metastasis of Non-small Cell Lung Cancer

“…Considerable progress has been achieved in the field of delivery agents, such as viral vectors, neutral lipid emulsions, liposomes, Poly (ethylene glycol) and chitosan, dendrimers and N-acetyl-D-galactosamin, which can be modified and formulated to serve the optimal target strategy (160). Issues which must be addressed include: i) the hybridizationdependent and -independent off-target effects, ii) the hepatotoxicity and other associated toxicities, iii) immunomodulatory effects, iv) the design of efficient delivery systems, v) the rapid clearance by the reticulo-endothelial system, vi) the enhancement of circulation time when injected into the bloodstream, vii) the delivery to metastases and vii) the endosomal escape (161)(162)(163). Fast renal clearance can be prevented by coupling miRNA with polyethylene glycol (PEG), albumins or cholesterol, which mediate shielding from renal clearance (164)(165)(166).…”

Natural Antisense Transcripts: Molecular Mechanisms and Implications in Breast Cancers

“…Functionally characterized NATs can be targeted by ASOs, called in this case antagoNATs, to block the interaction of the sense and antisense transcripts. The hybridization of ASOs with the antisense transcript would lead to its degradation, or to transcriptional de-repression at the chromatin level [ 187 ]. The first in vivo demonstration of antagoNAT efficacy was shown by Modarresi et al [ 188 ] and has been validated in other clinical contexts, detailed in the review by MacLeod et al [ 187 ].…”

Disulfide‐Unit Conjugation Enables Ultrafast Cytosolic Internalization of Antisense DNA and siRNA

“…[1] Effective delivery of the oligonucleotides (ONs) into the cells is important for clinical applications. [1] Effective delivery of the oligonucleotides (ONs) into the cells is important for clinical applications.…”

“…Antisense DNAand siRNAhave been widely used for gene silencing in basic research and in medicinal applications. [1] Effective delivery of the oligonucleotides (ONs) into the cells is important for clinical applications. [2] Fort his reason, delivery methods for ONs have been extensively studied.…”