Targeting miRNAs and Other Non-Coding RNAs as a Therapeutic Approach: An Update

Abstract

Since the discovery of the first microRNAs (miRNAs, miRs), the understanding of miRNA biology has expanded substantially. miRNAs are involved and described as master regulators of the major hallmarks of cancer, including cell differentiation, proliferation, survival, the cell cycle, invasion, and metastasis. Experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression, and because miRNAs act as tumor suppressors or oncogenes (oncomiRs), they have emerged as attractive tools and, more importantly, as a new class of targets for drug development in cancer therapeutics. With the use of miRNA mimics or molecules targeting miRNAs (i.e., small-molecule inhibitors such as anti-miRS), these therapeutics have shown promise in preclinical settings. Some miRNA-targeted therapeutics have been extended to clinical development, such as the mimic of miRNA-34 for treating cancer. Here, we discuss insights into the role of miRNAs and other non-coding RNAs in tumorigenesis and resistance and summarize some recent successful systemic delivery approaches and recent developments in miRNAs as targets for anticancer drug development. Furthermore, we provide a comprehensive overview of mimics and inhibitors that are in clinical trials and finally a list of clinical trials based on miRNAs.

Keywords: cancer; drug delivery; miRNA; microRNA; resistance; therapeutics.

Figure 1

The mechanisms of miRNA biogenesis and overview of points of interference with the endogenous miRNA pathway. miRNA biogenesis is a multistage process that starts with the transcription of a pri-miRNA by RNA polymerase II or III; the pri-miRNA is then processed in the nucleus to a pre-miRNA by the microprocessor complex Drosha and DGCR8. The pre-miRNA is exported by exportin 5 from the nucleus to the cytoplasm. (1) Under normal conditions, pre-miRNA is processed by DICER and TRBP into a mature miRNA duplex. Following the degradation of the passenger strand, the mature miRNA strand is incorporated into the RISC, which modulates gene expression by translational repression or mRNA degradation depending on the level of complementarity with its mRNA target. (2) The inhibition of biogenesis can be carried out in the nuclear or cytoplasmic compartment. Potential points of interference include blocking or enhancing production at the nuclear level, therapeutic miRNA replacement (miRNA mimics), the inhibition (anti-miR) of mature miRNA, or interaction with its target mRNA.

Figure 2

Routes of drug administration into the central nervous system. Intracerebroventricular administration through the Ommaya reservoir into lateral ventricles and intrathecal administration through the spinal column.