Targeting microRNAs in cancer: rationale, strategies and challenges

Key Points The rationale for using microRNAs (miRNAs) as anticancer drugs is based on two major findings: miRNA expression is deregulated in cancer compared with normal tissues and the cancer phenotype can be changed by targeting miRNA expression. One of the most appealing properties of miRNAs as therapeutic agents is their ability to target multiple genes, frequently in the context of a network, making them highly efficient in regulating distinct biological cell processes relevant to normal and malignant cell homeostasis There are two main strategies to target miRNA expression in cancer. Direct strategies involve the use of oligonucleotides or virus-based constructs to either block the expression of an oncogenic miRNA or to substitute for the loss of expression of a tumour suppressor miRNA. The indirect strategy involves the use of drugs to modulate miRNA expression by targeting their transcription and their processing. Several in vitro and in vivo studies using locked nucleic acid (LNA) antimiR have shown feasibility and high efficiency of this approach. A Phase I trial in humans using LNA anti-miR-122 is ongoing. This study will provide valuable information about pharmacokinetics and safety profiles. The challenges for developing miRNA-based therapeutics are the same as for siRNA therapeutics and comprise delivery, potential off-target effects and safety concerns. Reprogramming aberrant miRNA networks in cancer could be achieved by modulating several of the key miRNAs in a network using known drugs, including chemotherapy agents or biocompounds. miRNA effects are currently largely interpreted as the result of miRNA–mRNA 3′untranslated region (UTR) interactions that cause target post-translational inhibition or degradation. However, focusing on this mechanism to design miRNA therapeutics is likely to prove too simplistic, owing to the emerging miRNA mechanisms, which include decoy activity and 5′ UTR and direct DNA regulatory activities. MicroRNAs (miRNAs) are attracting increasing attention as promising targets for the treatment of cancer. Here, the authors discuss the role of miRNAs in cancer development, and discuss the rationale, the strategies and the challenges for developing therapeutics that modulate miRNAs. MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified