The Promise and Pursuit of MicroRNAs for Cancer Treatment.

In spite of at least six discrete classes of drugs available for cancer treatment, the quest for more biologic drugs continues. One type of biologic molecule that occurs naturally in the body is microRNA. MicroRNAs regulate post-transcriptional gene expression and can be under expressed in cancer (tumor suppressor microRNAs) or over expressed (oncogenic microRNAs). Strand-specific mimics of microRNAs have been developed and used successfully in vitro, in vivo, and in clinical trials, to control multiple aspects of cancer including metastasis, apoptosis and proliferation. Each microRNA is capable of binding a specific target mRNA or mRNAs, sometimes simultaneously interfering with multiple genes in a single pathway, or binding with a single nodal mRNA. Some microRNAs can facilitate chemotherapy that has stopped working, addressing the issue of drug resistance. Without chemical modification, microRNAs are too vulnerable to have lasting therapeutic value. Chemical modifications to microRNAs have provided nuclease resistance and greater stability and are the basis for microRNA mimics that can be used therapeutically. However, without a vehicle, microRNA mimics do not cross cell membranes. These nanoparticles can cause inflammatory reactions in patients. Additional modifications that enabled microRNA mimics to cross cell membranes include substituting uracil with 5-fluorouracil. Lessons from an siRNA therapeutic called Patisiran offer a roadmap for future success for microRNAs in cancer. This review provides a historical perspective of the continuing evolution of microRNA mimics for cancer treatment.