Non-codingRNAs (ncRNAs) represent a large class of molecules comprising short microRNAs, tRNAs and long ncRNAs (lncRNAs) that in concert regulate the expression of genes involved in the key pathways governing cancer development and progression. They represent ideal targets for personalized cancer therapies and if appropriately designed they can provide specific, non-toxic and effective therapeutic tools.The identification of novel therapeutic ncRNAs and the design of their appropiate formulation is a key aspect for their clinical applicability.
NcRNAs act in concert regulate multiple pathways governing cell differentiation, proliferation and motility. NcRNAs may also drive intercellular communication through cell-derived extracellular vesicles, including exosomes. These approaches are emerging as promising therapeutic tools. Deregulation of cellular ncRNAs in the heterogeneous tumor mass and in the microenvironment cells is implicated in tumor progression, increased immune tolerance, weak therapeutic response and increased metastatic potential. Thus, ncRNAs represent ideal targets for personalized cancer therapies. Indeed, because of the low toxicity and high target-specificity, RNA-based anti-cancer therapeutic approaches have recently become a forefront objective that has raised growing expectations in the scientific community. If appropriately designed, they are specific, non-toxic and address non-druggable targets. Multiple trials in different countries strongly suggest that ncRNAs offer unique advantages to traditional small molecule therapeutics.
The expectation of RISE-cONCReTE:
Current strategies for inhibitory-miRNA therapies are based on antisense antimiRs (LNA), LNA-antimiR constructs, antagomirs, and miRNA sponges. For instance, Regulus Therapeutics is actively exploring the value of anti-miRs in the treatment of diseases such as fibrosis, hepatitis C virus (HCV) infection, atherosclerosis and cancer. MIRagen Therapeutics is using chemically modified structures of miRNA (including miR-15/195, miR-29, and others) reaching preclinical development in pathologies such as metabolic and cardiovascular diseases. Miravirsen (SPC3649) is an LNA against miR-122 developed by Santaris Pharma A/S for the treatment of hepatitis C (HCV) currently in phase II clinical trial. RISE-cONCReTE proposes strategies for diminishing the miR mimetics/anti-miRs drug doses and the potential adverse reactions. In this regards the use of RNA aptamers specifically recognizing target cancer cells, carrying therapeutics ncRNAs may results in an evolution of the application of the ncRNA-based therapy. Nucleic-acid based aptamers are a new class of specific targeting molecules and represent high affinity ligands (kd in the nanomolar range). They have many advantages compared to antibodies including simpler production, small dimension allowing multiplexing, low toxicity, no immunogenicity and easy chemical modification to improve their stability or to develop conjugation strategies. The resulting approaches will provide stable and effective tools thus potentially improving the quality of life (QOL) in cancer patient.