PS 18. Small activating RNA (saRNA) in urological cancer as therapeutic options

Small nucleic acids such as antisense oligodeoxynucleotide, siRNA and microRNA are a class of promising drugs under active development for a variety of human diseases due to their relative small size and ability to modulate gene expression through different cellular mechanisms with high target specificity and low toxicity. However, almost the totality of the action modes of these nucleic acids is the suppression of target sequences. There is growing evidence that small RNA molecules can serve as activators of gene expression by targeting noncoding regulatory sequences. This novel mechanism, known as RNA activation (RNAa), is triggered by both endogenous and artificially designed small activating RNA (saRNA). By utilizing saRNA as a "ribodrug", RNAa offers expanded druggable targets for cancer treatment. A saRNA designed to target the p21 gene, a key negative regulator of the cell cycle and cell proliferation, can activate endogenous p21 protein in prostate and bladder cancer cells, and significantly impede in vivo tumor growth. These findings provide proof of concept that saRNA can be used to treat urological cancer via targeted activation of endogenous tumor suppressor genes and rationale for further preclinical development of saRNA therapeutics.