Development of Therapeutic dsP21-322 for Cancer Treatment

Abstract

Small activating RNAs (saRNAs) are a class of artificially designed short duplex RNAs targeted at the promoter of a particular gene to upregulate its expression via a mechanism known as RNA activation (RNAa) and hold great promise for treating a wide variety of diseases including those undruggable by conventional therapies. The therapeutic benefits of saRNAs have been demonstrated in a number of preclinical studies carried out in different disease models including cancer. With many tumor suppressor genes (TSGs) downregulated due to either epigenetic mechanisms or haploinsufficiency resulting from deletion/mutation, cancer is an ideal disease space for saRNA therapeutics which can restore the expression of TSGs via epigenetic reprogramming. The p21 gene is a TSG frequently downregulated in cancer and an saRNA for p21 known as dsP21-322 has been identified to be a sequence-specific p21 activator in a number of cancer types. In this chapter, we review preclinical development of medicinal dsP21-322 for cancer, especially prostate cancer and bladder cancer, and highlight its potential for further clinical development.

Upregulation of E‑cadherin expression mediated by a novel dsRNA suppresses the growth and metastasis of bladder cancer cells by inhibiting β-catenin/TCF target genes

“…RNAa is a recently discovered mechanism of gene regulation that provides a new therapeutic tool for the treatment of cancer ( 13 , 23 ). Our previous study demonstrated that endogenous miR-1236-3p and miR-370-5p induce p21 expression in bladder cancer cells.…”

Modulating the expression of tumor suppressor genes using activating oligonucleotide technologies as a therapeutic approach in cancer

“…This prevents the RB protein from becoming phosphorylated and, thus, prevents transcription factor E2F from being active and driving the transcription of genes involved in the S-phase of the cell cycle, such as DNA polymerase and cyclin A. 4 p21 can also induce apoptosis by suppressing the pro-apoptotic protein B-cell lymphoma-extra-large and activating caspase-3 and poly-ADP ribose polymerase. 4 Therefore, because of the anti-proliferative and pro-apoptotic roles of p21, there has been interest in targeting this protein in oncology.…”

“…(Refs. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ) TP53 P53 Commonly referred to as the guardian of the genome, p53 is activated in response to cellular stress to induce cell-cycle arrest, apoptosis, DNA repair and cell senescence. Bladder cancer, Pheochromocytoma In vivo (Bladder) In vivo (Pheochromocytoma) Wang et al., Lin et al.…”

Visualization of subdiffusive sites in a live single cell

“…The argonaute protein Ago2 is recruited to the non-coding transcript that overlaps the promoter during both gene silencing and activation [18,19,20]. p21 was susceptible to RNA activation by dsP21-322 RNA in prostate adenocarcinoma cells (PC-3) [18,21,22].…”

“…[22] and the articles cited therein). Ago2 could be found in both nuclear and cytoplasmic compartments of the cells [22,21]. Molecular beacons that included energy transfer pairs of Alexa Fluor 633 and SQ as dark acceptor (that is the molecule named BHQ3) were used before for direct probing of unamplified genomic DNA by homogeneous hybridization using two-color fluorescence cross-correlation technique [24,25] and for detecting microRNA122 in live cells [23].…”