Knockdown of β-catenin with Dicer-Substrate siRNAs Reduces Liver Tumor Burden In vivo

Abstract

Despite progress in identifying molecular drivers of cancer, it has been difficult to translate this knowledge into new therapies, because many of the causal proteins cannot be inhibited by conventional small molecule therapeutics. RNA interference (RNAi), which uses small RNAs to inhibit gene expression, provides a promising alternative to reach traditionally undruggable protein targets by shutting off their expression at the messenger RNA (mRNA) level. Challenges for realizing the potential of RNAi have included identifying the appropriate genes to target and achieving sufficient knockdown in tumors. We have developed high-potency Dicer-substrate short-interfering RNAs (DsiRNAs) targeting β-catenin and delivered these in vivo using lipid nanoparticles, resulting in significant reduction of β-catenin expression in liver cancer models. Reduction of β-catenin strongly reduced tumor burden, alone or in combination with sorafenib and as effectively as DsiRNAs that target mitotic genes such as PLK1 and KIF11. β-catenin knockdown also strongly reduced the expression of β-catenin–regulated genes, including MYC, providing a potential mechanism for tumor inhibition. These results validate β-catenin as a target for liver cancer therapy and demonstrate the promise of RNAi in general and DsiRNAs in particular for reaching traditionally undruggable cancer targets.

Anticancer siRNA cocktails as a novel tool to treat cancer cells. Part (A). Mechanisms of interaction

“…There are many reports on the application of dendrimers as vectors for nucleic acids, and RNAi-based anticancer therapy is also gaining much attention (Dudek et al, 2014;Li et al, 2013). Using dendrimers PAMAM, phosphorus and carbosilane as potential carriers of anticancer siRNAs (siBcl-2, siMcl-1, and siBcl-xl), which silence anti-apoptotic genes, and siScrambled siRNA sequence, we have monitored the formation of dendrimer/siRNA complexes, characterized them, and assessed their ability to protect oligonucleotide duplexes against nucleases.…”

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)

“…The siRNA effectively induced cleavage of targeted mRNA in the liver and demonstrated antitumor activity, including complete regression of metastatic lesion in the liver. This clinical trial, along with positive results from multiple pre-clinical studies targeting different molecules via nanoparticle-delivered siRNA, indicates that this modality of treatment is a viable option for HCC patients [45–47]. Indeed, the FDA has approved a recent clinical trial for nanoparticle-delivered PLK1 siRNA for HCC (http://investor.tekmirapharm.com/releasedetail.cfm?ReleaseID=850580).…”

Noncanonical Synthetic RNAi Inducers

“…Several studies use dsiRNA to silence therapeutically relevant genes in vivo (Table 1). Frequently, cancer-related genes and genes of viruses [50,51,[56][57][58][59] are chosen as targets for dsiRNAs [47][48][49]. Several researchers used TNFα gene as a target for the treatment of inflammatory and autoimmune diseases [52][53][54].…”

“…Several researchers used TNFα gene as a target for the treatment of inflammatory and autoimmune diseases [52][53][54]. Murine models are the most popular animal models among various studies that used dsiRNA in vivo [47][48][49][50][51][52][53][54]; however, there are studies where other animal models, for example, rats, were used [53,55]. An exciting example of dsiRNA application was described by Doré-Savard and his colleagues, who demonstrated, for the first time, the efficient suppression of target genes in central nervous system (CNS) of rats by dsiRNA [55].…”

“…In another study, potent 2′-O-methyl modified dsiRNAs targeted to β-catenin were designed [49]. It is known that β-catenin acts as the transcription factor and its overexpression causes the development of several types of cancer, including liver cancer.…”