Developing a pan cancer therapy based on DISE inducing short RNAs

ABSTRACT: RNA interference (RNAi) regulates gene expression through small RNAs, including microRNAs (miRNAs) and short interfering RNAs (siRNAs), that function via Argonaute-containing RNA-induced silencing complexes (RISCs). We previously discovered that certain small RNAs (sRNAs) with specific 6mer G-rich seed sequences (e.g., GGGGGC, or G5C) induce cell death by simultaneously targeting C-rich 3′UTR seed matches in essential survival genes (SGs), a mechanism termed Death Induced by Survival gene Elimination (DISE). Tumor-suppressive miRNAs (e.g., miR-34a-5p, miR-15/16-5p) harness this mechanism to selectively kill cancer cells, while sparing normal cells due to their unique seed composition. To evaluate therapeutic potential, we used lipopolyplexes (LPPs) formulated with tyrosine-modified low-molecular-weight polyethyleneimines and lipids to systemically deliver two classes of DISE-inducing sRNAs (Di-sRNAs): sG5C and sCAG (based on CAG trinucleotide repeats). In mouse models of ovarian cancer (OC), prostate cancer (PC), and a hepatocellular carcinoma (HCC) rat model, LPP-mediated delivery of Di-sRNAs significantly suppressed or eliminated tumors without adverse effects on normal tissues. We confirmed on-target engagement of predicted SGs in tumors. Furthermore, transcriptomic analyses across 10 major human cancers revealed that many sG5C-targeted SGs are consistently upregulated in tumors compared to normal tissues, with expression increasing with cancer stage highlighting a therapeutic window for selective targeting. These findings demonstrate the potential of LPP-delivered Di-sRNAs as a pan-cancer therapeutic strategy that exploits intrinsic differences in survival gene expression between cancerous and normal tissues. This work lays the foundation for the development of G-rich seed-based sRNAs as a broadly effective, mechanism-based anticancer therapy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Peter Faull  

LAB HEAD: Marcus Peter

PROVIDER: PXD069011 | Pride | 2026-06-29

REPOSITORIES: Pride