Developing a pan cancer therapy based on DISE-inducing short RNAs.

Area of Science:

• Molecular Biology
• Gene Regulation
• Cancer Therapeutics

Background:

• RNA interference (RNAi) utilizes small RNAs (sRNAs) within RNA-induced silencing complexes (RISCs) to regulate gene expression.
• Previously identified G-rich 6mer seed sequences in sRNAs can induce cell death by targeting essential survival genes (SGs), a process termed death induced by survival gene elimination (DISE).

Purpose of the Study:

• To evaluate the therapeutic potential of systemically delivered DISE-inducing sRNAs.
• To assess the efficacy and safety of lipopolyplex (LPP)-delivered sRNAs in preclinical cancer models.

Main Methods:

• Systemic delivery of two DISE-inducing sRNAs (sG5C and sCAG) encapsulated in lipopolyplexes (LPPs).
• Evaluation in mouse ovarian and prostate cancer models, and a rat hepatocellular carcinoma model.
• Transcriptomic analysis across 10 major human cancers to identify potential therapeutic targets.

Main Results:

• LPP-delivered sRNAs significantly reduced or eliminated tumors in multiple cancer models.
• Tumor targeting was confirmed, with no observed harm to normal tissues.
• Many sG5C-targeted SGs are consistently upregulated in tumors and correlate with cancer stage across diverse human cancers.

Conclusions:

• Lipopolyplex-delivered DISE-inducing sRNAs represent a promising pan-cancer therapeutic strategy.
• The consistent upregulation of targeted SGs in tumors suggests a viable therapeutic window for this approach.