Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin

Area of Science:

• Oncology
• Molecular Biology
• Drug Delivery Systems

Background:

• The Wnt/β-catenin pathway is frequently dysregulated in human cancers, presenting a significant therapeutic challenge.
• RNA interference (RNAi) offers a way to target previously undruggable genes, but effective delivery remains a hurdle.
• Lipid nanoparticles (LNPs) are promising for RNAi delivery but are often liver-restricted.

Purpose of the Study:

• To develop and optimize a lipid nanoparticle (LNP) formulation for tumor-selective delivery of RNAi therapeutics.
• To evaluate the efficacy of LNP-delivered Dicer-substrate siRNA (DsiRNA) targeting CTNNB1 (β-catenin) in various cancer models.
• To assess the safety and pharmacodynamic profile of the optimized LNP formulation in preclinical models and nonhuman primates.

Main Methods:

• Systematic tuning of LNP composition to create a prototype formulation (EnCore-R) for targeted delivery.
• Administration of EnCore-R loaded with CTNNB1-targeting DsiRNA to diverse subcutaneous, orthotopic, and metastatic cancer xenograft models.
• Assessment of DsiRNA biodistribution, tumor penetration, and pharmacodynamic effects, alongside tumor growth inhibition studies.
• Evaluation of repeated dose toxicity in nonhuman primates, monitoring for adverse effects like accelerated blood clearance and liver enzyme elevation.

Main Results:

• The EnCore-R LNP formulation enabled homogeneous and tumor-selective delivery of DsiRNA across multiple cancer types, independent of apolipoprotein-E.
• Significant inhibition of tumor growth was observed in Wnt-dependent colorectal and hepatocellular carcinoma models.
• Repeated dosing in nonhuman primates showed no signs of accelerated blood clearance or sustained liver transaminase elevation, indicating a favorable safety profile.

Conclusions:

• The developed EnCore-R LNP system facilitates targeted delivery of RNAi agents for Wnt/β-catenin pathway modulation in cancer.
• This approach demonstrates therapeutic potential in Wnt-dependent tumors, warranting further investigation for clinical translation.
• The formulation's safety profile in primates supports its progression towards clinical trials for cancer therapy.