Silexion Therapeutics Corp. has reported positive findings from an ongoing translational study evaluating the cellular uptake and gene-silencing mechanism of its lead RNA interference (RNAi) candidate, SIL204, being developed for KRAS-driven cancers.

The study, which forms part of Silexion's translational research programme supporting the Phase 2/3 clinical development of SIL204, found that the candidate can utilise naturally occurring circulating lipoproteins to facilitate cellular uptake and achieve dose-dependent knockdown of mutant KRAS expression in cancer cells.

In the study, human KRAS-driven cancer cells were treated with SIL204 in a carrier-free assay without synthetic transfection reagents. The cells demonstrated robust, dose-dependent gene silencing in the presence of physiological serum lipids. However, reducing serum lipid levels significantly decreased gene-knockdown efficiency, with the difference reaching statistical significance.

According to Silexion, the findings indicate that circulating lipoproteins have a functional role in the cellular uptake of SIL204 and subsequent KRAS gene silencing. The study also found that adding external human Low-Density Lipoprotein (LDL) did not further increase gene-silencing potency compared with complete serum.

The company said this suggests that naturally occurring lipoprotein levels may be sufficient to support SIL204 uptake without requiring external lipid supplementation or synthetic carrier systems.

Silexion said the findings provide mechanistic support for its ongoing pharmacokinetic and biodistribution studies. The company is also evaluating whether SIL204 can use endogenous lipid transport pathways for systemic delivery to tumour cells.

Dr. Mitchell Shirvan, Chief Scientific and Development Officer of Silexion Therapeutics, said the findings provide further understanding of how SIL204 enters target cancer cells and supports the candidate's continued translational development.

Ilan Hadar, Chairman and Chief Executive Officer of Silexion Therapeutics, said the findings support the company's broader development strategy for SIL204, including its potential use through systemic administration to address micro-metastases and distant disease.

Silexion is currently progressing its Phase 2/3 clinical programme in locally advanced pancreatic cancer, while clinical trial site initiation is underway at Tel Aviv Sourasky Medical Center and regulatory clearances have been obtained in Germany.

Additional preclinical studies are ongoing to evaluate the candidate's in vivo pharmacokinetics, cellular uptake kinetics and tissue biodistribution. These studies are intended to further assess the relationship between lipoprotein association, LDL receptor (LDLR) pathway engagement, systemic exposure and antitumour activity.

Silexion Therapeutics is a clinical-stage biotechnology company focused on developing RNAi-based treatments for solid tumours driven by mutated KRAS, a major oncogenic driver in human cancers.