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KRAS mutant allele-specific expression knockdown in pancreatic cancer model with systemically delivered bi-shRNA KRAS
Donald D Rao1, Xiuquan Luo1, Zhaohui Wang1
1Strike Bio, Dallas, TX, United States of America.
Abstract:
The KRAS oncogene, present in over 90% of pancreatic ductal adenocarcinomas, is most frequently the result of one of three gain-of-function substitution mutations of codon 12 glycine. Thus far, RAS mutations have been clinically refractory to both direct and selective inhibition by systemic therapeutics. This report presents the results of pre-clinical assessment of a lipoplex comprising a plasmid-encoded, modular bi-functional shRNA (bi-shRNA), which executes selective and multi-mutant allelic KRASG12mut gene silencing, encased within a fusogenic liposome systemic delivery vehicle. Using both a dual luciferase reporter system and a Restriction Fragment Length Polymorphism (RFLP) assay, selective discrimination of KRASG12mut from KRASwt was confirmed in vitro in PANC1 cells. Subsequently, systemic administration of the bi-shRNAKRAS fusogenic lipoplex into female athymic Nu/Nu mice bearing PANC1 xenografts demonstrated intratumoral plasmid delivery, KRASG12mut knockdown, and inhibition of tumor growth, without adverse effect. Clinical trials with the bi-shRNA lipoplex have been implemented.
Insights
A novel bi-functional shRNA (bi-shRNA) lipoplex effectively silenced KRASG12mut in pancreatic cancer cells and xenografts. This targeted gene silencing approach shows promise for treating KRAS-mutant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- KRAS mutations drive over 90% of pancreatic ductal adenocarcinomas.
- RAS mutations have historically been challenging to target with systemic therapies.
Purpose of the Study:
- To assess the preclinical efficacy of a novel bi-functional shRNA (bi-shRNA) lipoplex for selective KRASG12mut gene silencing.
- To evaluate the systemic delivery and therapeutic potential of this lipoplex in preclinical models.
Main Methods:
- Development of a fusogenic liposome-encased bi-shRNA targeting KRASG12mut.
- In vitro validation using dual luciferase reporter and RFLP assays in PANC1 cells.
- In vivo assessment in athymic mice bearing PANC1 xenografts, evaluating gene knockdown and tumor growth inhibition.
Main Results:
- Selective discrimination and silencing of KRASG12mut from KRASwt confirmed in vitro.
- Systemic administration achieved intratumoral plasmid delivery and KRASG12mut knockdown in vivo.
- Significant inhibition of tumor growth was observed without adverse effects.
Conclusions:
- The bi-functional shRNA lipoplex demonstrates potent and selective KRASG12mut knockdown.
- This targeted gene silencing strategy is a promising therapeutic approach for KRAS-mutant pancreatic cancer.
- Clinical trials have been initiated based on these positive preclinical findings.
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