OS06.2 Combination RNAi therapy against glioma stem cells via sustained lipopolymeric nanoparticle delivery delays tumor progression
Year: 2017
Type: conference-abstract
Abstract: Background: Glioma stem cells (GSCs) have been identified as the predominant contributor to the therapy resistance, recurrence, and progression of malignant glioma, particularly glioblastoma multiforme (GBM). However, GSCs are elusive therapeutic targets across the blood brain barrier, underscoring the urgent need to develop novel therapeutic targeting strategies. Further impeding the discovery of effective anti-GSC therapies, the complex intratumoral heterogeneity, identified via single cell RNAseq and transcriptome research, as well as the genomic adaptations by GSCs that evade therapeutic pressure, limit therapeutic efficacy of individual gene targeting. With recent breakthrough discoveries of genetic and epigenetic signatures of GSC mediated tumorigenesis, RNAi emerges as a promising anti-GSC therapeutic strategy to counteract tumorigenic genetic elements. HYPOTHESIS: We hypothesize that multiplexed RNAi using GSC targeting nanoparticles are effective counter measures against genetic drivers of GSC phenotypes. Methods: Based on a panel of qPCR and Western blotting analysis, we selected 2 suitable GSC candidates from patient derived glioma as therapeutic model targets. We then identified the novel lipopolymeric nanoparticle 7C1 as a pilot siRNA encapsulation candidate, and characterized its uptake dynamics in comparison with mouse brain endothelial cells and astrocytes. 7C1 demonstrates a striking affinity for GSCs, and multiplexed siRNA encapsulation in 7C1 was achieved using a microfluidic mixing device invented in our group. Results: In this report, we establish that 7C1 nano-encapsulation of multiplexed GSC RNAi is a flexible GSC targeting strategy when delivered directly to the brain tumor microenvironment. In vitro and in vivo GSC growth arrest is accomplished via concurrent siRNA knockdown of four transcription factors that engender the proneural GSC phenotype, namely SOX2, OLIG2, SALL2, and POU3F2. The therapeutic potential was most evident when the 7C1 multiplexed RNAi was delivered to mouse models of GBM created via intracranial xenograft of candidate GSCs via an AlzetTM osmotic pump (Durect Corp., Cupertino, CA, USA), which demonstrates a significant extension of median survival in patient derived GSC xenograft mouse models of aggressive GBM (9 days, log rank test, ***p=0.003). CONCLUSION: This pilot study validates an encouraging non-viral gene therapy platform to target GSCs, and demonstrates the potential capacity to channel infinite combinations of multiplexed RNAi schemes to address the intratumoral heterogeneity championed by GSCs. Future engineering to enhance the intratumoral distribution and enable long term delivery are underway to improve performance.
Source: Neuro-Oncology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2608512110