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Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6147-E6156. doi: 10.1073/pnas.1701911114. Epub 2017 Jul 10.

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression.

Author information

1
Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
2
Department of Chemical Engineering, Institute for Medical Engineering and Science, Harvard MIT Division of Health Science and Technology, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
3
Broad Institute of Harvard and MIT, Cambridge, MA 02142.
4
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
5
Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
6
Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208.
7
Department of Mechanical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208.
8
Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; maciej.lesniak@northwestern.edu.

Abstract

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.

KEYWORDS:

brain tumor-initiating cells; convection-enhanced delivery; glioblastoma transcription factor; lipopolymeric nanoparticle; siRNA

PMID:
28696296
PMCID:
PMC5544292
DOI:
10.1073/pnas.1701911114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: D.G.A. and R.L. have filed intellectual property protection related to the 7C1 nanoparticle. D.Y. has an evaluation agreement with Cell Signaling Technology regarding the use of the CellSimpleTM Cell Analyzer and reagents. The authors declare that they have no further competing interests.

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