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

Dou Yu, Omar F. Khan, Mario L. Suvà, Biqin Dong, Wojciech K. Panek, Ting Xiao, Meijing Wu, Yu Han, Atique Uddin Ahmed, Irina V Balyasnikova, Hao F Zhang, Cheng Sun, Robert Langer, Daniel G. Anderson, Maciej S Lesniak

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E6147-E6156
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number30
DOIs
StatePublished - Jul 25 2017

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Neoplastic Stem Cells
Glioblastoma
Brain Neoplasms
Nanoparticles
RNA Interference
Small Interfering RNA
SOXB1 Transcription Factors
RNAi Therapeutics
Therapeutics
Convection
Gene Targeting
Cell- and Tissue-Based Therapy
Heterografts
Epigenomics
Glioma
Genetic Therapy
Carcinogenesis

Keywords

  • Brain tumor-initiating cells
  • Convection-enhanced delivery
  • Glioblastoma transcription factor
  • Lipopolymeric nanoparticle
  • SiRNA

ASJC Scopus subject areas

  • General

Cite this

Yu, Dou ; Khan, Omar F. ; Suvà, Mario L. ; Dong, Biqin ; Panek, Wojciech K. ; Xiao, Ting ; Wu, Meijing ; Han, Yu ; Ahmed, Atique Uddin ; Balyasnikova, Irina V ; Zhang, Hao F ; Sun, Cheng ; Langer, Robert ; Anderson, Daniel G. ; Lesniak, Maciej S. / Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 30. pp. E6147-E6156.
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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.",
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Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression. / Yu, Dou; Khan, Omar F.; Suvà, Mario L.; Dong, Biqin; Panek, Wojciech K.; Xiao, Ting; Wu, Meijing; Han, Yu; Ahmed, Atique Uddin; Balyasnikova, Irina V; Zhang, Hao F; Sun, Cheng; Langer, Robert; Anderson, Daniel G.; Lesniak, Maciej S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 30, 25.07.2017, p. E6147-E6156.

Research output: Contribution to journalArticle

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T1 - Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

AU - Yu, Dou

AU - Khan, Omar F.

AU - Suvà, Mario L.

AU - Dong, Biqin

AU - Panek, Wojciech K.

AU - Xiao, Ting

AU - Wu, Meijing

AU - Han, Yu

AU - Ahmed, Atique Uddin

AU - Balyasnikova, Irina V

AU - Zhang, Hao F

AU - Sun, Cheng

AU - Langer, Robert

AU - Anderson, Daniel G.

AU - Lesniak, Maciej S

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AB - 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.

KW - Brain tumor-initiating cells

KW - Convection-enhanced delivery

KW - Glioblastoma transcription factor

KW - Lipopolymeric nanoparticle

KW - SiRNA

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