Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
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.
Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6147-E6156. doi: 10.1073/pnas.1701911114. Epub 2017 Jul 10.
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.
脑肿瘤起始细胞（BTICs）已被确定为导致弥漫性神经胶质瘤（尤其是胶质母细胞瘤，GBM）治疗抵抗、复发和进展的关键因素。BTICs 是难以捉摸的治疗靶点，存在于血脑屏障内，这突显了开发新型治疗策略的迫切需要。此外，BTIC 内在的肿瘤异质性和对治疗压力的适应能力，阻碍了有效抗 BTIC 治疗方法的发现，并限制了单个基因靶向的疗效。最近在 BTIC 肿瘤发生的遗传和表观遗传决定因素方面的发现，为 RNAi 介导的 BTIC 靶向提供了新的机会。在这里，我们表明，通过同时敲低四个转录因子（SOX2、OLIG2、SALL2 和 POU3F2）的 siRNA，可在体外和体内实现 BTIC 的生长停滞，这些转录因子驱动神经前 BTIC 表型，通过在脂多聚物纳米颗粒 7C1 中进行多重 siRNA 包封来实现。重要的是，我们证明了 7C1 纳米封装的多重 RNAi 是一种可行的 BTIC 靶向策略，当直接在体内用于已建立的小鼠脑肿瘤时。通过对流增强递送方法，可明显延长两种患者来源的 GBM BTIC 异种移植小鼠模型的中位生存时间，从而显示出治疗潜力。我们的研究表明，对 BTIC 进行多重靶向策略具有潜在优势，并建立了一个灵活的非病毒基因治疗平台，具有向肿瘤异质性提出的挑战传递多重 RNAi 方案的能力。
