Control of glioblastoma tumorigenesis by feed-forward cytokine signaling

Jahani‐Asl, Arezu; Yin, Hang; Soleimani, Vahab D.; Haque, Takrima; Luchman, H. Artee; Chang, Natasha C.; Sincennes, Marie-Claude; Puram, Sidharth V.; Scott, Andrew M.; Lorimer, Ian A. J.; Perkins, Theodore J.; Ligon, Keith L.; Weiss, Samuel; Rudnicki, Michael A.; Bonni, Azad

doi:10.1038/nn.4295

Cited by 89 publications

(92 citation statements)

References 41 publications

(50 reference statements)

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“…Although small-molecule antagonists or inhibitors of the stemness signaling pathways are being explored, the promising safety profile and genetargeting specificity render siRNAs the ideal therapeutic for modifications of the TF-driven epigenetic state and for prodifferentiation approaches toward malignant BTICs. Given that pro-stemness signaling mechanisms continue to be identified via extensive BTIC epigenetics analysis (63), it is clear that there are no "be-all and endall" BTIC targets in the context of various tumorigenic genetic subclasses. Combination siRNA targeting of identifiable targets for individual tumors in a personalized fashion becomes a rational goal of therapeutic development.…”

Section: Discussionmentioning

confidence: 99%

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

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

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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 BTICtargeting 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.siRNA | lipopolymeric nanoparticle | glioblastoma transcription factor | brain tumor-initiating cells | convection-enhanced delivery G lioblastoma (GBM) is one of the most challenging tumors to treat (1, 2). Despite decades of research and maximal clinical combination therapy encompassing surgical resection, chemotherapy, and radiation, the median life expectancy of patients has not been extended beyond 2 y after diagnosis (2). Increasing evidence suggests that the genetic, epigenetic, and signaling heterogeneity of GBM underlies the ineffectiveness of currently available therapeutics (1, 2). Additionally, therapeutic schemes devised to challenge brain tumor cells are frequently thwarted by insufficient delivery caused by pharmacokinetics, the blood-brain barrier (BBB), and an altered tumor microenvironment in which tumor-derived signaling recruits immunomodulatory cells and induces extracellular matrix remodeling to build safe harbors of tumorigenic niches (3-5). These obstacles call for tailored therapeutic strategies to counter tumor heterogeneity and overcome roadblocks in delivery. RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Pro...

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Section: Discussionmentioning

confidence: 99%

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

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

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“…Four subtypes (classical, mesenchymal, neural, and proneural) of GBM have been identified by an integrated genomic analysis of human glioma samples, with EGFR initially thought to be a prominent feature of the classical subtype (Verhaak et al 2010). The complex interactive nature of wtEGFR/EGFRvIII characterizes GBM (Inda et al 2010;Fan et al 2013;Nathanson et al 2014;Furnari et al 2015;Jahani-Asl et al 2016), which we sought to understand here to improve the efficacy of anti-EGFR therapy.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Zanca

Villa

Benítez³

et al. 2017

Genes Dev.

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In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.

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“…Ki-67 positivity was used as a cellular marker of proliferation, and has been previously associated with poorer prognosis and shorter survival [19, 28, 37]. EGFR is among the most commonly altered genes in high-grade glioma, with the EGFRvIII variant observed in around 25% of cases and strongly associated with tumor aggressiveness [1, 15, 20, 27]. IDH1 mutations are observed in around 80% of low-grade or secondary high-grade gliomas and associated with more favorable prognosis [3, 44].…”

Section: Methodsmentioning

confidence: 99%

Tissue microarray analysis for epithelial membrane protein-2 as a novel biomarker for gliomas

et al. 2017

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Epithelial membrane protein-2 (EMP2) expression is noted in many human cancers. We evaluated EMP2 as a biomarker in gliomas. A large tissue microarray of lower grade glioma (WHO grades II–III, n = 19 patients) and glioblastoma (GBM) (WHO grade IV, n = 50 patients) was stained for EMP2. EMP2 expression was dichotomized to low or high expression scores and correlated with clinical data. The mean EMP2 expression was 1.68 in lower grade gliomas versus 2.20 in GBMs (P = 0.01). The percentage of samples with high EMP2 expression was greater in GBMs than lower grade gliomas (90.0 vs. 52.6%, P = 0.001). No significant difference was found between median survival among patients with GBM tumors exhibiting high EMP2 expression and survival of those with low EMP2 expression (8.38 vs. 10.98 months, P = 0.39). However, EMP2 expression ≥2 correlated with decreased survival (r = −0.39, P = 0.001). The EMP2 expression level also correlated with Ki-67 positivity (r = 0.34, P = 0.008). The mortality hazard ratio for GBM patients with EMP2 score of 3 or higher was 1.92 (CI 0.69–5.30). Our findings suggest that elevated EMP2 expression is associated with GBM. With other biomarkers, EMP2 may have use as a molecular target for the diagnosis and treatment of gliomas.

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Control of glioblastoma tumorigenesis by feed-forward cytokine signaling

Cited by 89 publications

References 41 publications

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

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

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Tissue microarray analysis for epithelial membrane protein-2 as a novel biomarker for gliomas

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