BET inhibitors repress expression of interferon-stimulated genes and synergize with HDAC inhibitors in glioblastoma

Gusyatiner, Olga; Bady, Pierre; Pham, Minh Diêu Thanh; Lei, Yvonne; Park, Jungyeon; Daniel, Roy Thomas; Delorenzi, Mauro; Hegi, Monika E.

doi:10.1093/neuonc/noab115

Cited by 21 publications

(28 citation statements)

References 51 publications

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“…The RNA-seq data reported in Gusyatiner et al [ 6 ] served as input and was obtained in the GBM derived sphere line LN-2683GS upon treatment with 1 μM JQ1 or DMSO over a time course of 48 h with three biological replicates. Differential gene expression analysis used a model with full interaction between treatment and time (edgeR package).…”

Section: Methodsmentioning

confidence: 99%

BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression

et al. 2022

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Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of developing rational combination treatments for glioblastoma, we analyzed BETi-induced differential gene expression in glioblastoma derived-spheres, and identified 6 distinct response patterns. To uncover emerging actionable vulnerabilities that can be targeted with a second drug, we extracted the 169 significantly disturbed DNA Damage Response genes and inspected their response pattern. The most prominent candidate with consistent downregulation, was the O-6-methylguanine-DNA methyltransferase (MGMT) gene, a known resistance factor for alkylating agent therapy in glioblastoma. BETi not only reduced MGMT expression in GBM cells, but also inhibited its induction, typically observed upon temozolomide treatment. To determine the potential clinical relevance, we evaluated the specificity of the effect on MGMT expression and MGMT mediated treatment resistance to temozolomide. BETi-mediated attenuation of MGMT expression was associated with reduction of BRD4- and Pol II-binding at the MGMT promoter. On the functional level, we demonstrated that ectopic expression of MGMT under an unrelated promoter was not affected by BETi, while under the same conditions, pharmacologic inhibition of MGMT restored the sensitivity to temozolomide, reflected in an increased level of γ-H2AX, a proxy for DNA double-strand breaks. Importantly, expression of MSH6 and MSH2, which are required for sensitivity to unrepaired O6-methylguanine-lesions, was only briefly affected by BETi. Taken together, the addition of BET-inhibitors to the current standard of care, comprising temozolomide treatment, may sensitize the 50% of patients whose glioblastoma exert an unmethylated MGMT promoter.

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Section: Methodsmentioning

confidence: 99%

BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression

et al. 2022

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“…The next day 10 5 cells were transplanted stereotactically in a volume of 5 µl (Hanks’ balanced salt solution, HBBS, with phenol red, no calcium, no magnesium; Thermo Fisher Scientific) into the striatum (coordinates: bregma 0.5 mm anterior, 2 mm lateral and 3 mm ventral)[ 58 ] of male immunocompromised mice (n = 3–6/patient; age, 6–8 weeks; NOD-SCID gamma knock-out mice, NOD.Cg-Prkdcscid II2rgtm1Wjl/SzJ, bred in-house) using a micro pump (injection rate 5 µl/1 min, Stoelting). For the procedure, anesthetized mice were placed into a stereotactic frame, and fixed with a mouth piece (Stoelting) as previously described [ 19 ]. Mice were checked daily and sacrificed at first signs of neurologic symptoms (lethargy, ataxia and seizures) or body weight loss (> 10%).…”

Section: Methodsmentioning

confidence: 99%

Metabolic and transcriptomic profiles of glioblastoma invasion revealed by comparisons between patients and corresponding orthotopic xenografts in mice

Cudalbu

Bady

Lai

et al. 2021

acta neuropathol commun

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The invasive behavior of glioblastoma, the most aggressive primary brain tumor, is considered highly relevant for tumor recurrence. However, the invasion zone is difficult to visualize by Magnetic Resonance Imaging (MRI) and is protected by the blood brain barrier, posing a particular challenge for treatment. We report biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes observed in patient derived orthotopic xenografts (PDOX) in the mouse and the corresponding patients’ tumors. The evolution of metabolic changes, followed in vivo longitudinally by 1H Magnetic Resonance Spectroscopy (1H MRS) at ultra-high field, reflected growth and the invasive properties of the human glioblastoma transplanted into the brains of mice (PDOX). Comparison of MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel MRS analyses sampled across different areas of the patients’ tumors. Pathway analyses of the transcriptome associated with the metabolite profiles of the PDOX, identified molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling. Specific analysis of expression signatures from the invaded mouse brain, revealed extent of invasion dependent induction of immune response, recapitulating respective signatures observed in glioblastoma. Integrating metabolic profiles and gene expression of highly invasive PDOX provided insights into progression and invasion associated mechanisms of extracellular matrix remodeling that is essential for cell–cell communication and regulation of cellular processes. Structural changes and biochemical properties of the extracellular matrix are of importance for the biological behavior of tumors and may be druggable. Ultra-high field MRS reveals to be suitable for in vivo monitoring of progression in the non-enhancing infiltration zone of glioblastoma.

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“…Another recent research investigated RNA expression of GBM-derived sphere-line treated with the BET inhibitor JQ1. The inhibition of BET resulted in a significant modulation of genes responding to Interferon-alpha (enhanced in about 50% of GBM) through a direct transcriptional inhibition more than interference to the JAK (Janus Kinase) -STAT (Signal transducer and activator of transcription) pathway ( 39 ).…”

Section: Immune Cells and Glioblastomamentioning

confidence: 99%

“…These two factors act through proteins belonging to the BET family. To date, BET inhibitors have been assessed on phase I trials with more of them showing a safety profile (39)(40)(41)(42)(43)(44)(45)(46)(47). A further investigation of these agents could be important for patients with GBM.…”

Section: Targeting the Microenvironment In Glioblastomamentioning

confidence: 99%

Glioblastoma Microenvironment: From an Inviolable Defense to a Therapeutic Chance

Nunno¹,

Franceschi

Tosoni

et al. 2022

Front. Oncol.

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Glioblastoma is an aggressive tumor and is associated with a dismal prognosis. The availability of few active treatments as well as the inexorable recurrence after surgery are important hallmarks of the disease. The biological behavior of glioblastoma tumor cells reveals a very complex pattern of genomic alterations and is partially responsible for the clinical aggressiveness of this tumor. It has been observed that glioblastoma cells can recruit, manipulate and use other cells including neurons, glial cells, immune cells, and endothelial/stromal cells. The final result of this process is a very tangled net of interactions promoting glioblastoma growth and progression. Nonetheless, recent data are suggesting that the microenvironment can also be a niche in which glioblastoma cells can differentiate into glial cells losing their tumoral phenotype. Here we summarize the known interactions between micro-environment and glioblastoma cells highlighting possible therapeutic implications.

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BET inhibitors repress expression of interferon-stimulated genes and synergize with HDAC inhibitors in glioblastoma

Cited by 21 publications

References 51 publications

BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression

BET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression

Metabolic and transcriptomic profiles of glioblastoma invasion revealed by comparisons between patients and corresponding orthotopic xenografts in mice

Glioblastoma Microenvironment: From an Inviolable Defense to a Therapeutic Chance

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