Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit

Groves, Andrew; Cooney, Tabitha

doi:10.3389/fcell.2022.1089898

Cited by 4 publications

(2 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other epigenetic targets that are currently being tested in preclinical and phase 1 clinical studies as diagnostic biomarkers or therapeutic targets in paediatric brain cancers include DNMT, LSD1, lysine methyltransferase and bromodomain and extra‐terminal (BET) protein inhibitors. 131 Of these, BET inhibitors used in combination with other molecular inhibitors such as tazemetostat (EZH2 inhibitor), 132 CREB‐binding protein inhibitor 133 or NOTCH pathway inhibitor MRK‐003 134 have shown promising therapeutic outcomes in in vitro and in vivo pHGG models. Currently, a phase 1 clinical trial of BET inhibitors (BMS‐986158 and BMS‐986378) is underway to determine its safety and pharmacokinetic profile in children with primary or relapsed brain cancer (NCT03936465).…”

Section: Targeting Epigenetic Alterations: Alternative Diagnostic And...mentioning

confidence: 99%

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma

Johns,

Williams,

Smith

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

Paediatric and adult astrocytomas are notably different, where clinical treatments used for adults are not as effective on children with the same form of cancer and these treatments lead to adverse long‐term health concerns. Integrative omics‐based studies have shown the pathology and fundamental molecular characteristics differ significantly and cannot be extrapolated from the more widely studied adult disease. Recent clinical advances in our understanding of paediatric astrocytomas, with the aid of next‐generation sequencing and epigenome‐wide profiling, have led to the identification of key canonical mutations that vary based on the tumour location and age of onset. These driver mutations, in particular the identification of the recurrent histone H3 mutations in high‐grade tumours, have confirmed the important role epigenetic dysregulations play in cancer progression. This review summarises the current updates of the classification, epidemiology, pathogenesis and clinical management of paediatric astrocytoma based on their grades and the ongoing clinical trials. It also provides novel insights on genetic and epigenetic alterations as diagnostic biomarkers, highlighting the potential of targeting these pathways as therapeutics for this devastating childhood cancer.

show abstract

Section: Targeting Epigenetic Alterations: Alternative Diagnostic And...mentioning

confidence: 99%

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma

Johns,

Williams,

Smith

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

“…While direct therapeutic targeting of H3K27M has not been possible, targeting of epigenetic and transcription regulators has shown promise in several pre-clinical models of DMG (reviewed in [15,16]). Among these regulators, the histone chaperone Facilitates Chromatin Transcription (FACT) comprising of two protein subunits; SSRP1 and SPT16, has garnered attention [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Chromatin remodeling with combined FACT and BET inhibition disrupts oncogenic transcription in Diffuse Midline Glioma

Holliday,

Khan,

Ehteda

et al. 2024

Preprint

View full text Add to dashboard Cite

Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategies against this highly aggressive cancer. One such target is the Facilitates Chromatin Transcription (FACT) histone chaperone. We found FACT to be enriched at developmental gene promoters, coinciding with regions of open chromatin and binding motifs of core DMG regulatory transcription factors. Furthermore, FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4 at promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG.In vitro, a combinatorial therapeutic approach using the FACT inhibitor CBL0137, coupled with BET inhibition revealed potent and synergistic cytotoxicity across a range of DMG cultures, with H3K27M-mutant cells demonstrating heightened sensitivity. These results were recapitulatedin vivo, significantly extending survival in three independent orthotopic PDX models of DMG. Mechanistically, we show that CBL0137 treatment decreased chromatin accessibility, synergizing with BET inhibition to disrupt transcription, silencing several key oncogenes includingMYC, PDGFRAandMDM4, as well as causing alterations to the splicing landscape. Combined, these data highlight the therapeutic promise of simultaneously targeting FACT and BRD4 in DMG, proposing a novel strategy for combating this devastating pediatric brain tumor.

show abstract

Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma—Recent Advances

Kowalczyk,

Zarychta,

Marszołek

et al. 2024

Cancers

View full text Add to dashboard Cite

High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with HGG is the surgical resection of the tumor combined with chemotherapy and radiotherapy. Despite intensive treatment, the 5-year overall survival in pediatric patients is below 20–30%. This rate is even lower for the most common HGG in adults (glioblastoma), at less than 5%. It is, therefore, essential to search for new therapeutic methods that can extend the survival rate. One of the therapeutic options is the use of immune cells (T lymphocytes/natural killer (NK) cells) expressing a chimeric antigen receptor (CAR). The objective of the following review is to present the latest results of preclinical and clinical studies evaluating the efficacy of CAR-T and CAR-NK cells in HGG therapy.

show abstract

Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit

Cited by 4 publications

References 75 publications

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma

Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma

Chromatin remodeling with combined FACT and BET inhibition disrupts oncogenic transcription in Diffuse Midline Glioma

Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma—Recent Advances

Contact Info

Product

Resources

About