• BRAF
• Brain tumor
• Druggable pathway
• Glioma
• MAPK
• Personalized medicine
• Targeted therapy

• Humans
• Child
• Brain Neoplasms/drug therapy
• Brain Neoplasms/surgery
• Pediatrics
• Neurosurgery/methods
• Europe
• Molecular Targeted Therapy/methods
• Societies, Medical
• Neurosurgical Procedures/methods

• Università Cattolica del Sacro Cuore

• 1p/19q-codeleted
• Astrocytoma
• Chemotherapy
• Gliomas
• Isocitrate dehydrogenase type mutant
• Oligodendroglioma
• Pediatric gliomas
• Radiotherapy

• Child
• Humans
• Quality of Life
• Neurocutaneous Syndromes
• Brain Neoplasms/diagnosis
• Brain Neoplasms/therapy
• Neurology/methods
• Survivors

• AYA (adolescents and young adults)
• BRAF
• IDH mutation
• PI3K-AKT pathway
• WHO CNS5
• gliomas
• histone mutations
• targeted therapy

• Diagnostics
• Glioblastoma
• Glioma
• Next generation sequencing

• KCC2
• NKCC1
• PBT24
• SF8628
• SLC5A8
• pediatric glioblastoma
• valproic acid

• P-MIP-20-36. Lietuvos Mokslo Taryba

It is necessary to elucidate the individual effects of temozolomide (TMZ) on carcinogenesis and tumor resistance to chemotherapy mechanisms. The study aimed to investigate the TMZ 50 and 100 μM dose effect difference between PBT24 and SF8628 cell line high-grade pediatric glioblastoma (phGBM) xenografts in a chicken chorioallantoic membrane (CAM) model, on PCNA and EZH2 immunohistochemical expression in the tumor and on the expression of NKCC1, KCC2, E- and N-cadherin genes in TMZ-treated and control cell groups in vitro. TMZ at a 100 μg dose reduced the incidence of PBT24 xenograft invasion into the CAM, CAM thickening and the number of blood vessels in the CAM (p < 0.05), but did not affect the SF8628 tumor in the CAM model. The TMZ impact on PBT24 and SF8628 tumor PCNA expression was similarly significantly effective but did not alter EZH2 expression in the studied tumors. The TMZ at 50 μM caused significantly increased RNA expression of the NKCC1 gene in both studied cell types compared with controls (p < 0.05). The expression of the KCC2 gene was increased in PBT24 TMZ-treated cells (p < 0.05), and no TMZ effect was found in SF8628-treated cells. The study supports the suggestion that individual sensitivity to TMZ should be assessed when starting treatment.

• CAM
• EZH2
• KCC2
• NKCC1
• PCNA
• pediatric glioblastoma
• temozolomide

• Animals
• Antineoplastic Agents, Alkylating/pharmacology
• Apoptosis/drug effects
• Apoptosis/genetics
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Carcinogenesis/drug effects
• Carcinogenesis/genetics
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• Chickens
• Chorioallantoic Membrane/drug effects
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/genetics
• Glioblastoma/drug therapy
• Glioblastoma/genetics
• Humans
• Male
• Rats
• Temozolomide/pharmacology

Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, due in great part to treatment resistance driven by complex DNA repair mechanisms. pHGGs have recently been divided into molecular subtypes based on mutations affecting the N-terminal tail of the histone variant H3.3 and the ATRX/DAXX histone chaperone that deposits H3.3 at repetitive heterochromatin loci that are of paramount importance to the stability of our genome. This review addresses the functions of H3.3 and ATRX/DAXX in chromatin dynamics and DNA repair, as well as the impact of mutations affecting H3.3/ATRX/DAXX on treatment resistance and how the vulnerabilities they expose could foster novel therapeutic strategies.

Despite their low incidence, pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are the leading cause of mortality in pediatric neuro-oncology. Recurrent, mutually exclusive mutations affecting K27 (K27M) and G34 (G34R/V) in the N-terminal tail of histones H3.3 and H3.1 act as key biological drivers of pHGGs. Notably, mutations in H3.3 are frequently associated with mutations affecting ATRX and DAXX, which encode a chaperone complex that deposits H3.3 into heterochromatic regions, including telomeres. The K27M and G34R/V mutations lead to distinct epigenetic reprogramming, telomere maintenance mechanisms, and oncogenesis scenarios, resulting in distinct subgroups of patients characterized by differences in tumor localization, clinical outcome, as well as concurrent epigenetic and genetic alterations. Contrasting with our understanding of the molecular biology of pHGGs, there has been little improvement in the treatment of pHGGs, with the current mainstays of therapy—genotoxic chemotherapy and ionizing radiation (IR)—facing the development of tumor resistance driven by complex DNA repair pathways. Chromatin and nucleosome dynamics constitute important modulators of the DNA damage response (DDR). Here, we summarize the major DNA repair pathways that contribute to resistance to current DNA damaging agent-based therapeutic strategies and describe the telomere maintenance mechanisms encountered in pHGGs. We then review the functions of H3.3 and its chaperones in chromatin dynamics and DNA repair, as well as examining the impact of their mutation/alteration on these processes. Finally, we discuss potential strategies targeting DNA repair and epigenetic mechanisms as well as telomere maintenance mechanisms, to improve the treatment of pHGGs.

• (peri)centromere
• ATRX
• DAXX
• DNA repair
• alternative lengthening of telomere (ALT)
• chemoresistance
• chromatin dynamics
• genomic instability
• pediatric high-grade gliomas
• synthetic lethality
• telomerase
• telomere
• variant H3.3 histone

We evaluate the topographic distribution of diffuse midline gliomas and hemispheric high-grade gliomas in children with respect to their normal gene expression patterns and pathologic driver mutation patterns. We identified 19 pediatric patients with diffuse midline or high-grade glioma with preoperative MRI from tumor board review. 7 of these had 500 gene panel mutation testing, 11 patients had 50 gene panel mutation testing and one 343 gene panel testing from a separate institution were included as validation set. Tumor imaging features and gene expression patterns were analyzed using Allen Brain Atlas. Twelve patients had diffuse midline gliomas and seven had hemispheric high-grade gliomas. Three diffuse midline gliomas had the K27M mutation in the tail of histone H3 protein. All patients undergoing 500 gene panel testing had additional mutations, the most common being in ACVR1, PPM1D, and p53. Hemispheric high-grade gliomas had either TP53 or IDH1 mutation and diffuse midline gliomas had H3 K27M-mutation. Gene expression analysis in normal brains demonstrated that genes mutated in diffuse midline gliomas had higher expression along midline structures as compared to the cerebral hemispheres. Our study suggests that topographic location of pediatric diffuse midline gliomas and hemispheric high-grade gliomas correlates with driver mutations of tumor to the endogenous gene expression in that location. This correlation suggests that cellular state that is required for increased gene expression predisposes that location to mutations and defines the driver mutations within tumors that arise from that region.

• Child
• Glioma/therapy
• Humans
• Oncolytic Virotherapy
• Oncolytic Viruses/genetics

• clinical trial
• glioma
• immune microenviroment
• immunotherapy
• mouse model

• R01 NS122165 NINDS NIH HHS
• R37 NS094804 NINDS NIH HHS

• DNA damage repair
• PARP1
• XRCC1
• pediatric high-grade gliomas
• prognostic clustering

• EZH2
• PCNA
• chicken embryo chorioallantoic membrane model
• dichloroacetate
• glioblastoma
• magnesium
• sodium

• Biomarker
• Cancer
• Diagnostic marker
• Progression
• TTN-AS1
• lncRNA

• ATRX
• G34R
• HGG
• cancer
• epigenetics
• hemispheric pHGG
• pHGG
• pediatric high-grade glioma

• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/genetics
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Brain Neoplasms/pathology
• Child
• Glioma/drug therapy
• Glioma/genetics
• Glioma/pathology
• Humans
• Molecular Targeted Therapy
• Neoplasm Grading

• R37-NS094804 NINDS NIH HHS
• R01-NS105556 NINDS NIH HHS
• 1R21NS107894 NINDS NIH HHS
• R01-NS076991 NINDS NIH HHS
• R01-NS096756 NINDS NIH HHS

Glioblastoma is an aggressive and difficult to treat cancer. Recent data have emerged implicating that histone modification level may play a crucial role in glioma genesis. The histone lysine methyltransferase G9a is mainly responsible for the mono- and di-methylation of histone H3 lysine 9 (H3K9), whose overexpression is associated with a more aggressive phenotype in cancer. However, the detailed correlations between G9a and glioblastoma genesis remain to be further elucidated. Here, we show that G9a is essential for glioblastoma carcinogenesis and reveal a probable mechanism of it in cell proliferation control. We found that G9a was highly expressed in glioblastoma cells, and knockdown or inhibition of G9a significantly repressed cell proliferation and tumorigenesis ability both in vitro and in vivo. Besides, knockdown or inhibition of G9a led to a cell cycle arrest in G2 phase, as well as decreased the expression of CDK1, CDK2, Cyclin A2, and Cyclin B1, while it induced the activation of autophagy. Further investigation showed that G9a deficiency induced cell proliferation suppression, and activation of autophagy was rescued by overexpression of the full-length c-Myc. Chromatin immunoprecipitation (ChIP) assay showed that G9a was enriched on the −2267 to −1949 region of the c-Myc promoter in LN-229 cells and the −1949 to −1630 region of the c-Myc promoter in U-87 MG cells. Dual-luciferase reporter assay showed that c-Myc promoter activity was significantly reduced after knockdown or inhibition of G9a. Our study shows that G9a controls glioblastoma cell proliferation by transcriptionally modulating oncogene c-Myc and provides insight into the capabilities of G9a working as a potential therapeutic target in glioblastoma.

• G9a
• autophagy
• c-Myc
• cell proliferation
• glioblastoma

Glioblastoma multiforme is an aggressive grade IV lethal brain tumour with a median survival of 14 months. Despite surgery to remove the tumour, and subsequent concurrent chemotherapy and radiotherapy, there is little in terms of effective treatment options. Because of this, exploring new treatment avenues is vital. Brain tumours are intrinsically electrically active; expressing unique patterns of ion channels, and this is a characteristic we can exploit. Ion channels are specialised proteins in the cell’s membrane that allow for the passage of positive and negatively charged ions in and out of the cell, controlling membrane potential. Membrane potential is a crucial biophysical signal in normal and cancerous cells. Research has identified that specific classes of ion channels not only move the cell through its cell cycle, thus encouraging growth and proliferation, but may also be essential in the development of brain tumours. Inhibition of sodium, potassium, calcium, and chloride channels has been shown to reduce the capacity of glioblastoma cells to grow and invade. Therefore, we propose that targeting ion channels and repurposing commercially available ion channel inhibitors may hold the key to new therapeutic avenues in high grade gliomas.

Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

• glioblastoma multiforme
• glioma
• ion channel
• ion channel inhibitor
• membrane potential

• Clinical trials
• Epigenetic
• Kinase
• Pediatric high-grade glioma
• Therapeutics