Pediatric and adult histone altered tumors …

General Child Neurology

Updated 04.29.2025
Released 10.24.2021
Expires For CME 04.29.2028

Pediatric and adult histone altered tumors

Authors: Jigisha Thakkar MD, Michelle Seu MD MS, Diego D Luy MD, Vikram C Prabhu MD

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Editor: Rimas V Lukas MD

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Pediatric and adult histone altered tumors

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Introduction

Overview

Pediatric and adult diffuse gliomas harboring histone alterations potentially comprise a variety of subtypes of gliomas. A subgroup of diffuse midline gliomas harboring the H3K27M mutation was previously classified as brainstem gliomas or diffuse intrinsic pontine gliomas. The proposed cell of origin for these tumors is the neural precursor-like cell in the ventral pons expressing nestin and OLIG-2 (63). There are other high-grade tumors baring the same, as well as other, histone alterations. The most common locations are brainstem, thalamus, and spinal cord (61). Patient age and specific histone alterations are associated with neuroanatomic location.

In the 2007 World Health Organization classification of central nervous system tumors, diffuse intrinsic pontine glioma was not yet defined as a separate entity. It was classified and graded according to the definition criteria of supratentorial diffuse gliomas (62). The 2016 WHO classification of CNS tumors identified H3K27M-mutant diffuse midline glioma as a unique entity with distinct clinical behavior and molecular features. This CNS tumor is a diffuse (infiltrating) glioma with predominantly astrocytic differentiation and a K27M mutation in either the H3F3A or HIST1H3B/C genes (63). The 2021 WHO classification of CNS tumors further modified the classification of gliomas (64). Adult and pediatric gliomas were independently categorized. Pediatric diffuse gliomas were then separated into prognostically and biologically distinct groups (pediatric high- and low-grade glioma). High-grade pediatric gliomas were further classified into biologically distinct groups, largely based on alteration in the histone genes (Table 1). The histone-altered tumors were placed into two categories (diffuse midline glioma H3K27-altered, diffuse hemispheric glioma H3G34-mutant) in the pediatric-type diffuse high-grade glioma group, although they occur in adults as well. Nomenclature was revised to “diffuse midline glioma, H3K27-altered” because there are now four subtypes of diffuse midline glioma that are defined by the driving oncohistone alteration: (1) H3.3 p.K28M (K27M)-mutant, (2) H3.1 or 3.2 p.K28M (K27M)-mutant, (3) H3-wildtype with EZHIP overexpression, and (4) EGFR-mutant (81).

Table 1. 2021 WHO Classification of Pediatric Diffuse High-Grade Glioma and Key Diagnostic Genes, Molecules, Pathways, or Combinations

Pediatric-type diffuse high-grade gliomas	Genes/Molecular Profiles Characteristically Altered
Diffuse midline glioma, H3K27 altered	H3K27, TP53, ACVR1, PDGFRA, EGFR, EZHIP overexpression
Diffuse hemispheric glioma, H3G34-mutant	H3G34, TP53, ATRX
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	IDH-wildtype, H3-wildtype, PDGFRA, MYCN, EGFR (methylome)*
Infant-type hemispheric glioma	NTRK family, ALK, ROS, MET
Abbreviations: WHO, World Health Organization; IDH, isocitrate dehydrogenase; ATRX, alpha thalassemia or mental retardation syndrome X-linked; EGFR, epidermal growth factor receptor; PDGFRA, platelet-derived growth factor receptor alpha; TP53, tumor protein p53; ACVR1, activin a receptor type 1; EZHIP, EZH inhibitory protein; ALK, anaplastic lymphoma kinase; NTRK, neurotrophic tyrosine receptor kinase gene fusion. * methylome testing offers particular diagnostic guidance From: (64)

Key points

	• Pediatric diffuse gliomas are separated into prognostically and biologically distinct groups.
	• High-grade pediatric gliomas were further classified into biologically distinct groups, largely based on alteration in the histone genes.
	• Tumors with these histone aberrancies occur in adults as well and have some unique features in that patient population

Clinical manifestations

Presentation and course

	• Neurologic symptoms vary based on the involvement of midline structures.
	• H3K27M mutant diffuse midline gliomas are more common in children than adults.
	• There is no gender preponderance, but girls may have worse prognosis than boys.

Symptoms vary based on involvement of different midline structures and generally develop over 1 to 2 months (63; 31; 80). Cranial neuropathies can cause expected symptomatology: diplopia, ptosis, facial pain or numbness, facial palsy, tinnitus, hearing loss, vertigo, dysarthria, and dysphagia. Involvement of motor and sensory pathways causes weakness, hypoesthesia, hyperesthesia, and gait abnormalities. High CSF pressure causes headache, nausea, and vomiting. Other CNS symptoms may include seizures and persistent hiccups.

H3K27M mutant diffuse midline gliomas have an incidence rate of 0.06 per 100,000 population and a median diagnosis age of 14 years (75). H3K27M mutant diffuse midline gliomas have been extensively described in children and are less frequently seen in adults (92). In children, H3K27M-mutant gliomas occur frequently within the brainstem, particularly the pons, whereas in adults they occur more frequently within the thalamus and spinal cord. Rare adult cases have been reported in the corpus callosum, hypothalamus, pineal region, basal ganglia, and third ventricle. They primarily occur at a median age of 7 years (5 to 11 years) in the pons and 24 years in the thalamus. In adults, the median age at diagnosis is 32 years old (range 18–82 years). There is no gender preponderance, though newer studies suggest that among those with diffuse midline glioma, girls have a worse prognosis than boys (23; 51).

In a retrospective study of adult midline gliomas, the H3K27M mutation was identified in 15% of cases (89). In this series, the most common midline locations for H3K27M-mutated tumors were midbrain, pons, and cerebellum. In the pediatric population, this mutation is identified in approximately 27% of gliomas (71).

Meanwhile, H3K27M mutations are observed much less frequently in diffuse non-midline gliomas. In a 2024 retrospective review of both diffuse midline and non-midline gliomas, only two of 51 total patients (18 children and 33 adults) had tumors with a non-midline location; these non-midline gliomas also seemed more frequently associated with PDFGRA mutations (47). Furthermore, H3G34-mutant diffuse hemispheric gliomas are reported to occur in less than 1% of all gliomas and in 15% of high-grade gliomas. The median age at diagnosis is 15.8 years, with a male to female ratio of 1.46:1, and they are commonly located in the frontal lobe (22).

Prognosis and complications

H3K27M-mutant midline gliomas are associated with poor prognosis despite timely and optimal treatment and are designated as a grade 4 entity in the 2016 WHO Classification (63). The rate of leptomeningeal metastases is 40% (14).

Overall survival is typically 7 to 11 months in children and 8 to 28 months in adults (92; 109). Overall survival with standard care is slightly longer in adults with these tumors compared to adult patients with IDH wildtype glioblastoma but shorter compared to patients with WHO grade 4 IDH-mutant astrocytomas (65). K27M mutation is a significant independent prognostic marker for poor outcome among pediatric glioblastomas (56). Furthermore, as compared to H3.1K27M mutation, H3.3K27M mutation is associated with shorter survival, higher metastatic relapses, and poorer response to radiotherapy (104; 18). However, there is heterogeneity in the behavior of gliomas with H3K27M mutations. Prognosis for circumscribed gliomas or thalamic or diffuse non-midline gliomas with H3K27M mutations remains less certain (78).

H3K27M mutation significantly influences prognosis in children, but its relationship to prognosis is less clear in adults (69; 32; 34). Tumor protein 53 (TP53) mutations were associated with high-grade histology and shorter survival in non-pediatric H3K27M diffuse midline gliomas (52).

Patients with NF1-associated high-grade midline gliomas (H3K27M-mutant and non-histone mutant) have extremely poor prognosis (PFS: 3 months, OS: 5–7 months), worse than high-grade gliomas developing in non-NF1 patients (PFS: 6 months, OS: 10–11 months) (40). Notably, in an MR imaging analysis of 30 pediatric patients with constitutional mismatch repair deficiency (CMMRD) syndrome, such patients were more likely to present with diffuse hemispheric high-grade gliomas associated with multiple developmental venous anomalies, cavernomas, and “NF1-like” or subcortical high T2-FLAIR signal intensities (86).

Enhancer of zeste homolog 2 (EZH2) overexpression plays an oncogenic role in various solid malignancies and is a poor prognostic factor in glioma (108). H3K27M mutation, high EZH2 expression, and low P16 expression are associated with high-grade midline gliomas and poor median survival (34). Low-grade midline gliomas have high H3K27me3 expression and low membrane-associated transporter protein (MATP) protein expression (34). EZH2 overexpression and consequently greater EZH2-regulated poly ADP-ribose polymerase (PARP-1) expression may modulate chemoresistance of gliomas to temozolomide (59).

Patients with H3G34-mutant gliomas have a better prognosis than H3K27M mutant tumors. Median time to progression is approximately 10 months, median overall survival is approximately 17 months, and median time from progression to death is approximately 5 months (22). The 1-, 2-, and 3-year survival estimates are 70%, 39%, and 21%. Survival was better in patients over 18 years old who underwent near or gross-total resection. G34V-mutant tumors had significantly worse overall survival when compared to G34R-mutant tumors (22; 99). Many patients were noted to have distant recurrence (26%).

A retrospective study of H3K27-altered diffuse midline gliomas or H3G34-mutant diffuse hemispheric glioma found a higher risk of developing leptomeningeal disease in each of these subgroups (30). In this study, median time from tumor diagnosis to leptomeningeal disease was 12.9 months for H3K27 patients and 5.6 months for H3G34-mutant patients.

Our understanding of the impact of various molecular biomarkers in these rare CNS tumors continues to evolve. It is likely that some of the markers discussed will help codify specific subgroups of tumors and others will fall by the wayside.

Biological basis

	• Frequency of isocitrate dehydrogenase (IDH) mutation in the midline region has been reported to be low.
	• Supratentorial high-grade gliomas have mutations in H3F3A (located on chromosome 1q) encoding histone H3.3
	•Specific mutations are seen in different brain locations (G34R/V restricted to hemispheric tumors and K27M occurring in the midline).

Etiology and pathogenesis

Frequency of IDH mutation in the midline region has been reported to be low (94).

H3K27M-mutant gliomas are IDH-wildtype, lack 1p/19q co-deletion, and are defined by the presence of K27M mutation in the H3F3A or HIST1H3B/C genes, which encode the histone H3 variants H3.3 and H3.1 in both children and adults (92). These histone mutations are mutually exclusive from the other common mutations that define distinct infiltrating glioma types.

Histones are basic nuclear proteins responsible for the nucleosome structure within eukaryotic cells. Among the five classes of histones, some are expressed only during the S phase, whereas others are replacement histones that are replication-independent and expressed in quiescent or terminally differentiated cells.

Supratentorial high-grade gliomas have mutations in H3F3A (located on chromosome 1q) encoding histone H3.3. H3.3 is a replacement histone subclass that is encoded by two distinct genes, H3.3A (H3F3A) and H3.3B. This leads to the creation of oncohistones.

Oncohistones in high-grade gliomas have specific associated mutations and brain locations. G34R/V is restricted to hemispheric tumors, whereas K27M occurs in the midline (94; 104; 21). K27M mutations occur in two main histone variants H3.3 and H3.1 and result in lysine to methionine exchange at position 27 of H3F3A or HIST1H3B/C genes. G34 mutations of H3.3 result in glycine to arginine exchange at codon 34 of H3F3A (104).

At the most basic level, K27M mutation impairs normal development by halting cellular differentiation (49). Over 85% of diffuse midline glioma tumors have a K27M mutation in histone genes that drives abnormal growth (67).

The H3K27M-mutated midline gliomas are further divided into two subgroups, H3.1 K27M and H3.3 K27M (18).

H3.3 K27M mutation. H3.3 K27M mutation occurs at the median age of 7.5 years. Patients with this mutation have a poor prognosis and frequent leptomeningeal dissemination; they are more likely to have an oligodendroglial histologic phenotype, poor response to radiation, and median survival of 9 months (21). H3.3 K27M mutant pediatric high-grade glioma are enriched for PDGFRA amplification (94). These tumors are seen all over the midline structures (18). Approximately 20% of tumors previously categorized as pediatric glioblastomas harbor this mutation (42). The H3.3 K27M mutation suppresses serine 31 phosphorylation and mitotic fidelity, thus, elucidating a potential mechanism through which this mutation directly drives gliomagenesis (25).

H3.1 K27M mutation. H3.1 K27M mutation occurs at the median age of 5.5 years. Patients with this mutation are likelier to have an astroglial differentiation, a good response to radiation, and a median survival of 15 months (21). H3.1 K27M tumors are associated with ACVR1 mutations (07). These tumors are almost exclusively found in the pons (18).

H3K27M-mutant diffuse midline gliomas frequently share genetic alterations, including tumor protein 53 (TP53) overexpression, alpha-thalassemia/mental retardation X-linked (ATRX) loss, monosomy 10, activin A receptor type 1 (ACVR) mutation, poly ADP-ribose polymerase (PARP1) overexpression, cyclin D1-3(CCND1-3), and cyclin-dependent kinase (CDK4/CDK6) mutations (92; 31). TP53 mutations occur in about 40% of diffuse intrinsic pontine gliomas and represent the second most frequent mutation, correlated with worse overall survival (14).

H3K27M mutation is mutually exclusive or rarely co-occurs with IDH1 mutation, telomerase reverse transcriptase (TERT) promoter mutation, epidermal growth factor receptor (EGFR) amplification, and BRAF-V600E mutation (92; 69; 31). Prototypic alterations of adult primary glioblastoma IDHwt (eg, EGFR amplification, CDKN2A/B homozygous deletions, PTEN mutations) are rarely seen in childhood (94; 56). Meanwhile, O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation is found in 75% of G34-mutant subtype tumors and in 3% of K27 mutant tumors (56; 69).

Molecular profiling has revealed differences between adult and pediatric H3K27M-mutant diffuse midline gliomas. Higher frequencies of ATRX loss and H3.3 mutation are found in adult than in pediatric H3K27M-mt diffuse midline gliomas (109). TERT promoter mutations and O6-methylguanine DNA methyltransferase promoter methylation were not detected in pediatric patients but are present in a few adult patients.

H3K27 wild type occurs at a median age of 6 years, with a median survival of 9 months (21). These tumors have recurrent and mutually exclusive mutations in either ACVR1 or EGFR and are characterized by high expression of EZHIP associated to its promoter hypomethylation (01). Prognosis is poor, similar patients with H3K27M midline glioma.

Diffuse glioma, H3.3 G34-mutant are a distinct grade 4 entity described in the WHO 2021 classification (64). H3G34-mutant diffuse hemispheric glioma was first described in 2012. Point mutations in the H3F3A gene, encoding for the histone variant H3.3, result in amino acid substitution at codon 34 from either glycine-to-arginine (G34R) or, more rarely, glycine-to-valine (G34V) (22). Co-occurring molecular alterations include ATRX mutation in 93%, TP53 mutation in 88%, PDGFA point mutation in 45%, PDGFRA amplification in 11%, and MGMT promoter methylation in 70% (99).

Diagnostic workup

Diagnosis is made with both imaging and histologic confirmation. Radiographic criteria alone are used for tumors with midline locations associated with serious procedural complications (48). Imaging primarily includes a brain MRI with and without gadolinium contrast administration. MRI abnormalities include diffuse, T2 expansile signal changes in the midline structures.

High-grade midline glioma (MRI) (1)

MRI of a patient with H3K27M mutant midline glioma. (1A) Brain MRI axial view post gadolinium contrast with heterogenous enhancement in the pons. (1B) Brain MRI T2 flair sequence with expansile hyperintensity in the pons withou...
High-grade midline glioma (MRI) (2)

MRI of a patient with H3K27M-mutant midline glioma. (2A) Brain MRI axial view, post gadolinium contrast with heterogenous enhancement in the left thalamus. (2B) Brain MRI T2 flair sequence with expansile hyperintensity in the l...

In most cases, little or no enhancement is noted after the administration of gadolinium at initial diagnosis. Occasionally, areas of necrosis with surrounding serpiginous contrast enhancement can be present. A retrospective study that characterized imaging features of 24 diffuse midline gliomas found distinguishing features in H3K27-mutant midline gliomas as compared to their H3wild-type counterparts (07). In H3K27-mutant gliomas, there was an absence of perilesional edema at low frequency of strong contrast enhancement. Contrast enhancement of intermediate or higher and rim enhancement was associated with microscopically detected microvascular proliferation. Necrosis on MRI is less frequently seen than in the H3wt high-grade midline gliomas (07). H3G34 tumors demonstrate contrast enhancement and diffusion restriction on MRI. Artificial intelligence applications have been increasingly used to enhance diagnostic accuracy (radiographically and genetically) and prognosticate various forms of glioma (35; 58).

PET imaging with amino acid tracers, such as 18-F-dihydroxy-phenylalanine (F-DOPA) is able to discriminate H3K27M-mutant from wild-type diffuse midline gliomas and has demonstrated correlation of higher tracer uptake with worse prognosis (110; 82).

Traditional WHO grading for diffuse intrinsic pontine gliomas was not prognostic. Outcomes for grade 2, 3, and 4 tumors are equally poor (14). Next-generation sequencing can help accurately classify these tumors, improve understanding of unique tumor biology, and provide important insights into prognosis and management (11; 101). Reports have shown that biopsy of these tumors is safe (48). Modern neuronavigation tools allow accurate 3D localization of deep structures in the brain and identification of major vessels prior to surgery, which greatly minimizes surgical complications (48). Within just the past several years, various multi-institutional trials have published invaluable data on the feasibility of large-scale targeted trials regularly involving biopsies (91).

Once tissue is obtained, both the macroscopic and microscopic evaluation can provide insight into the underlying disease. Macroscopically, these tumors cause enlargement and distortion of anatomical structures by diffuse infiltration. Microscopically, they typically have an astrocytic morphology or an oligodendroglial pattern. Mitotic activity is present in most cases but is not necessary for diagnosis (63). Features such as microvascular proliferation and necrosis may be seen. Immunohistochemistry reveals expression of neural cell adhesion molecule 1 (NCAM1), S100, oligodendrocyte transcription factor 2 (OLIG2) on tumor cells (63). Microtubule-associated protein 2 (MAP2) expression is also common. Immunoreactivity of glial fibrillary acidic protein (GFAP) is variable, and synaptophysin can be focal. Chromogranin A and neuronal nuclei (NeuN) are not typically expressed (63).

Biopsy carries the risk of neurologic injury due to anatomical location of midline gliomas. Minimally invasive techniques like liquid biopsy to detect biomarkers of H3K27M in CSF, blood, and urine for diagnosis and monitoring treatment response are under investigation (15). CSF is a particularly valuable source of biomarkers, as it contains a higher concentration of tumor-derived circulating tumor DNA (ctDNA) as well as histone dimers and tetramers that can aid analysis of a tumor’s mutational profile (105). Two secreted proteins, cyclophilin A (CypA) and dimethylarginase 1 (DDAH1), are upregulated in CSF samples from patients with diffuse intrinsic pontine gliomas (88). Detecting tumor-derived circulating tumor DNA (ctDNA) from CSF samples can help with analysis of the tumor’s mutational profile. However, obtaining CSF entails performing a lumbar puncture, a procedure that comes with unique risks and benefits that should be weighed on an individualized basis.

Management

Anatomic location of the tumor severely limits any opportunity for meaningful surgical resection. Radiation remains the mainstay of treatment and usually consists of standard fractionated radiation to a dose of 54-59Gy (over 30 fractions) (21).

Photon-based radiotherapy to a range of 54 to 59.4 Gy given in 30 to 33 fractions of 1.8 Gy daily for 6 weeks, as well as hypo-fractionated radiation (39 to 45 Grays given in 13 fractions of 3.0 Grays over 3 to 4 weeks), has been utilized with similar survival rates (73; 53; 106). In recent years, the evolution of radiation therapy has largely revolved around optimizing modes of delivery, exploring synergistic effects of radiation in combination with other therapies, and better characterizing the inflammatory response of the tumor immune microenvironment (06; 77; 39).

Monotherapy and combination chemotherapy have also been trialed but with uniformly poor results (46; 97). Temozolomide has limited value in treating pediatric H3K27M-mutant gliomas, likely due to the higher likelihood of unmethylated MGMT variants (20; 87). It is still often used in the treatment of adult tumors. It is likely that the pivotal trials that established the standard of care for adult high-grade gliomas included histone mutated tumors, although this was not specifically evaluated. Pre-radiation chemotherapy has shown improvement in overall survival and progression-free survival in a small series of patients (100; 43), although how to best interpret these data in the current WHO 2021 era is uncertain. In a series of adult patients, surgery was followed by concurrent radiation and temozolomide and, subsequently, maintenance temozolomide (90). At recurrence, a combination of re-radiation, bevacizumab, and lomustine were utilized, similar to what is typically used in recurrent glioblastoma IDHwt. Median survival benefit after re-irradiation (30 to 36 Grays) for recurrent disease ranges from 3 to 4 months (54; 16). H3G34 mutant tumors have a higher frequency of MGMT methylation and are, thus, treated like IDH wild-type glioblastoma (24).

Future directions

Novel ongoing treatment trials include convection-enhanced therapies, targeted therapies, and immunotherapy (eg, vaccine therapies, CAR-T cells).

Convection-enhanced delivery. Convection-enhanced delivery is a therapeutic strategy that allows for targeted treatment of a specific region via a stereotactically placed cannula and hydraulic syringe pump, which allows for direct intraparenchymal infusion of drugs via a pressure gradient. Not only does this method allow for relatively safe and homogeneous drug delivery, but it can also be monitored in real time using MR perfusion imaging (57). Some studies have shown safe placement of convection-enhanced delivery catheters into the brainstem in humans (93). However, the anatomic location, characteristics of the surrounding brain parenchyma, and size of the tumor itself can influence the success of this technique as the treatment field must cover the entire tumor area and maintain an effective pressure gradient to ensure proper drug delivery (03).

Immunotherapy.

Peptide-based vaccine therapy. Glioma-associated antigens interleukin-13 receptor alpha 2 (IL-13Rα2), EphA2, and survivin are commonly overexpressed in pediatric gliomas (74). A pilot study of subcutaneous vaccination with glioma-associated antigen epitope peptides in HLA-A2-positive children with newly diagnosed brainstem and high-grade gliomas was well tolerated and has preliminary evidence of immunologic and clinical responses (85).

Dendritic cell vaccines. Dendritic cell vaccines work by way of dendritic cells taking up peptides from glioma-associated antigens and presenting them on their surface with major histocompatibility complex molecules, thus, leading to the reactivation of tumor-specific T cells (02). Autologous dendritic cell vaccines can be safely administered by intradermal injection and have been used to generate a diffuse intrinsic pontine glioma-specific immune response detected in peripheral blood mononuclear cells and CSF (10).

A 2023 compassionate use study demonstrated the safety and immunogenicity of the first-in-human treatment of progressive H3K27M diffuse midline glioma with a H3K27M-specific long peptide vaccine (44). In this study, eight patients received the long peptide vaccine, resulting in CD4+ T cell-dominated mutation-specific immune responses, as well as a median overall survival after vaccination of 12.8 months.

Chimeric antigen receptor-modified (CAR)T cells targeting disialoganglioside (GD2)-GD2-CART. GD2 is highly expressed in H3K27M-mutant glioma cells. Preclinical studies have demonstrated GD2 as a novel immunotherapy target in H3K27M mutant diffuse midline gliomas, and antitumor efficacy of GD2-CAR T-cells delivered systemically (72). The first-in-human phase I clinical trial included four patients with H3K27M-mutant diffuse intrinsic pontine glioma or diffuse midline glioma treated with GD2-CAR T cells administered intravenously, with subsequent intraventricular infusions (66). GD2-CAR T therapy produced toxicities that were largely related to tumor location and reversible with intensive supportive care. Radiographic response was seen in three patients but was not durable. Proinflammatory cytokines were increased in plasma and CSF. In another phase 1 trial of nine patients with H3K27M-mutant diffuse midline gliomas who received intravenous doses of autologous GD2-CART following lymphodepleting chemotherapy, all patients had neurologic improvement (70). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91%, and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrollment. BrainChild-03, a phase 1 trial of repetitive intracerebroventricular dosing of B7-H3-targeting chimeric antigen receptor T cells for 21 children with recurrent or refractory CNS tumors and diffuse midline gliomas, showed tolerability and clinical efficacy (98).

Oncolytic virotherapy. Oncolytic viruses (eg, herpes simplex virus, adenovirus, poliovirus, reovirus, parvovirus, among others) have emerged as feasible tumoricidal agents in the treatment of both diffuse midline gliomas and high-grade gliomas (50). A single-center trial of newly diagnosed pediatric patients with diffuse intrinsic pontine glioma who underwent oncolytic viral therapy (DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells) followed by radiation revealed changes in T-cell activity and stabilization to the reduction of tumor size (38). Adverse events related to virotherapy were largely grade 1 or grade 2, with only one event of grade 3 and no grade 4 or 5 events (38). Oncolytic adenovirus Delta-24-RGD in combination with ONC201 was found to elicit potent antitumor responses in both in vitro and mouse models of diffuse midline gliomas and high-grade gliomas (26). Overall, the greatest obstacles for the widespread implementation of peptide-based vaccine therapies have to do with the lack of standardized guidelines to evaluate vaccine responses in these regimens, as well as the therapeutic resistance posed by tumor heterogeneity and immune evasion mechanisms (26). Other ongoing investigations for diffuse midline gliomas include neo-antigen heat shock protein vaccine (rHSC-DIPGVax) in combination with checkpoint blockade for treatment (12).

Targeted therapies. K27M mutation drives gliomagenesis by alteration of an important site of posttranslational modification in the histone H3 variants and leads to altered DNA methylation and gene expression profiles (94; 09). Ongoing efforts aim to study the efficacy of therapeutics targeting histone-modifying enzymes for midline gliomas with histone H3 mutations (55; 102).

Panobinostat. Panobinostat is a general histone deacetylase inhibitor that has shown good in vitro efficacy against diffuse intrinsic pontine gliomas (45; 83). Panobinostat synergizes with histone demethylase inhibitor GSKJ4 in H3.3K27M mutant diffuse intrinsic pontine gliomas cells (45). Together, these data suggest a promising therapeutic strategy for diffuse intrinsic pontine gliomas. Compassionate use of panobinostat in four adult patients with H3K27M-mutant glioma revealed good tolerability without any serious adverse effects (60). Infusions of the water-soluble formulation of panobinostat (MTX110) directly into the tumor using an implantable subcutaneous pump connected with a catheter directly implanted into the pons showed safety and feasibility as well as a favorable trend in overall survival in a phase 1 study of patients with diffuse midline glioma (95). However, there is still much to explore within the context of preclinical models. For example, HDAC inhibitors (eg, panobinostat, vorinostat, entinostat, and pyroxamide) in concert with carbonic anhydrase 9 (CA9) inhibitors have shown therapeutic potential in preclinical models of diffuse intrinsic pontine gliomas (37).

ONC201 (dordaviprone). ONC201 is a small-molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) that crosses the blood-brain barrier and exhibits P53 independent anticancer efficacy. DRD2 expression within the central nervous system is highest in midline structures of the brain. DRD2 is a G protein-coupled receptor that promotes tumor growth and has emerged as a therapeutic target for gliomas that overexpress this receptor (17). H3K27M-mutant diffuse midline gliomas have been reported to exhibit elevated expression and dependency on DRD2 as a downstream epigenetic consequence of the mutation (19). It has an exceptional safety profile and has been reported to have clinical and radiographic responses in both recurrent and frontline settings (19; 29). ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3K27M-mutant diffuse midline gliomas in an integrated analysis (04). The use of data amalgamated from three different clinical trials and an expanded access program with a focus only on a subset of the patients in that cohort for efficacy endpoint analysis makes interpretation of the data complex and difficult. The overall response rate (RANO-HGG) was 20.0%, the median time to response was 8.3 months (range: 1.9 to 15.9), and the median duration of response was 11.2 months. Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue, and no grade 4 TR-TEAEs, deaths, or discontinuations occurred. The FDA has received a new drug application for ONC201 seeking its accelerated approval for the treatment for patients with recurrent H3K27M-mutant diffuse gliomas. An international phase 3 randomized, double-blind, placebo-controlled study (ACTION study) is currently evaluating the benefit of ONC201 after frontline radiation on overall survival and progression-free survival (05).

ONC206 is another drug in the same class actively undergoing investigation (107).

Cdk4/6 inhibitors. CDK alterations are described in about 30% to 40% of diffuse midline gliomas. Cdk4/6 inhibitors (palbociclib, ribociclib, and abemaciclib), tyrosine kinase inhibitors, and other agents that more specifically target these mutations are being explored in patients with diffuse midline gliomas (28; 96; 79). Other potential therapeutic targets tested with in vivo studies include bromodomain and extraterminal (BET) bromodomain inhibitors alone or in combination with other classes of drugs to exploit synergistic effects (83).

mTOR inhibitors. PI3K/AKT/mTOR pathway is dysregulated in more than 50% of diffuse midline gliomas. A single-center study from Italy reported significant benefit in overall survival with utilization of personalized treatment based on tumor molecular alterations. mTOR inhibition with everolimus was associated with the best overall survival (27).

EGFR inhibitors. EGFR is overexpressed in 80% to 85% of high-grade gliomas. Anti-EGFR therapies have shown limited benefit in small subsets of patients (13; 41; 84; 08; 33). A phase 3 trial of concomitant radiation and outpatient nimotuzumab (IgG1 antibody that targets EGFR) was feasible, with survival outcomes similar to radiation therapy and intensive chemotherapy in a hospitalized setting (36). Another phase 2 trial of nimotuzumab with concomitant radiation and vinorelbine revealed a median overall survival of 15 months (68). Nimotuzumab-vinorelbine and similar combination therapies have been increasingly investigated and compared against the outcomes of more conventional regimens (76; 103).

Multiple phase I and II trials are currently ongoing to test novel agents to treat midline gliomas with histone mutation in a frontline and recurrent setting. An understanding of molecular pathology and ongoing efforts to improve diagnostic tools and therapy holds promise for future advances in prognosis.

References

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111: References especially recommended by the author or editor for general reading.

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Pediatric and adult histone altered tumors

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Introduction

Overview

Table 1. 2021 WHO Classification of Pediatric Diffuse High-Grade Glioma and Key Diagnostic Genes, Molecules, Pathways, or Combinations

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Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

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Pediatric and adult histone altered tumors

Cite this article

Introduction

Overview

Table 1. 2021 WHO Classification of Pediatric Diffuse High-Grade Glioma and Key Diagnostic Genes, Molecules, Pathways, or Combinations

Key points

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Diagnostic workup

Management

Future directions

Media

References

Contributors

Authors

Editor

Former Authors

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Also in This Category

Vestibular schwannoma

Palliative and end-of-life care for neuro-oncology patients

Ataxia-telangiectasia

Tovorafenib

Developmental delay in children: evaluation and management

Neonatal opioid withdrawal syndrome

Guillain-Barre syndrome in children

Vorasidenib

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