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Pediatric high-grade glioma: distinct biology, distinct trials

CC-BY-4.0vfr_10815170943966df

id: vfr_10815170943966df
license: CC-BY-4.0
findings: 115
accepted core: 0
contested: 0

115

findings

76

links

113

sources

115

evidence

0

contested

0.82

avg conf

recordoverview state sources proofenginereviewbodygraph

State

The accepted finding bundles: the reviewed findings that make up this frontier’s state. Each carries its statement, the evidence and confidence behind it, its review state, and its links to other findings.

by type

observational42
mechanism32
therapeutic27
diagnostic8
methodological4
epidemiological2

by review state

unreviewed115

finding bundle anatomy

A finding bundle is the durable object. Source graphs, citation stance, candidate gaps, and agent summaries are derived signals until a review event accepts a reviewable change into this record.

finding statement

EZH2 inhibition (tazemetostat, valemetostat) and HDAC inhibition (panobinostat, vorinostat) have been studied in pediatric H3K27M glioma based on the H3K27M-induced PRC2 dysfunction; clinical activity has been modest and the epigenetic-targeting class is largely supplanted by ONC201 in current trial design.

therapeutic

evidence

experimental · manual state transition; control details require source inspection

115 atoms

provenance

Hashizume et al. Nat Med 2014; review: Vitanza et al. Curr Treat Options Oncol 2019

review state

The example finding is unreviewed. Frontier changes still pass through reviewable changes and accepted events.

115 accepted events

derived signals

Links, candidate gaps, bridges, citation stance, nearby papers, and generated summaries route review. They do not rewrite the record by themselves.

64 linked findings153 reviewable changes

115 findings

proposedunder reviewacceptedcontestedunreviewedretracted

finding bundle
unreviewed
EZH2 inhibition (tazemetostat, valemetostat) and HDAC inhibition (panobinostat, vorinostat) have been studied in pediatric H3K27M glioma based on the H3K27M-induced PRC2 dysfunction; clinical activity has been modest and the epigenetic-targeting class is largely supplanted by ONC201 in current trial design.
vf_15a271fe4cfec720
therapeutic0.62 confidence
evidence unit
experimental · manual state transition; control details require source inspection
source handle
Hashizume et al. Nat Med 2014; review: Vitanza et al. Curr Treat Options Oncol 2019
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Atypical teratoid/rhabdoid tumor (ATRT) of the CNS has biallelic SMARCB1 (INI1) loss in nearly all cases; SMARCA4 loss is the alternative driver in rare cases. Survival has improved with intensive chemotherapy + radiation in older children but infant ATRT remains very poor prognosis.
vf_2260dd622b7ce258
diagnostic0.85 confidence
evidence unit
observational · manual state transition
source handle
Johann et al. Cancer Cell 2016 (ATRT molecular subgroups); Reddy et al. Pediatr Blood Cancer 2020 (treatment outcomes)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric brain tumor research is increasingly conducted within consortia (PNOC, COG, SIOPE, CBTN) that pool patient-derived models and run co-clinical trials; the consortia infrastructure has accelerated rare-tumor biology questions but pediatric oncology trial enrollment remains challenging due to small populations.
vf_283ae7501e4057b7
methodological0.75 confidence
evidence unit
observational · manual state transition
source handle
PNOC published trials; CBTN annual reports; review: Bornhorst et al. Pediatr Blood Cancer 2022
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric SHH-medulloblastoma carrying TP53 mutations (germline or somatic) has poor prognosis distinct from sporadic SHH-medulloblastoma; this stratification is now standard in WHO 2021 and informs trial enrollment for Li-Fraumeni syndrome surveillance.
vf_294a990663b2e3fa
diagnostic0.85 confidence
evidence unit
observational · manual state transition
source handle
Zhukova et al. J Clin Oncol 2013; Waszak et al. Nature 2018 (germline TP53)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Craniopharyngioma WHO grade 1 is biologically benign but anatomically complex (sella + suprasellar location); modern treatment combines limited resection with radiation, and BRAF/MEK inhibition is being explored for papillary craniopharyngioma carrying BRAF V600E (Brastianos 2023).
vf_2ca80acf94cc2daf
therapeutic0.78 confidence
evidence unit
observational · manual state transition
source handle
Brastianos et al. NEJM 2023 (papillary craniopharyngioma BRAF V600E); Apps et al. Pituitary 2018
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Cognitive late effects of pediatric brain-tumor treatment are dose-dependent and most severe in younger children; whole-brain radiation in patients under 5 years produces severe IQ decline, prompting strategies to defer or avoid radiation (proton therapy, methotrexate-based chemotherapy, autologous stem-cell rescue) where oncologically feasible.
vf_3f47d04838f5fdca
observational0.86 confidence
evidence unit
observational · manual state transition
source handle
Mulhern et al. J Clin Oncol 2005; Merchant et al. Cancer 2009 (proton outcomes)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Medulloblastoma molecular subgroups (WNT, SHH, Group 3, Group 4) drive risk-stratification and treatment intensity; WNT subgroup has 90+ percent 5-year OS while Group 3 with MYC amplification has under 50 percent, and reduced-intensity therapy is being trialed in WNT cases to spare cognitive late effects.
vf_4e17575a22b8b1fa
therapeutic0.86 confidence
evidence unit
observational · manual state transition
source handle
Cavalli et al. Cancer Cell 2017; Ramaswamy et al. Acta Neuropathol 2016
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric BRAF-V600E-positive low-grade gliomas respond strongly to dabrafenib + trametinib combination, with phase 3 superiority over carboplatin + vincristine in the FIREFLY-2 program; combined BRAF/MEK inhibition is now first-line for BRAF V600E pediatric LGG.
vf_52da4409427114c4
therapeutic0.88 confidence
evidence unit
experimental · manual state transition; control details require source inspection
source handle
Hargrave et al. Lancet Oncol 2023; Bouffet et al. NEJM 2023 (FIREFLY-2)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric infant brain tumors (under 3 years) face severe radiation late-effect risks; chemotherapy-only protocols (Baby POG, COG ACNS0334) avoid or delay radiation, with autologous stem-cell rescue as standard for infant medulloblastoma and ATRT. Survival has improved but neurocognitive outcome remains the dominant long-term concern.
vf_571bae7006ffeef7
therapeutic0.84 confidence
evidence unit
observational · manual state transition
source handle
Geyer et al. J Clin Oncol 2005 (Baby POG); Cohen et al. Cancer 2015 (infant medulloblastoma)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Hippocampal-avoidance whole-brain radiotherapy reduces cognitive late effects in pediatric medulloblastoma craniospinal protocols and is now incorporated in NRG/COG protocols where oncologically feasible; the technique balances oncologic coverage of leptomeningeal disease with hippocampal sparing.
vf_58f662c710bb9661
therapeutic0.78 confidence
evidence unit
experimental · manual state transition; control details require source inspection
source handle
Brown et al. J Clin Oncol 2020 (CC001); Kazda et al. Strahlenther Onkol 2014
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Group 3 medulloblastoma with MYC amplification represents the most aggressive medulloblastoma subgroup with poorest survival; high-dose chemotherapy with autologous stem-cell rescue is investigated for this subset. The mechanistic driver is MYC-driven proliferation plus altered translation regulation.
vf_6333fc5320b02cb1
observational0.85 confidence
evidence unit
observational · manual state transition
source handle
Northcott et al. Nature 2017 (Cavalli et al. subgroups); Roussel and Robinson, Cold Spring Harb Perspect Biol 2013
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
FGFR fusions in pediatric low-grade glioma (1-4 percent of cases) are now a targetable driver; pemigatinib and infigratinib are being studied in pediatric-friendly trials. The class extends precision medicine in pediatric LGG beyond MAPK pathway BRAF inhibition.
vf_6f1fe3e6bb160a35
therapeutic0.55 confidence
evidence unit
case_report · manual state transition
source handle
Subbiah et al. Cancer Discov 2019 (FGFR fusions); pediatric LGG NCI MATCH cohort
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric posterior fossa group A (PFA) ependymoma occurs in infants and young children, has a CIMP-low methylation phenotype, and is biologically and clinically distinct from group B (PFB) which occurs in older children/adults with much better prognosis; CIN1A loss is a frequent PFA molecular feature.
vf_70ede8d3d90320c4
observational0.78 confidence
evidence unit
observational · manual state transition
source handle
Pajtler et al. Cancer Cell 2015; Pajtler et al. Acta Neuropathol 2018
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric high-grade glioma in NF1 patients (neurofibromatosis type 1) often arises in optic pathway and may behave more indolently than sporadic HGG; mechanistic drivers include NF1-loss-induced RAS hyperactivity, with selumetinib showing efficacy in this molecular setting (Fangusaro 2019).
vf_746329b3a240315c
observational0.78 confidence
evidence unit
observational · manual state transition
source handle
Fangusaro et al. Lancet Oncol 2019 (selumetinib NF1-LGG); Helfferich et al. Pediatr Drugs 2016
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric HGG review gap: H3 G34-mutant and H3/IDH-wildtype hemispheric high-grade glioma claims need age, anatomic site, and molecular-driver qualifiers before they are compared with diffuse midline glioma claims.
vf_7700beb83de2f06f
methodological0.44 confidence1 link
evidence unit
theoretical · manual state transition · Homo sapiens
source handle
v0.301 pediatric HGG external-review depth wave
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Pediatric posterior fossa group A (PFA) ependymoma's CIMP-low signature reflects loss of the H3K27me3 repressive mark, partially analogous to (but mechanistically distinct from) H3K27M-mutant midline glioma; this convergence suggests common epigenetic vulnerabilities for therapeutic targeting.
vf_7d1cbdf1befed4ef
mechanism0.65 confidence
evidence unit
observational · manual state transition
source handle
Bayliss et al. Sci Transl Med 2016; Pajtler et al. Acta Neuropathol 2018
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Hemispheric pediatric HGG with H3G34R/V mutation typically affects adolescents and young adults, has higher mutational burden than midline H3K27M tumors, and shows slightly better prognosis though still poor; molecular distinction matters for trial stratification.
vf_836feae4415740ad
diagnostic0.82 confidence
evidence unit
observational · manual state transition
source handle
Mackay et al. Cancer Cell 2017; Sturm et al. Cancer Cell 2012
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
ONC201 (DRD2 antagonist + ClpP agonist) demonstrated objective responses in H3K27M-mutant diffuse midline glioma in phase 2 (Arrillaga-Romany 2024); the ACTION phase 3 trial is enrolling, and ONC201 is the first targeted therapy with a credible regulatory path in DIPG.
vf_86bc629e875ff052
therapeutic0.65 confidence
evidence unit
experimental · manual state transition; control details require source inspection
source handle
Arrillaga-Romany et al. Neuro-Oncology 2024 (ONC201 phase 2); ACTION trial NCT05580562
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric HGG immune microenvironment is more T-cell-poor than adult GBM and shows distinct macrophage profiles; immune checkpoint inhibitors as monotherapy have not produced phase 2 activity, paralleling the adult-GBM negative pattern but with even lower baseline TMB.
vf_8b1f9eafa9d42848
observational0.74 confidence
evidence unit
observational · manual state transition
source handle
Lin et al. Cancer Cell 2018; ICR/CCR pediatric HGG immune profiling
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric brain tumor patients have substantially higher rates of post-treatment endocrinopathy (growth hormone deficiency, thyroid dysfunction, hypothalamic obesity) than adult brain-tumor survivors; longitudinal endocrine surveillance is now standard in pediatric brain-tumor survivorship clinics.
vf_8c5eb0cbf4b658ef
observational0.84 confidence
evidence unit
observational · manual state transition
source handle
Schmiegelow et al. Eur J Cancer 2003; Patterson et al. Pediatr Blood Cancer 2017
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric high-grade gliomas are biologically distinct from adult counterparts; histone H3 mutations (H3K27M, H3G34R/V) are present in approximately 80 percent of midline pediatric HGGs and are nearly absent in adult GBM, defining separate WHO 2021 entities.
vf_8d289f0d2f89f8ba
diagnostic0.92 confidence
evidence unit
observational · manual state transition
source handle
Schwartzentruber et al. Nature 2012; Mackay et al. Cancer Cell 2017 (HERBY)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric HGG review gap: DMG H3 K27-altered therapeutic claims need source-grounded separation between early ONC201 signals, phase 1 GD2 CAR-T feasibility signals, and unresolved survival benefit before any translation-facing summary is updated.
vf_90300004763c84b7
methodological0.42 confidence1 link
evidence unit
theoretical · manual state transition; placebo-controlled clinical trial where source reports control arm · Homo sapiens
source handle
v0.301 pediatric HGG external-review depth wave
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Pediatric secondary CNS malignancies after curative cancer treatment occur in approximately 8 percent of survivors at 30 years post-treatment; the risk is highest after CNS radiation in early childhood. Most are meningiomas (benign histology, anatomically complex).
vf_991fc000cf39e56b
epidemiological0.84 confidence
evidence unit
observational · manual state transition
source handle
Reulen et al. JAMA 2011 (BCCSS); Bowers et al. J Clin Oncol 2017
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
DIPG/DMG biopsy biopsies (when performed) reveal frequent simultaneous H3K27M, ACVR1 (R206H), TP53, and PDGFRA mutations; the multi-driver landscape complicates single-target therapy and motivates combinations targeting the histone axis + downstream signaling.
vf_a4bf8009d02fe876
observational0.83 confidence
evidence unit
observational · manual state transition
source handle
Buczkowicz et al. Nat Genet 2014; Wu et al. Nat Genet 2014
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric tumor mutational burden is significantly lower than adult tumor mutational burden across CNS tumor types; the corollary is that immune checkpoint inhibitor monotherapy is even less likely to be effective in pediatric brain tumors than in adult ones, except for rare cases of constitutional MMR deficiency (CMMRD) where TMB is markedly elevated.
vf_a562772739f07509
observational0.78 confidence
evidence unit
observational · manual state transition
source handle
Campbell et al. Cell 2017 (pediatric pan-cancer TMB); Bouffet et al. J Clin Oncol 2016 (CMMRD case)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Diffuse intrinsic pontine glioma (DIPG) median survival remains under 12 months despite five decades of trials; H3K27M-mutant midline glioma is now the WHO 2021 designation, and the prognosis is fundamentally driven by tumor-intrinsic biology and pontine location more than treatment intensity.
vf_a9e086d51fc748d6
observational0.88 confidence
evidence unit
meta_analysis · manual state transition
source handle
Hoffman et al. Lancet Oncol 2018; Cooney et al. Cancer 2020
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric anaplastic ependymoma (now WHO 2021 supratentorial ZFTA-fusion-positive or YAP1-fusion-positive) requires molecular subtyping for prognosis; complete resection plus radiation is the most consistent prognostic factor and trial stratification by molecular subgroup is now standard.
vf_b3600339901cafee
diagnostic0.84 confidence
evidence unit
observational · manual state transition
source handle
Pajtler et al. Cancer Cell 2015; Tauziede-Espariat et al. Acta Neuropathol 2024
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric ATRT subgroups (TYR, MYC, SHH defined by methylation) require subgroup-stratified treatment intensity; younger ATRT patients with MYC subgroup or metastatic disease have particularly poor prognosis and high-dose chemotherapy + autologous stem-cell rescue is a frequent approach without consensus standard-of-care.
vf_c618d66d61d5359d
therapeutic0.74 confidence
evidence unit
observational · manual state transition
source handle
Johann et al. Cancer Cell 2016; Reddy et al. Pediatr Blood Cancer 2020
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric DIPG biopsy is now considered safe and clinically actionable in expert hands, reversing the 2010s consensus against biopsy; modern stereotactic technique has very low morbidity and biopsy-derived molecular data drives precision-trial enrollment.
vf_dbc39c8ba55c13ae
methodological0.82 confidence
evidence unit
observational · manual state transition
source handle
Roujeau et al. J Neurooncol 2007; Williams et al. Neurosurgery 2020 (modern series)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Choroid plexus carcinoma (WHO grade 3) is rare and typically occurs in young children; treatment combines surgery with multi-agent chemotherapy and craniospinal radiation in older children. TP53 germline mutation evaluation is now standard given Li-Fraumeni association.
vf_e5f79a81a5f38dde
therapeutic0.75 confidence
evidence unit
observational · manual state transition
source handle
Wrede et al. Cancer 2009 (CPC outcomes); Mistry et al. Pediatr Blood Cancer 2018
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Standard-of-care for newly diagnosed DIPG remains focal radiotherapy alone (54 Gy in 30 fractions); concurrent chemotherapy has not produced overall-survival improvement in randomized trials, and the field continues to test combination approaches without a confirmed positive standard-changing trial.
vf_f5950323a1dabcb0
therapeutic0.84 confidence
evidence unit
meta_analysis · manual state transition
source handle
Cohen et al. Pediatr Blood Cancer 2017; ACNS0126 follow-up; review: Hennika et al. Front Oncol 2017
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Pediatric germ cell tumors of the CNS (germinomas in pineal/suprasellar region) are exquisitely radiosensitive; modern treatment combines reduced-dose chemotherapy + radiation to limit cognitive late effects, with overall survival now exceeding 90 percent. AFP and beta-HCG biomarkers stratify germ cell vs nongerminomatous.
vf_f679c6e97cbd0c1b
therapeutic0.85 confidence
evidence unit
observational · manual state transition
source handle
Calaminus et al. Lancet Oncol 2013; Bartels et al. Pediatr Blood Cancer 2020
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3K27M mutations (lysine-to-methionine substitutions at position 27 of histone H3.3 or H3.1) are present in 80-90% of diffuse midline gliomas and diffuse intrinsic pontine gliomas, occurring as early somatic events during pons development
vf_b0ee9364cb5635e1
observational20240.95 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Pediatric Diffuse Midline Glioma H3K27-Altered (PMC11120159)
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
H3K27M acts as a dominant-negative inhibitor of PRC2, impeding genome-wide H3K27me3 and H3K27me2 spread while paradoxically retaining methylation at CpG island regions, creating a globally silenced epigenome with selective promoter derepression
vf_e38529682f65a609
mechanism20190.92 confidence2 links
evidence unit
theoretical · manual state transition
source handle
H3K27M induces defective chromatin spread of PRC2 (Nature Communications, s41467-019-09140-x)
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
H3K27M-expressing gliomas remain trapped in oligodendrocyte precursor cell (OPC) developmental states via OLIG2-driven transcriptional programs, with loss of H3K27M restoring capacity for neuronal differentiation and eliminating tumor-forming potential in vivo
vf_a6742773d6952fdf
mechanism20210.88 confidence1 link
evidence unit
theoretical · manual state transition
source handle
H3.3-K27M drives neural stem cell-specific gliomagenesis (Cancer Cell, S1535-6108(21)00049-0)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Patients with H3K27M-mutant DMG demonstrate median overall survival of 10.1-14.4 months from diagnosis, with 5-year survival <2%, compared to 54-60 Gy focal radiotherapy as the only standard-of-care intervention showing modest survival benefit
vf_730821613735146b
observational20240.93 confidence1 link
evidence unit
theoretical · manual state transition
source handle
H3 K27M-altered glioma treatment landscape (Neuro-Oncology, S110/7475775)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
MGMT promoter unmethylation and elevated MGMT expression confer resistance to temozolomide in H3K27M gliomas; three of four patient-derived DMG cell lines showed MGMT-driven TMZ resistance independent of MGMT methylation status
vf_7bd0c5cb3f52944d
mechanism20190.86 confidence1 link
evidence unit
theoretical · manual state transition
source handle
MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant DMG (Frontiers Oncology)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
GD2-CAR T-cell therapy (IV followed by intracerebroventricular dosing) induced volumetric tumor regression >50% in 5/11 H3K27M glioma patients, durable complete response in 1/11, and sustained survival >2 years in several participants with median OS improvement over historical controls
vf_2f0c819aebfe3b01
therapeutic20220.89 confidence1 link
evidence unit
theoretical · manual state transition
source handle
GD2-CAR T cell therapy for H3K27M-mutated gliomas (Nature, s41586-022-04489-4)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
ONC201/GsONC201 treatment in 28 H3K27M-mutant DIPG patients achieved median overall survival of 18 months; reirradiation-treated patients showed OS of 22 months versus 12 months without reirradiation, suggesting synergy between ONC201 and radiation
vf_f6fd98935260314b
therapeutic20210.85 confidence
evidence unit
theoretical · manual state transition
source handle
ONC201 clinical efficacy in H3K27M-mutant gliomas (Cancer Discovery)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3K27M-mutant gliomas exhibit minimal T-cell and NK-cell infiltration with predominantly M2-polarized macrophage accumulation, creating an immunologically 'cold' microenvironment with low PDL-1 expression and absent cytokine signaling
vf_7f6da3752d579c3d
observational20240.84 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Exploring the tumor microenvironment in DIPG (PMC12164617)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3K27M-driven gliomas exploit dual PRC2-inhibition mechanisms via the K27M oncohistone itself and EZHIP (PFA ependymoma-associated protein), which directly contact EZH2 catalytic site in structurally parallel fashion and stabilize narrow H3K27me3 peaks at CpG islands
vf_e92904b020588cde
mechanism20190.89 confidence
evidence unit
theoretical · manual state transition
source handle
EZHIP inhibits PRC2 activity through H3K27M-like mechanism (Nature Communications, s41467-019-09981-6)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3K27M-mutant DMGs show a high-frequency, mutually exclusive association with ACVR1 mutations (R206H, R258G, G328E, G356E in kinase domain) that confer constitutive TGF-β signaling activation and enhanced proliferation in vitro
vf_526b99cd8ff15fc4
observational20240.87 confidence1 link
evidence unit
theoretical · manual state transition
source handle
H3K27M mutant glioma: Disease definition and biological underpinnings (Neuro-Oncology, S92/7306459)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Targeting DNA repair (homologous recombination blockers) combined with PI3K/EGFR inhibitors and radiotherapy induces synthetic lethality in patient-derived DIPG models, suggesting multi-pathway DNA-damage sensitization overcomes radiotherapy resistance
vf_2391a24d566733fb
mechanism20240.80 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Targeting DNA Repair and Survival Signaling in DIPG (PMC10762335)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Neuronal differentiation induced by drug combinations in H3K27M gliomas upregulates synaptic and dendritic genes while suppressing malignant signatures; H3K27M-knockout cells show increased differentiation-associated gene expression and complete loss of tumor-forming capacity in vivo
vf_5da432d0d1f60577
therapeutic20250.83 confidence
evidence unit
theoretical · manual state transition
source handle
Cellular Reprogramming of H3K27M pediatric glioma to neuron-like state (Acta Neuropathologica Communications)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3.3K27M drives context-dependent activation of the CREB5/ID1 axis via super-enhancer remodeling, maintaining stem-like transcriptional states; CREB5 inhibition or KDM6B targeting restores H3K27me3 and suppresses stemness in H3K27M-mutant cells
vf_de80700e4fa9447d
mechanism20250.82 confidence1 link
evidence unit
theoretical · manual state transition
source handle
An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains stemness (Nature Communications, s41467-025-58795-2)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3K27M recruits MLL1 methyltransferase at super-enhancer and promoter loci independently of PRC2 inhibition, suggesting parallel epigenetic programming via active H3K4me3 deposition that reinforces oncogenic gene expression in DIPG
vf_0f3b43505f3ac327
mechanism20210.78 confidence
evidence unit
theoretical · manual state transition
source handle
H3-K27M-Mutant Nucleosomes Interact with MLL1 to Shape the Glioma Epigenetic Landscape (bioRxiv, 2021.08.09.455680)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
A subgroup of H3K27M-mutant DMGs with concurrent MAPK pathway alterations (BRAF/FGFR1 mutations) or EGFR/ACVR1 mutations define distinct molecular subtypes with differential survival and drug responsiveness, suggesting genomic context-dependent therapeutic strategies
vf_1a3806f509b88c1a
observational20230.81 confidence
evidence unit
theoretical · manual state transition
source handle
A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered (Acta Neuropathologica)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
ONC201 (dordaviprone) demonstrates a 20% objective response rate and 40% disease control rate in pooled analyses of recurrent H3K27M-mutant diffuse midline glioma across five clinical trials (n=50), with median response duration of 11.2 months.
vf_bfa0b46128b73855
observational0.92 confidence3 links
evidence unit
theoretical · manual state transition
source handle
JCO integrated efficacy analysis; FDA accelerated approval dossier, 2025
review state
unreviewed
downstream effect
3 downstream links
inspect finding →
finding bundle
unreviewed
Thalamic location and older age (adult vs pediatric) are independent favorable prognostic factors for ONC201 response and survival; thalamic tumors show significantly better outcomes in real-world compassionate use cohorts (n=174).
vf_b9d6c5c40b15e0c2
observational0.88 confidence1 link
evidence unit
theoretical · manual state transition
source handle
European Journal of Cancer compassionate use program (Gustave Roussy), 2024
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3K27M-mutant tumors show 2.5-fold greater sensitivity to ONC201 cytotoxicity (median IC50 ~0.6 µM) compared to wildtype H3 glioma cultures (median IC50 ~1.5 µM), indicating mutation-selective drug activity.
vf_0fd7eaae574d9d92
observational0.85 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Neuro-oncology mechanism review; pre-clinical in vitro assays
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
ONC201 activates the mitochondrial protease ClpP as a primary mechanism, inducing selective degradation of mitochondrial proteins, integrated stress response activation, and TRAIL-mediated apoptosis; ClpP expression is identified as a biomarker of response.
vf_d2ead0145a97a4f1
mechanism0.89 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Neuro-oncology mechanistic review and ClpP activation studies, 2023-2024
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3K27M disrupts PRC2-mediated H3K27 trimethylation globally via sequestration of the complex at poised enhancers, causing epigenetic dysregulation and altered chromatin compaction; ONC201 reversal of H3K27M phenotype operates through ClpP-stress, not PRC2 restoration.
vf_35f210ebd4b1b2c4
mechanism0.87 confidence
evidence unit
theoretical · manual state transition
source handle
PRC2 structural and mechanistic studies; H3K27M epigenetic profiling
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Reirradiation at time of ONC201 initiation is associated with significantly longer overall survival after drug start in pediatric patients (n=102 children in compassionate use cohort), but effect modest in adults; median OS after ONC201 4.7 months overall.
vf_02e91f2225519943
observational0.80 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Real-world compassionate use data, Gustave Roussy, 2024
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
ONC201 antagonizes dopamine receptor D2; DRD2 antagonism blocks pro-survival signaling; dual targeting of DRD2 and ClpP produces synergistic metabolic collapse and apoptosis through integrated stress response.
vf_26c616dc8e45573d
mechanism0.84 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Mechanistic studies in endometrial and CLL models; pharmacological profiling
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Pediatric H3K27M-mutant DMG patients exhibit shorter median overall survival (3.65 months, 95% CI 2.73-4.40) than adults (7.37 months, 95% CI 4.27-13.90); low KPS and omission of trimodality therapy independently predict poor outcomes in both age groups.
vf_8ec3f30b3e4aada4
observational0.86 confidence1 link
evidence unit
theoretical · manual state transition
source handle
West China Hospital comparative cohort analysis, 2016-2021; n=105 (51 adults, 54 children)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
FDA grants accelerated approval to dordaviprone (August 6, 2025) for pediatric (age ≥1 year) and adult patients with progressive H3K27M-mutant DMG post-prior therapy, based on 20% objective response rate and durable disease control; first-ever systemic therapy approval for this indication.
vf_82179ae647552ad2
therapeutic0.95 confidence1 link
evidence unit
theoretical · manual state transition
source handle
FDA accelerated approval, August 2025; Jazz Pharmaceuticals regulatory announcement
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
ONC201 is well-tolerated with only grade 1-2 adverse events reported; no grade 4 treatment-related AEs; most common grade 3 AE is fatigue (10%); safety profile supports use in pediatric populations age ≥1 year.
vf_c1ccf18e8026c937
therapeutic0.90 confidence
evidence unit
theoretical · manual state transition
source handle
Pooled safety analysis across five clinical trials; compassionate use programs
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Blood-based liquid biopsy (FoundationOne Liquid CDx) shows critically limited sensitivity (2.8%) for H3K27M mutation detection in DMG compared to tissue-based comprehensive genomic profiling (92.2% with FoundationOne CDx), restricting clinical biomarker utility for therapy monitoring.
vf_9c0fd2815af7dc5a
diagnostic0.85 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Real-world Japanese C-CAT database analysis; n=114 diffuse midline glioma patients
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3K27M-mutant DMG exhibits elevated m6A (N6-methyladenosine) enrichment on cell-motility transcripts; FTO inhibition induces S-phase arrest and downregulates cell cycle regulators, revealing epi-transcriptomic vulnerability orthogonal to H3K27M's chromatin effects.
vf_313769b4fba6a0bb
mechanism0.75 confidence1 link
evidence unit
theoretical · manual state transition
source handle
DMG patient-derived culture m6A profiling and FTO inhibitor studies, 2026
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
German-sourced compassionate-use ONC201 (GsONC201) in adult Chinese H3K27M-DMG patients shows 63% response rate when combined with standard radiotherapy vs. 15% for radiotherapy alone (p=0.01), but does not improve median OS (18.9 vs. 16.0 months, p=0.57) in small cohort.
vf_625d02b86fe9f0da
observational0.72 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Real-world multi-center Hong Kong retrospective study; n=27 adult Chinese patients
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Diffuse hemispheric glioma with H3 G34 mutation (H3G34R/V) represents a molecularly distinct entity from H3 K27M diffuse midline glioma, characterized by supratentorial hemispheric location, preferential occurrence in adolescents/young adults, and fundamentally different epigenetic landscape centered on H3K36 methylation dysregulation rather than H3K27me3 reduction.
vf_0b5f0d0ee73eb867
observational20230.95 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Williams et al. 2023 (10.1007/s00401-023-02609-6); Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults 2021 (10.1093/noajnl/vdab061)
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas display a distinctive perineuronal infiltration pattern with prominent perineuronal satellitosis rather than perivascular association, reflecting altered neurotropism that recapitulates in H3.3 G34R-engineered murine orthotopic models.
vf_b8afa0bfe85725bb
mechanism20260.80 confidence
evidence unit
theoretical · manual state transition
source handle
Okubo et al. 2026 (10.1016/j.bbrc.2026.153471); H3F3A-G34R mutant high grade neuroepithelial neoplasms 2019 (10.1186/s40478-019-0731-5)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
DMRTA2 transcription factor, highly expressed in radial glial progenitors during fetal brain development, is specifically upregulated in H3G34-mutant hemispheric gliomas and drives maintenance of radial-glia-like (RG) cell states; DMRTA2 loss impairs tumorigenicity and drives neuronal differentiation.
vf_c3f5fea24271f673
mechanism20260.75 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Royston et al. 2026 (10.1111/jcmm.71092)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas exhibit constitutively elevated H3K36me3 (trimethylation at H3 lysine 36), which disrupts normal chromatin architecture and represses genes normally silenced by H3K27me3, creating an epigenetic state intermediate between wildtype and H3K27M-mutant tumors.
vf_28682e1efe7e242b
mechanism20170.85 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Oncogenic Mechanisms of Histone H3 Mutations 2016 (10.1101/cshperspect.a026443); H3K36 trimethylation-mediated biological functions in cancer 2021 (10.1186/s13148-021-01187-2)
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
PDGFRA-positive oligodendrocyte precursor cell (OPC)-like subpopulations emerge as potential tumorigenic origins in H3G34-mutant hemispheric gliomas; these OPC-like cells at different differentiation states drive lineage transitions and maintain stemness properties essential for tumor maintenance.
vf_0aa0b78694770236
mechanism20250.70 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Tian et al. 2025 (10.1002/pdi3.70027); Single-Cell Profiling of Pediatric High-Grade Gliomas
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3G34R-mutant diffuse hemispheric gliomas are hypersensitive to PARP inhibitor combination regimens (palbociclib + olaparib or niraparib) due to alternative lengthening of telomeres (ALT)-driven ATRX-loss-associated DNA repair vulnerability; this is a distinct mechanistic vulnerability absent in K27M gliomas.
vf_763a7009f1584ec6
therapeutic20240.75 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Alternative lengthening of telomere-based immortalization renders H3G34R-mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens 2024 (10.1093/neuonc/noae228)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Median overall survival in pediatric/young-adult H3G34-mutant hemispheric gliomas ranges from 20-25 months across retrospective multicenter cohorts; female sex, high preoperative Karnofsky performance status (≥80), and gross/extensive surgical resection are associated with improved outcomes.
vf_c807d05cc49c5ea8
observational20250.80 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors 2022 (10.1093/noajnl/vdac133); Nakatogawa et al. 2025 (10.1186/s40478-025-01989-y)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas show distinct DNA methylation profiles clustering separately from K27M diffuse midline gliomas and wildtype IDH-mutant gliomas; methylation-based classification can be used as independent diagnostic criterion and predicts molecular subclass even in non-midline H3K27M gliomas.
vf_d162fec2891e607d
diagnostic20250.85 confidence
evidence unit
theoretical · manual state transition
source handle
Nakatogawa et al. 2025 (10.1186/s40478-025-01989-y); cIMPACT-NOW update 6 2020 (10.1111/bpa.12832)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas frequently acquire TP53 wildtype status and CDKN2A homozygous deletion but show lower incidence of MGMT methylation compared to adult IDH-wildtype glioblastomas, creating a distinct molecular signature with specific CDK4/6 inhibitor vulnerabilities.
vf_467bafabec51e43b
observational20230.80 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults 2021 (10.1093/noajnl/vdab061); P16 immunohistochemistry is a sensitive and specific surrogate marker for CDKN2A homozygous deletion 2023 (10.1186/s40478-023-01573-2)
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas exhibit robust upregulation of interferon-response genes and positive enrichment for multiple oncogenic signatures (Myc target genes, proliferation pathways); this interferon signature may contribute to immunotherapy resistance and differential tumor microenvironment composition.
vf_925bf50e7b3d8491
mechanism20260.70 confidence
evidence unit
theoretical · manual state transition
source handle
Okubo et al. 2026 (10.1016/j.bbrc.2026.153471); Generation and multi-dimensional profiling of a childhood cancer cell line atlas 2023 (10.1016/j.ccell.2023.03.007)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas show altered metabolic dependencies including enhanced lipid metabolism and glucose utilization compared to K27M tumors; metabolic flexibility of glioma stem cells and cross-talk between metabolism and epigenetic regulation (α-ketoglutarate as H3K36me3 cofactor) creates distinct metabolic vulnerabilities.
vf_038fff4583d6a364
mechanism20260.70 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Metabolic dependencies and neural progenitor dysregulation: driving forces in paediatric high-grade glioma development 2026 (10.1007/s10555-026-10325-2)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas presenting in infants and very young children may be histologically and clinically misclassified as 'infant-type hemispheric glioma' without molecular testing; however, WHO CNS5 classification now mandates H3F3A/H3.3 mutation testing to distinguish true H3G34-mutant cases requiring distinct treatment approaches.
vf_5cc4d6aa542cc80b
diagnostic20250.75 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Revisiting pediatric HGGs and PNETs according to the WHO CNS5 criteria 2025 (10.1093/noajnl/vdaf175); Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification 2022 (10.32074/1591-951x-830)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas arising adjacent to prior radiation fields or in patients with germline TP53 mutations (Li-Fraumeni syndrome) suggest a link to cancer predisposition syndromes and radiation-associated tumorigenesis; routine germline sequencing is warranted in pediatric H3G34 cases.
vf_1607f129d5cdf5b0
epidemiological20250.65 confidence
evidence unit
theoretical · manual state transition
source handle
Revisiting pediatric HGGs and PNETs according to the WHO CNS5 criteria 2025 (10.1093/noajnl/vdaf175)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas show poor response to conventional radiotherapy and chemotherapy (temozolomide + radiation standard regimens); emerging therapeutic strategies target metabolic vulnerabilities (PI3K/Akt pathway inhibition), ALT-associated DNA repair (PARP + CDK4/6 combinations), and immune microenvironment (CAR-T cells, oncolytic viruses).
vf_bc4f51762a89e905
therapeutic20240.70 confidence
evidence unit
theoretical · manual state transition
source handle
Therapeutically targeting the unique disease landscape of pediatric high-grade gliomas 2024 (10.3389/fonc.2024.1347694); A review of diffuse hemispheric glioma, H3 G34-mutant disease development, DNA repair, microenvironment, and treatments on the horizon 2025 (10.1038/s41698-025-01070-w)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3G34-mutant hemispheric gliomas are molecularly and clinically distinct from H3K27M-mutant non-midline (hemispheric) gliomas despite sharing histone mutations; H3K27M-NDMG presents in older adults (median 45 years), shows comparable survival (~20 months), but has identical methylation signatures to H3K27M diffuse midline gliomas, necessitating location-independent molecular classification.
vf_83d864f7644ebc1b
observational20250.80 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Nakatogawa et al. 2025 (10.1186/s40478-025-01989-y); Imaging features associated with H3 K27-altered and H3 G34-mutant gliomas: a narrative systematic review 2022 (10.1186/s40644-022-00500-3)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
ACVR1 R206H mutations occur in ~25% of DIPG cases and constitutively activate BMP signaling through the ALK2 kinase domain, independent of ligand binding.
vf_e664284b89862208
mechanism20190.92 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Hayashi et al. 2019 Nature Communications
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
ACVR1 R206H cooperates with H3.1K27M to activate Stat3 signaling and mesenchymal markers in vitro; full tumorigenesis requires additional co-drivers such as PDGFA or p53 loss in vivo.
vf_de03332c66323b46
mechanism20190.88 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Hayashi et al. 2019 Nature Communications
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
ALK2 inhibitors (LDN212854, LDN214117, LDN193189) cross the blood-brain barrier, suppress ACVR1-mutant DIPG growth in orthotopic xenografts, and significantly extend survival in preclinical models.
vf_2d3e414ec9d8e6b9
therapeutic20190.90 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Carvalho et al. 2019 Communications Biology
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
BMP2 and BMP7 are produced by tumor-intrinsic cells in H3.3K27M DIPG and synergize with H3.3K27M to induce a quiescent-invasive phenotype, distinct from proliferative growth.
vf_3dcb99c6af6d5538
mechanism20240.87 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Besson et al. 2024 eLife
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Radial glial stem-like cells are spatially enriched in the neuron-rich invasive niche of H3K27M DIPG; FAM20C-mediated signaling is essential for invasive growth in this niche.
vf_686449eba7b5aa59
mechanism20230.85 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Rojas-Charry et al. 2023 Nature Communications
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
DIPG arises from a developmental cell population in the ventral pons with heightened responsiveness to Hedgehog signaling; this population peaks temporally and spatially during mid-childhood (ages 6-8).
vf_5b9bf50c5abfd979
mechanism20110.86 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Monje et al. 2011 PNAS; Foreman et al. 2020+ developmental timing literature
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
TP53 mutations (~60%) and PPM1D truncating mutations (~30% of TP53 wild-type cases) are obligate partners of H3K27M in DIPG, arising clonally with H3K27M and maintained throughout tumor evolution.
vf_a0537caeb9dd21ee
observational20160.91 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Buczkowicz et al. 2014 Nature Genetics; Mackay et al. 2016 Nature Communications
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
TP53 wild-type, PPM1D-mutant DIPGs show heightened sensitivity to MDM2 antagonists, indicating retained p53 pathway vulnerability despite PPM1D-mediated Wip1 overexpression.
vf_fb5016c2f917c1b4
therapeutic20210.82 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Buell et al. 2021 Acta Neuropathologica Communications
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
GD2-CAR T cells administered intravenously and/or intracerebroventricularly achieve clinical and radiographic responses in 3 of 4 H3K27M DIPG patients in a phase I trial, without on-target off-tumor toxicity.
vf_97bb0892807d6ac9
therapeutic20220.89 confidence
evidence unit
theoretical · manual state transition
source handle
Majzner et al. 2022 Nature
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3K27M-induced global H3K27 hypomethylation is paradoxically accompanied by regional H3K27 hyperacetylation, driving super-enhancer activation and oncogenic transcription programs dependent on BRD4 and CBP.
vf_a6a15615c23d80d0
mechanism20200.88 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Nagaraja et al. 2017; Madhusoodanan et al. 2020 Cell Death & Disease
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Combined CBP and BET inhibition (ICG-001 + JQ1) reverses inadvertent super-enhancer activation that persists under monotherapy, synergistically reducing DIPG cell growth and prolonging survival.
vf_bf703b393597cf63
therapeutic20200.84 confidence
evidence unit
theoretical · manual state transition
source handle
Madhusoodanan et al. 2020 Cell Death & Disease
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
ACVR1 wild-type DIPGs (~75% of cases) maintain H3K27M-BMP signaling activation through alternative mechanisms and co-drivers (primarily TP53, PIK3R1, FGFR/BRAF in rare cases), indicating pathway redundancy.
vf_296fe62b57354516
observational20220.79 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Integrated genomic studies (Buczkowicz et al., Castel et al., recent structural variant analyses)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Non-inflammatory tumor microenvironment of DIPG (relative to glioblastoma) limits infiltration of T cells and restricts CAR T efficacy; local intracerebroventricular delivery overcomes this barrier more effectively than systemic administration.
vf_5929d17f93b49af3
mechanism20220.83 confidence
evidence unit
theoretical · manual state transition
source handle
Louveau et al. 2018; Majzner et al. 2022
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
H3K27M mutations drive global H3K27 hypomethylation and euchromatin remodeling, creating a pediatric-specific epigenetic landscape absent in typical adult GBMs.
vf_945677df9a84a8b7
mechanism20230.95 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Persson et al. 2022 (Neuro-oncology); Jackson et al. 2023 (Neuro-oncology)
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
Infant-type hemispheric gliomas harbor RTK fusions (ALK 47%, NTRK 22.5%, ROS1 20.4%) in 86.5% of cases, versus rare fusions in adult GBM.
vf_67cef1807019cd59
observational20260.92 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Chavaz et al. 2026 (Neuro-oncology meta-analysis, n=164)
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
Pediatric HGGs show intact blood-brain barriers with heterogeneous, infiltrative tumor tissue, limiting chemotherapy penetration compared to adult GBMs' disrupted BBB.
vf_d9f870c130904109
mechanism20220.85 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Pachocki & Hol 2022 (Journal of Neuroinflammation); Chavaz et al. 2026
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Pediatric HGGs display 'cold' immune microenvironments with low PD-1/PD-L1/CTLA-4 expression and low tumor mutational burden, explaining checkpoint inhibitor failures.
vf_6d5bc149715e8896
mechanism20220.88 confidence2 links
evidence unit
theoretical · manual state transition
source handle
Persson et al. 2022 (Neuro-oncology); Khairkhah et al. 2026 (Neoplasia)
review state
unreviewed
downstream effect
2 downstream links
inspect finding →
finding bundle
unreviewed
IDH-mutant pediatric HGGs (5-15% of cases) show prognostically favorable outcomes with better therapy response, reversing the adult pattern where IDH-mutant gliomas are lower-grade.
vf_4f57dae9b1c8d3bb
observational20250.82 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Valvi et al. 2025 (Frontiers Molecular Neuroscience review)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
BRAF V600E mutations in pediatric HGGs (7% prevalence) do not significantly impact progression-free survival, unlike their importance in adult BRAF-driven gliomas.
vf_6f242be917558fa4
observational20250.72 confidence
evidence unit
theoretical · manual state transition
source handle
Karim et al. 2025 (Frontiers Oncology, n=130 Egyptian cohort)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Surgical extent of resection (EOR) in pediatric HGG is paradoxically both life-saving and a major risk factor for early mortality, with residual tumor and surgery-alone being strongest death predictors.
vf_aa5b589539213380
observational20260.87 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Chavaz et al. 2026 (Neuro-oncology meta-analysis, n=164 infant-type HGG)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Craniospinal radiochemotherapy (CSI-RCT) in pediatric HGG induces grade 3-4 hematotoxicity in 36.8% but remains feasible; rarely employed in adult recurrent GBM due to toxicity fears.
vf_8b9a266bd5b8da50
therapeutic20250.84 confidence
evidence unit
theoretical · manual state transition
source handle
Valentini et al. 2025 (Clinical Oncology, HIT-HGG/HIT-GBM cohort n=19)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Oncolytic virotherapy (HSV G-207, DNX-2401, adenovirus) shows clinical signals in pediatric HGG with median OS 4.1-47.7 months and manageable toxicity, not standard in adult GBM.
vf_01f22a209c3a7756
therapeutic20250.75 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Velammal et al. 2025 (Child's Nervous System systematic review, n=40 pediatric patients)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
DMG with H3K27M mutations show enriched H2B1K-derived immunopeptides, revealing histone turnover as a disease mechanism; targeted therapy increases immunopeptide load in DMG but decreases it in GBM.
vf_18627eeb4f9fc968
mechanism20260.79 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Khairkhah et al. 2026 (Neoplasia immunopeptidomics study)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
MMR deficiency in high-grade gliomas confers TMZ resistance through immune microenvironment remodeling (myeloid immunosuppression, CD8+ exhaustion), not elevated tumor mutational burden.
vf_6d815c2d1decc76d
mechanism20250.83 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Puigdelloses Vallcorba et al. 2025 (Journal of Clinical Investigation)
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Pediatric GBM cells are sensitive to P-eIF2α phosphorylation modulation (salubrinal, raphin-1) combined with PARP-1 inhibitors and radiation, a combination not standard in adult GBM treatment.
vf_d7f237c484db3663
therapeutic20220.76 confidence
evidence unit
theoretical · manual state transition
source handle
Eytan et al. 2022 (Frontiers Oncology)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Bevacizumab alternating chemotherapy (BAC) improves recurrent adult grade 4 glioma survival (median OS 29 vs 19 months) in adult cohorts; pediatric trial data lacking.
vf_31924c9845d4dc97
therapeutic20250.74 confidence
evidence unit
theoretical · manual state transition
source handle
Liu et al. 2025 (Neuro-oncology Advances, n=95 adult recurrent HGG)
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Adult Stupp protocol (concurrent TMZ + radiotherapy) produced no survival benefit in pediatric GBM/HGG (ACNS0126 trial), unlike its 14.6-month OS benefit in adults.
vf_78a0cedf2d1cceb5
observational20110.92 confidence1 link
evidence unit
theoretical · manual state transition
source handle
COG ACNS0126 phase II trial
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
ACNS0423 modest improvement over ACNS0126 (3-yr EFS 22% vs 11%, p=0.019 with addition of lomustine) demonstrates insufficient efficacy ceiling; survival rate still critically low despite incremental advance.
vf_b634c43d011f00b1
observational20160.91 confidence1 link
evidence unit
theoretical · manual state transition
source handle
COG ACNS0423 phase II trial
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Bevacizumab + irinotecan (PBTC-022) anti-angiogenic therapy failed in pediatric recurrent GBM despite adult activity: only 6% objective response rate vs ≥20-30% in adult recurrent GBM, all but one patient progressed at 5 months.
vf_fdf73c97da49b959
observational20100.89 confidence1 link
evidence unit
theoretical · manual state transition
source handle
PBTC-022 efficacy study
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
H3K27M mutation (found in ~80% pediatric DMG, ~60% adult DMG) confers age-dependent prognosis: median OS 7-11 months in children vs 8-28 months in adults despite equivalent mutation status.
vf_9b4448c7d232846f
observational20220.88 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Diffuse midline glioma H3K27M multi-cohort analysis
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
BIOMEDE trial (N=233, diffuse intrinsic pontine glioma): None of three targeted-therapy arms (erlotinib, dasatinib, everolimus) + radiation exceeded radiotherapy alone on primary OS endpoint, revealing fundamental inadequacy of single-pathway inhibition in pediatric HGG.
vf_26edfbefc6b5cbb8
observational20260.93 confidence1 link
evidence unit
theoretical · manual state transition
source handle
BIOMEDE phase 2 international trial, Nature Medicine
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Only 4% of pediatric HGG RNA-seq differentially expressed genes (383 DEGs) overlap with differentially methylated cytosines, indicating transcriptional dysregulation uncoupled from DNA methylation—adult-derived epigenetic assumptions fail.
vf_0bdcf4be725c614b
observational20210.82 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Sex-specific differences pediatric/adult glioblastoma methylome-transcriptome analysis
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Pediatric glioma express functionally active P-glycoprotein, MRP1, and BCRP transporters on tumor vasculature and glioma cells—adult-derived chemotherapies suffer attenuated CNS penetration via age-dependent blood-brain barrier efflux pump capacity.
vf_fb3beea791c934bb
mechanism20130.85 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Pediatric HGG drug efflux transporter immunohistochemical and functional analysis
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Pediatric patients exhibit CYP3A4 hepatic metabolic rates reaching 30-40% of adult levels by 1 month postnatal, attaining adult levels only between 3-12 months; adult TMZ/alkylating-agent pharmacokinetics and dosing schedules are age-invalid.
vf_615dea30504e4ffe
mechanism20240.87 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Age-dependent CYP3A4 ontogeny physiologically based pharmacokinetic modeling
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Mandatory molecular profiling in BIOMEDE (exome sequencing, copy-number alterations) identified co-occurring pathway alterations and validated stratification—absence of biomarker-driven enrollment in prior adult-derived pediatric trials contributed to negative outcomes.
vf_4171b4670921b306
observational20210.88 confidence
evidence unit
theoretical · manual state transition
source handle
BIOMEDE trial exome sequencing and molecular architecture
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
BRAF V600E + H3K27M co-mutant pediatric gliomas show reduced aggressiveness and longer survival (>5 years in some cases) vs H3K27M monoaltered; adult-derived single-drug regimens cannot address pathway-specific vulnerabilities.
vf_4f312d5b0868a108
observational20230.80 confidence1 link
evidence unit
theoretical · manual state transition
source handle
Pediatric DMG molecular subtyping and BRAF-targeted therapy response
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
Cranial radiation in pediatric HGG survivors shows dose- and volume-dependent neurocognitive decline persisting years posttreatment, plus secondary malignancy risk (grade 3+ gliomas, meningiomas); adult-scaled 54-60 Gy protocols cause developmentally-inappropriate late morbidity.
vf_a9f5d96d67799a9a
observational20230.89 confidence
evidence unit
theoretical · manual state transition
source handle
Modern radiotherapy pediatric brain tumor late effects systematic review
review state
unreviewed
downstream effect
no declared downstream links
inspect finding →
finding bundle
unreviewed
Oncolytic HSV-1 G207 phase I pediatric HGG trial achieved 12.2-month median OS (5 of 12 patients >18 months survival) without dose-limiting toxicities—mechanism (lytic immunity + oncolytic spread) is distinct from chemotherapy and demonstrates mechanism-appropriate design necessity.
vf_5d212e0a9caf0c4e
observational20210.87 confidence1 link
evidence unit
theoretical · manual state transition
source handle
G207 phase I pediatric high-grade glioma trial, New England Journal of Medicine
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
IDH1-mutant pediatric HGG (5-10% incidence, vs ~35% adult GBM) shows distinct molecular context and response to olutasidenib + TMZ; CONNECT TarGeT-D biomarker-driven enrollment demonstrates pediatric-specific precision trial architecture.
vf_1823c24df2a66f27
observational20240.81 confidence1 link
evidence unit
theoretical · manual state transition
source handle
CONNECT TarGeT-D olutasidenib phase 2 pediatric HGG trial
review state
unreviewed
downstream effect
1 downstream link
inspect finding →
finding bundle
unreviewed
ONC201 phase I pediatric DMG/DIPG trial established pediatric-weight-scaled dosing (adult RP2D 625 mg scaled to body weight) with recommended phase II dose determination—adult oncology regimens require de novo pediatric pharmacokinetic/pharmacodynamic validation.
vf_aaea990730118b73
observational20220.84 confidence1 link
evidence unit
theoretical · manual state transition
source handle
ONC201 phase I dose escalation/expansion pediatric DMG trial, Neuro-Oncology
review state
unreviewed
downstream effect
1 downstream link
inspect finding →