No approved-drug candidate for diffuse pediatric-type high-grade glioma, h3-wildtype and idh-wildtype is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
RCSB Protein Data Bank · entry 6BKX · 1.65 Å · ligand ISOCITRIC ACID (ICT). Experimental structure, not a prediction.
The 2019 review states that temozolomide, combined with surgery and radiotherapy, has not improved outcomes for paediatric high-grade gliomas over past decades. It notes that these tumours are now classified into molecular subgroups defined by histone 3, IDH, and MAPK pathway mutations, which provides a rationale for targeted therapies and drug repurposing, but no specific drug is shown to work in the review itself.
A 2014 study of 35 infants with diffuse high-grade astrocytomas (8 anaplastic astrocytomas, 27 glioblastomas) found that chromosomal alterations were significantly less frequent than in older children and adults. Only 2 of 34 cases (5.9%) had H3F3A K27M mutations, both in the posterior fossa. PDGFRA amplifications were absent, and CDKN2A loss occurred in only two cases. Gains of 1q (22.7%) and losses of 6q (18.2%) were identified, along with loss of SNORD on chromosome 14q32 in 27.3% of infant tumours, a change not previously described in gliomas. The authors conclude that infant high-grade gliomas appear to be a distinct genetic entity.
A 2025 study retrospectively analysed 165 adolescent and young adult patients (aged 15–39) with suspected high-grade glioma. Molecular classification by DNA methylation profiling confirmed 30 cases of paediatric-type H3-/IDH-wildtype high-grade glioma and 43 cases of glioblastoma, IDH-wildtype. Preliminary analysis of 14 paediatric-type H3-/IDH-wildtype and 25 glioblastoma cases in this age group showed comparable clinical outcomes: median progression-free survival was 14.3 months for paediatric-type H3-/IDH-wildtype and 9.2 months for glioblastoma. Ongoing analyses include genetic alterations, overall survival, and symptom burden.
A 2022 genomic study of 390 H3F3A-mutant diffuse gliomas WHO grade 4 (304 H3K27M-mutant diffuse midline gliomas, 86 H3G34-mutant diffuse hemispheric gliomas) found that 52% of H3K27M-mutant patients were older than 20 years, 30% older than 30, and 18% older than 40. Clonal FGFR1 hotspot mutations occurred exclusively in 21% of H3K27M-mutant tumours and were associated with a higher median age at diagnosis (32.5 years). NF1 alterations were more frequent in H3K27M-mutant (31%) than H3G34-mutant (8.1%) tumours, as were PIK3CA/PIK3R1 alterations (27.9% vs 15.1%). CDK4/6 amplifications and CDKN2A/B deletions were enriched in H3G34-mutant tumours (26%) compared to H3K27M-mutant (7%). PDGFR alterations were present in 32.5% of H3G34-mutant and 18% of H3K27M-mutant tumours. What remains missing are prospective trials that stratify patients by these molecular subgroups, adequate funding for such trials in the adolescent and young adult population, and validated biomarkers to predict which patients might benefit from the targeted agents suggested by these genomic findings.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Frontiers in Oncology · 2012 · 193 citations · open access
Pediatric High Grade Glioma: a Review and Update on Tumor Clinical Characteristics and Biology
AbstractHigh grade gliomas (HGG) are one of the most common central nervous system (CNS) tumors encountered in adults, but they only represent approximately 8-12% of all pediatric CNS tumors. Historically, pediatric HGG were thought to be similar to adult HGG since they appear histologically identical; however, molecular, genetic, and biologic data reveal that they are distinct. Similar to adults, pediatric HGG are very aggressive and malignant lesions with few patients achieving long-term survival despite a variety of therapies. Initial treatment strategies typically consist of a gross total resection (GTR) when feasible followed by focal radiotherapy combined with chemotherapy. Over the last few decades, a wealth of data has emerged from basic science and pre-clinical animal models helping to better define the common biologic, genetic, and molecular make-up of these tumors. These data have not only provided a better understanding of tumor biology, but they have also provided new areas of research targeting molecular and genetic pathways with the potential for novel treatment strategies and improved patient outcomes. Here we provide a review of pediatric non-brainstem HGG, including epidemiology, presentation, histology, imaging characteristics, treatments, survival outcomes, and an overview of both basic and translational research. An understanding of all relevant pre-clinical tumor models, including their strengths and pitfalls is essential in realizing improved patient outcomes in this population.
https://doi.org/10.3389/fonc.2012.00105Pediatric Blood & Cancer · 2019 · 40 citations
Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies
AbstractPediatric high-grade gliomas (pHGG) constitute 8% to 12% of primary brain tumors in childhood. The most widely utilized treatment encompasses surgical resection followed by focal radiotherapy and temozolomide. However, experiences over past decades have not demonstrated improved outcomes. pHGG have been classified into different molecular subgroups defined by mutations in histone 3, IDH gene, MAPK pathway, and others, thereby providing a rationale for various targeted therapies. Additionally, immunotherapy and drug repurposing have also become attractive adjunctive treatments. This review focuses on past, present, and emerging treatments for pHGG integrating molecular research with the mainstream pediatric drug development in Europe and the United States to sketch a way forward in the development of novel therapeutic approaches. The implementation of randomized clinical trials with adaptive designs, underpinned by a robust biological rationale, and harnessing collaboration between the pharmaceutical industry, academia, regulators and patients/parents organizations will be essential to improve the outcomes for these children.
https://doi.org/10.1002/pbc.28011Brain Pathology · 2014 · 39 citations · open access
Genetic Analysis of Diffuse High‐Grade Astrocytomas in Infancy Defines a Novel Molecular Entity
AbstractPediatric high-grade gliomas are considered to be different when compared to adult high-grade gliomas in their pathogenesis and biological behavior. Recently, common genetic alterations, including mutations in the H3F3A/ATRX/DAXX pathway, have been described in approximately 30% of the pediatric cases. However, only few cases of infant high-grade gliomas have been analyzed so far. We investigated the molecular features of 35 infants with diffuse high-grade astrocytomas, including 8 anaplastic astrocytomas [World Health Organization (WHO) grade III] and 27 glioblastomas (WHO grade IV) by immunohistochemistry, multiplex ligation probe-dependent amplification (MLPA), pyrosequencing of glioma-associated genes and molecular inversion probe (MIP) assay. MIP and MLPA analyses showed that chromosomal alterations are significantly less frequent in infants compared with high-grade gliomas in older children and adults. We only identified H3F3A K27M in 2 of 34 cases (5.9%), with both tumors located in the posterior fossa. PDGFRA amplifications were absent, and CDKN2A loss could be observed only in two cases. Conversely, 1q gain (22.7%) and 6q loss (18.2%) were identified in a subgroup of tumors. Loss of SNORD located on chromosome 14q32 was observed in 27.3% of the infant tumors, a focal copy number change not previously described in gliomas. Our findings indicate that infant high-grade gliomas appear to represent a distinct genetic entity suggesting a different pathogenesis and biological behavior.
https://doi.org/10.1111/bpa.12210Frontiers in Molecular Neuroscience · 2025 · 4 citations · open access
IDH mutant high-grade gliomas
AbstractGliomas are the most common type of malignant primary central nervous system (CNS) tumors, resulting in significant morbidity and mortality in children and adolescent and young adult (AYA) patients. The discovery of mutations in isocitrate dehydrogenase (IDH) genes has dramatically changed the classification and understanding of gliomas. IDH mutant gliomas have distinct clinical, pathological, and molecular features including a favorable prognosis and response to therapy compared to their wildtype counterparts. Although more common in adults, 5-15% of pediatric gliomas have IDH mutations. In this review, we provide a comprehensive summary of the current knowledge on IDH mutant high-grade gliomas (HGG), including their biology, clinical features, diagnosis, treatment, and prognosis. We also discuss future directions in research and clinical management with particular attention to the AYA cohort.
https://doi.org/10.3389/fnmol.2025.1662414Blood · 2020 · 3 citations
Clinical Benefit and Tolerability of Crenolanib in Children with Relapsed Acute Myeloid Leukemia Harboring Treatment Resistant FLT3 ITD and Variant FLT3 TKD Mutations Treated on Compassionate Access
AbstractBackground: FLT3-mutant pediatric AML represents a biological and clinically diverse disease and is associated with a poor outcome. Sorafenib has limited activity against tyrosine kinase domain mutations. Crenolanib is a pan-FLT3 inhibitor, which, at the time of this compassionate use program, had already been safely administered to over 55 children (age 2-18) with diffuse intrinsic pontine glioma as well as high grade gliomas. Crenolanib at a dose of 66mg/m2 TID has been well tolerated in pediatric patients. Methods: We here report our experience with five consecutive children (ages 4-12y) who received crenolanib for FLT3 mutant AML on a compassionate basis between April 2017 to October 2019. All patients treated had IRB/local ethics approval prior to treatment and all patients' guardians signed informed consent forms. Results: Patient Characteristics: Of the five patients, three were refractory to induction therapy and required salvage therapy to get into remission. All five patients were then able to undergo HSCT, but all subsequently relapsed. Two patients were successfully salvaged and underwent a second HSCT. Only two pts received sorafenib. By the time of the compassionate use request, all children had exhausted all standard and experimental therapies (3-9 prior therapies, Table 1). Two patients had FLT3-ITDs and three had FLT3 kinase domain mutations (A848P in one, D835H in another and both D835H and D835E in trans in third). Co-occurring events included KMT2A fusion/mutations in three pts as follows: i) one pt with KMT2A-rearranged infant AML, ii) one with treatment-related AML with KMT2A fusion and t(9;11) and iii) a third patient with KMT2A fusion along with p53 mutation. Another patient with biphenotypic AML had a co-occurring NOTCH1 mutation with 9;14 translocation. Three patients had complex karyotypes and a number of translocations were identified including t(9;11), t(3;5), t(1;16), and t(9;14) (Table 1). In addition to bone-marrow disease and circulating blasts, all patients had extramedullary AML. Three patients had CNS leukemia. Three patients had non-CNS extramedullary AML (submandibular, testicular, liver and spleen). Treatment: Crenolanib was given with curative intent to three patients, one in combination with Vyxeos (liposomal cytarabine/daunorubicin), one with high-dose cytarabine, and one as maintenance therapy after her second HSCT. Two patients received crenolanib as palliation for rapidly progressing AML. Tolerability: All children tolerated crenolanib well. Reasons for crenolanib discontinuation were bridge to HSCT in two patients and completion of 12 months of maintenance in another. One patient stopped crenolanib early as he developed fungal pneumonia and one patient stopped due to lack of benefit. Only one patient required dose reduction due to grade 2 transaminitis. There were no cardiac toxicities, pericardial effusion, fluid retention or weight gain. Response: Four of five patients reported clinical benefit with crenolanib. Interestingly, the child with KMT2A-rearranged infant AML achieved a molecular CR after salvage therapy with Vyxeos plus crenolanib. This child was successfully bridged to a second HSCT and remains in remission one year after the start of his compassionate use crenolanib. Another patient with KMT2A fusion, p53 mutation and CNS AML achieved a CR with crenolanib + sorafenib, was successfully bridged to 2nd HSCT and received one year of post-transplant crenolanib maintenance. She remains in remission 3.5 years after initiation of crenolanib. The third patient with KMT2A fusion was successfully bridged to allo HSCT but relapsed 4 months after HSCT (she did not receive maintenance). The patient with bi-phenotypic AML (and D835H mutation) had a quick reduction in circulating blasts (within 24 h) but died of fungal sepsis. The fifth patient received reduced doses of crenolanib due to transaminitis and did not have a clinical benefit. Conclusion: This series of five children with multiply relapsed FLT3-mutant AML shows that treatment with full doses of crenolanib can be safely combined with salvage chemotherapy. Rapid remissions could be obtained even in patients with co-occurring KMT2A, 3q, and p53 mutations. Crenolanib, which is novel type-I pan FLT3 inhibitor, was able to inhibit variant FLT3 mutations (D835H, D835E and D848P). Crenolanib can be safely combined with ITT (2 of these children remain alive 1-3.5 years). Figure Disclosures Rubnitz: AbbVie Inc.: Research Funding. Karol:AbbVie Inc.: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study. . Pathan:Arog Pharmaceuticals: Current Employment. Messahel:AROG Pharmaceuticals: Current Employment.
https://doi.org/10.1182/blood-2020-140399Neuro-Oncology · 2025 · 0 citations · open access
PTHP-13. Clinical and molecular features of IDH- and H3-wildtype high-grade glioma groups in adolescent and young adult (AYA) patients
AbstractAbstract High-grade gliomas (HGG) present a molecularly diverse group of aggressive tumors occurring in patients of any age, and are particularly understudied in adolescents and young adult patients (AYAs) aged 15-39 years. Previous studies have indicated that the more recently DNA methylation-defined subgroup of pediatric-type HGG, H3-/IDH-wildtype (pedHGG, H3-/IDH-wildtype), is more prevalent in AYAs than in children, whereas glioblastoma, IDH-wildtype (GBM), is relatively rare in AYAs. However, the molecular-pathological landscapes of pedHGG, H3-/IDH-wildtype, and in particular whether these are linked to distinct clinical features and outcomes, remain poorly understood. In this monocentric study, we retrospectively analyzed a cohort of n=165 AYA patients with a suspected diagnosis of HGG, treated at our institution between 2000 and 2025. Molecular classification into pedHGG, H3-/IDH-wildtype, and GBM, was confirmed in n=30 and n=43 cases, respectively, by genome-wide DNA methylation profiling. Furthermore, we identified an additional n=20 pedHGG, H3-/IDH-wildtype, in younger pediatric and older adult patients, and contrasted these with their AYA counterparts as well as n=20 age-matched GBM. Targeted exome-sequencing was performed for n=50 tumors. A comprehensive clinical assessment was performed for n=100 patients where clinical data was available. Our preliminary analyses of n=14 pedHGG, H3-/IDH-wildtype, and n=25 GBM in the AYA population show comparable clinical outcomes between the two molecular subgroups. Median progression-free survivals were 14.3 and 9.2 months in pedHGG H3-/IDH-wildtype, and GBM, respectively. Ongoing analyses include assessment of genetic alterations, as well as clinical endpoints including overall survival, radiological features, symptom burden, seizure frequency, tumor therapy and associated adverse events. Our work provides deeper insights into the potentially distinct clinical consequences of different molecular glioma groups in AYA patients.
https://doi.org/10.1093/neuonc/noaf201.1070Neuro-Oncology · 2022 · 0 citations · open access
P04.04.A A comprehensive genomic study of 390 H3F3A-mutant pediatric-type diffuse high-grade gliomas WHO CNS grade 4
AbstractAbstract Background Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG) H3G34-mutant - occur in all age groups and can have significant variation in clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections of H3F3A-mutant gliomas analyzed to date, identifying subsets defined by recurrently co-mutated genes. Material and Methods We identified 390 H3F3A-mutant diffuse gliomas WHO grade 4 (201 females and 189 males) that were profiled in the comprehensive genomic profiling program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology review, and patient clinical data was assessed Results Our cohort comprised 304 (77.9%) H3K27M-mutant DMG WHO grade 4 (156 females and 148 males) and 86 H3G34-mutant DHG (45 females and 41 males) with a median age of 20 years (1- 74 years). H3K27M-mutant DMG distributed equally between pediatric and adult patients, with 52% of the patients older than 20 years, 30% older than 30 years, and 18% older than 40 years at the time of first diagnosis. Clonal FGFR1 hotspot mutations were exclusively detected in K27M-mutant DMG (n = 64/304, 21%; p=0.0001), with a significant association with a higher age at first diagnosis (median 32.5 years), and with a wide tumor distribution across the diencephalon. Additional genes which were significantly more frequently altered in K27M-mutant compared to G34-mutant diffuse gliomas included NF1 (31% vs. 8.1%; p=0.0001) and PIK3CA/PIK3R1 (27.9% vs. 15.1%; p=0.016). Conversely, targetable alterations of the cell-cycle pathway (CDK4/6 amplifications and CDKN2A/B deletions) were enriched in H3G34-mutant DHG (26%) compared to H3K27M-mutant DMG (7%). Potentially targetable PDGFR alterations were present in 32.5% of H3G34-mutant DHG and in 18% of H3K27M-mutant DMG. Conclusion These data expand our understanding of the tumor-specific molecular features of pediatric-type high-grade gliomas, identifying cohort sub-structure by recurrent co-mutations, which can inform diagnosis and clinical trial design.
https://doi.org/10.1093/neuonc/noac174.119Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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