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Molecular Insights into Pediatric Brain Tumors: Unraveling the Complexity of Pathogenesis and Identifying New Therapeutic Targets

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 October 2025) | Viewed by 4993

Special Issue Editors

Prof. Dr. Xiao-Nan Li

E-Mail Website
Guest Editor
Department of Pediatrics, Northwestern University and Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
Interests: pediatric brain tumors; patient-derived orthotopic xenograft models; recurrent tumor; invasion; drug testing
Special Issues, Collections and Topics in MDPI journals
Dr. Holly Lindsay

E-Mail Website
Guest Editor
1. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
2. Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA
Interests: pediatric brain tumors; clinical trials; target therapy; drug response and therapy resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brain tumor remains the number one cause of cancer-related death in children. Despite advances in genetic and epigenetic analysis and successful molecular subtyping over the past decade, our understanding of pediatric tumor biology is still at its infancy and there has been very limited progresses in developing new and effective therapies. Radiation remains the mainstay for nearly all types of childhood brain tumors. In addition to the discovery of biological differences between pediatric and adult brain tumors and diverse heterogeneities even within the same pathological entities, pediatric brain tumors often carry fewer gene mutations and are driven by epigenetic abnormalities.

While there is an urgent need of new and more in-depth studies on tumor biology, pediatric brain cancers as a group are rare tumors and the study results are frequently scattered in different journals. The purpose of this Special Issue is to create a platform to support the rapid publication of new findings and assemble a collection set of research papers to facilitate efficient and broad distributions. Reports on tumorigenesis investigation, analysis of genetic and epigenetic abnormalities, development of targeted therapy, identification of diagnostic markers and mechanistic examination of therapy responsiveness are all welcome. Study materials can be cultured cells, animal models or patient tumor tissues. Defining the cell of origin of tumor initiation or of critical malignant phenotypes (invasion and metastasis), and understanding molecular mechanisms of therapy resistance and tumor relapse, as well as deciphering biological determinants of cancer disparity are also highly desired. 

Prof. Dr. Xiao-Nan Li
Dr. Holly Lindsay
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

 

Keywords

  • brain tumor
  • pediatric tumor biology
  • molecular subtyping
  • radiation therapy
  • genetic and epigenetic abnormalities
  • tumorigenesis investigation
  • targeted therapy
  • diagnostic markers
  • therapy resistance
  • tumor relapse

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Published Papers (4 papers)

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Research

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18 pages, 1244 KB  
Article
Targeting Pediatric Glioblastomas by Combining OLIG2 Inhibitor CT-179 with Fractionated Radiation in a Panel of Patient-Derived Orthotopic Xenograft Mouse Models
by Holly Lindsay, Yuchen Du, Lin Qi, Huiyuan Zhang, Sibo Zhao, Frank K. Braun, Mari Kogiso, Clifford Stephan, Gordon Alton, Gregory Stein, Graham Beaton, Santosh Kesari, Steve Neuhauser, Tim Stearns, Jeff Chuang, Emily L. Jocoy, Carol J. Bult, Beverly Teicher, Malcolm A. Smith and Xiao-Nan Li
Int. J. Mol. Sci. 2026, 27(3), 1543; https://doi.org/10.3390/ijms27031543 - 4 Feb 2026
Viewed by 900
Abstract
The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To [...] Read more.
The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of an OLIG2 inhibitor CT-179 in pHGG, we determined the OLIG2 mRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0–10 µM) with and without radiation (XRT) (0–8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined at 15–240 mg/kg (oral) alone or combined with XRT (2 Gy/day × 5 days). Changes in animal survival times were analyzed using the Kaplan–Meier method, followed by pair-wise comparisons. Increased OLIG2 mRNA expression was detected in seven out of ten PDOX models. CT-179 inhibited cell viability in a time- and dose-dependent manner in all eight pGBM xenograft tumors (IC50 0.03–10 µM) and was potentiated by XRT (0.03–1 µM). Oral gavage (24 mg/kg) of CT-179 for 5 days led to effective penetration in mouse cerebrum (3232.7 ± 569.2 ng/g), cerebellum (1563.3 ± 269.6 ng/g), brain stem (1685.3 ± 309 ng/g), and PDOX tumors (1814 ± 110.3 ng/g) vs. 361.3 ± 1.5 ng/mL in serum. CT-179 alone was not active at 200 mg/kg in four models, although it was moderately effective at 240 mg/kg in one model. When combined with XRT, a significant extension of animal survival times was observed in two out of four models. Doses needed to eliminate OLIG2 expression in vitro varied from 0.3 to >1 µM in pGBM cells. In summary, our data showed that orally administered CT-179 penetrated the blood–brain barrier (BBB) and exhibited potential for inhibiting pGBM growth when combined with XRT. Full article
(This article belongs to the Special Issue Molecular Insights into Pediatric Brain Tumors: Unraveling the Complexity of Pathogenesis and Identifying New Therapeutic Targets)
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Review

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26 pages, 2620 KB  
Review
EZHIP in Pediatric Brain Tumors: From Epigenetic Mimicry to Therapeutic Vulnerabilities
by Tiziana Servidei, Serena Gentile, Alessandro Sgambato and Antonio Ruggiero
Int. J. Mol. Sci. 2026, 27(2), 963; https://doi.org/10.3390/ijms27020963 - 18 Jan 2026
Viewed by 1227
Abstract
Enhancer of zeste homologs inhibitory protein (EZHIP) is a eutherian-specific protein, with poorly defined developmental functions and physiological expression restricted to germ cells. Its aberrant re-expression characterizes posterior fossa ependymoma subtype A and a subset of diffuse midline gliomas with wild-type histone H3—aggressive [...] Read more.
Enhancer of zeste homologs inhibitory protein (EZHIP) is a eutherian-specific protein, with poorly defined developmental functions and physiological expression restricted to germ cells. Its aberrant re-expression characterizes posterior fossa ependymoma subtype A and a subset of diffuse midline gliomas with wild-type histone H3—aggressive pediatric brain tumors marked by global loss of the repressive H3 lysine 27 trimethylation (H3K27me3). Functionally analogous to the H3 lysine 27 to methionine (H3K27M) oncohistone, EZHIP inhibits Polycomb repressive complex 2 (PRC2), altering genome-wide H3K27me3 distribution and fate commitment. Unlike H3K27M, EZHIP is epigenetically silenced under physiological conditions yet inducible, suggesting context-dependent oncogenic roles. Its intrinsically disordered structure enables multifunctional interactions and biological versatility. Beyond brain tumors, EZHIP has emerged as an oncogenic driver in osteosarcoma, underscoring broader relevance across cancers. This review integrates current insights into EZHIP—from gene discovery and the mechanism of PRC2 inhibition to its emerging roles in metabolism, DNA repair, 3D chromatin regulation, and development. We outline EZHIP’s clinico-pathological significance in pediatric and adult malignancies, with an emphasis on EZHIP-driven hindbrain tumors. Finally, we discuss therapeutic opportunities, from the direct targeting of intrinsically disordered proteins to the indirect modulation of EZHIP-associated epigenetic and metabolic landscapes, highlighting implications for tumor evolution and precision oncology. Full article
(This article belongs to the Special Issue Molecular Insights into Pediatric Brain Tumors: Unraveling the Complexity of Pathogenesis and Identifying New Therapeutic Targets)
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17 pages, 1561 KB  
Review
From Molecular Alterations to the Targeted Therapy: Treatment of Thalamic Glioma in Pediatric Patients
by Yasin Yilmaz
Int. J. Mol. Sci. 2026, 27(2), 695; https://doi.org/10.3390/ijms27020695 - 9 Jan 2026
Viewed by 1004
Abstract
Thalamic gliomas are among the most challenging pediatric brain tumors due to the delicate functions of the thalamus. Limited surgical intervention leads to the use of adjuvant therapies, including targeted therapy. Thalamic gliomas can be divided into two distinct groups: diffuse midline glioma [...] Read more.
Thalamic gliomas are among the most challenging pediatric brain tumors due to the delicate functions of the thalamus. Limited surgical intervention leads to the use of adjuvant therapies, including targeted therapy. Thalamic gliomas can be divided into two distinct groups: diffuse midline glioma (DMG) and low-grade glioma (LGG). The most common mutations that can be targeted for treatment are the KIAA1549-BRAF fusion; BRAF V600E mutation; EGFR, FGFR, PDGFR, NTRK, and CDK4/6 mutations; other MAP kinase pathway alterations; and PI3K/AKT/mTOR activation. The bithalamic high-grade glioma especially demonstrates EGFR mutations which makes it a distinct entity. Targeted therapy, including tyrosine kinas inhibitors has been shown to improve the overall survival compared to conventional therapy in certain situations. Demonstrating the mutation carried by the tumor is very critical in this regard. The purpose of this article is to focus on the treatment of thalamic glioma in pediatric patients in light of molecular information. Full article
(This article belongs to the Special Issue Molecular Insights into Pediatric Brain Tumors: Unraveling the Complexity of Pathogenesis and Identifying New Therapeutic Targets)
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Other

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9 pages, 3332 KB  
Case Report
Targeted Inhibition in Pediatric MET and ALK-Altered Hemispheric Gliomas: Objective Responses Followed by Treatment Resistance
by David Wilson, Sateesh Jayappa, Lora Parker, Eylem Ocal, Tomoko Tanaka, Murat Gokden and Kevin Bielamowicz
Int. J. Mol. Sci. 2025, 26(20), 9864; https://doi.org/10.3390/ijms26209864 - 10 Oct 2025
Cited by 1 | Viewed by 1056
Abstract
Pediatric-type diffuse high-grade gliomas (pHGGs) tend to have a dismal prognosis. Some of these gliomas feature alterations in genes such as ROS1, ALK, MET, and NTRK1–3. Despite development of targeted agents, the therapeutic application of these agents in pHGGs is still unclear. The [...] Read more.
Pediatric-type diffuse high-grade gliomas (pHGGs) tend to have a dismal prognosis. Some of these gliomas feature alterations in genes such as ROS1, ALK, MET, and NTRK1–3. Despite development of targeted agents, the therapeutic application of these agents in pHGGs is still unclear. The aim of this retrospective case series is to report the outcome of two patients with pHGGs who were treated at Arkansas Children’s Hospital with targeted agents (Cabozantinib for a MET fusion in patient 1 and Lorlatinib for an ALK fusion in patient 2) with an initial, objective response followed by treatment resistance. Each diagnosis was determined based on histology, targeted tumor sequencing, and methylation profiling. In both cases, relapse occurred while on targeted inhibition. Recurrent tumor sequencing for patient 2 revealed a MET copy gain suggesting a mechanism of resistance in this patient. Pediatric high-grade gliomas with targetable alterations can show objective responses to pathway inhibition. Relapse after initial response may warrant additional surgical samples to identify new alterations which can lead to changes in therapy. Larger prospective cohorts are needed to study targeted agents in this population, and earlier integration of these agents may be beneficial. Full article
(This article belongs to the Special Issue Molecular Insights into Pediatric Brain Tumors: Unraveling the Complexity of Pathogenesis and Identifying New Therapeutic Targets)
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