2026-07-11 | Mapping epigenetic alterations across brain tumor hallmarks.
Central nervous system tumors represent a heterogeneous group of diseases, mainly localized in the brain. Among them, malignant brain tumors represent some of the most aggressive cancers. In adults, only approximately 30% of patients diagnosed with glioblastoma survive beyond two years. Similarly, several pediatric-predominant brain tumors, including medulloblastoma, diffuse intrinsic pontine glioma, and ependymoma, remain among the deadliest solid tumors in children. Therefore, a deeper understanding of brain tumor biology is imperative for the development of more effective therapeutic strategies. Dysregulated epigenetic control has emerged as a critical driver of brain tumor initiation and progression, influencing malignant phenotypes across multiple stages of the disease. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, regulate gene expression programs that contribute to all hallmarks of cancer by modulating the activity of tumor suppressor genes and oncogenes. Given the central role of epigenetics in brain tumorigenesis and the potentially reversible nature of these alterations, epigenetic mechanisms represent particularly attractive therapeutic targets. Although several epigenetic drugs have shown promising results in preclinical and clinical studies, their clinical application remains constrained by a limited knowledge of the brain tumor epigenome and by challenges related to tumor location and drug delivery. In this review, we summarize key epigenetically regulated genes and dysregulated microRNAs across major brain tumor types and link these alterations to specific cancer hallmarks. We further highlight representative examples of epigenetic therapies whose effects converge on hallmark-associated oncogenic processes.
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2026-07-10 | Strategic modulation to avoid radiation toxicities for brain integrity (SMART-BRAIN).
Patients with medulloblastoma require craniospinal irradiation (CSI) to optimize disease control; however, cranial irradiation is associated with significant morbidity. We sought to develop a novel target volume (CTV_2340 cGy) and explore dosimetric benefits to minimize cognitive toxicity. We conducted a literature review to confirm patterns of failure for average risk medulloblastoma to develop the CTV_2340 definition approach. Five patients (ages 4-16 years) were identified and proton and photon plans were generated for the new CTV_2340. Planning target goals included V100% ≥ 95% (the entire volume receiving at least 95% prescription dose) and V98% ≥ 97%. Proton planning included 3D robust optimization +/- 2 mm and +/- 2% range uncertainties. Photon plans included a 1 mm planning target volume. Medulloblastoma principally recurs in the ventricular system, periventricular region, cortical surface, or posterior fossa, supporting potential omission of remaining non-target-brain (NTB, e.g. white matter tracts, thalami). The novel CTV_2340 included these regions with a 1 mm brain expansion. All proton-based plans achieved appropriate target coverage. Median whole brain volumes were 1317.1 cc (range: 1116.0-1442.1), reflecting brain size over the age spectrum. Median NTB was 15% of the brain volume (9-31%), whereas the hippocampi were < 1%. Median NTB_V12Gy and V18Gy were: 91.7% (79.3-92.3) and 70.2% (59.8-78.2). Median NTB_minimum and NTB_mean were: 2.1 Gy (0.8-2.9) and 19.4 Gy (18.0-20.2). CTV_2340 overlapped with the hippocampi, limiting hippocampal sparing (median V18 Gy 99.1%). Photon-based planning showed inferior target coverage with minimal sparing. This study introduces a strategic approach to reduce radiotherapy-related neurotoxicity in medulloblastoma through proton-based sparing of critical brain regions. Multi-institutional studies are warranted to further advance this approach.
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2026-07-10 | Paediatric therapeutic development workshop on medulloblastoma.
The second Paediatric Therapeutic Development Workshop focused on medulloblastoma. Between 60-70% of patients with medulloblastoma survive, but survivors have significant long-term side effects, and the highest-risk groups have a probability of survival <10%. Thus, the unmet need is to develop therapeutics targeting specific vulnerabilities in medulloblastoma including poor prognosis disease groups (SHH-medulloblastoma, MYCN amplified or TP53 mutated; and Group 3 medulloblastoma, c-MYC amplified) and developing less-toxic therapies for good prognosis disease (WNT-medulloblastoma). The Workshop concluded that (i) targeting SRC by a degrader is a high priority, (ii) inhibition of c-MYC and MYCN tumour-relevant functions for poor prognosis groups is a priority, (iii) targeting WNT-medulloblastoma via a radiolabelled theranostic antibody is an innovative approach for good prognosis tumours to further reduce toxicity, and (iv) B7-H3 has many advantages for CAR T-cell and ADC-based approaches. Based on currently available evidence, combinations of central nervous system penetrant selective PARP-1, CHK1/2 or CDK9 inhibitors with an ATR inhibitor could potentially be evaluated in early-phase trials for high-risk patients; however, these combinations require robust evaluation in pre-clinical models first. Early-phase clinical studies should be international, have novel designs to address small patient numbers and based on an understanding of biology with correlative biological studies. Both developing therapeutics targeting specific vulnerabilities in medulloblastoma and evaluating combinations of existing medicinal products are required to improve outcome and reduce long term sequalae.
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