Neuro-oncology最新文献

Background: Glioblastoma (GBM) is a highly aggressive brain tumor with limited treatment options. Tumor-associated astrocytes (TAAs) are crucial components of the GBM microenvironment, yet the contribution of alternative splicing (AS) in TAAs to tumor progression remains unclear.

Methods: Transcriptomic and molecular analyses of GBM-associated astrocytes revealed a GBM-induced isoform switch in the RNA-binding protein Quaking (QKI) from the QKI-6 isoform to QKI-5 isoform. The biological role of QKI-5 was examined through gain- and loss-of-function approaches in human astrocytes and co-culture systems with patient-derived glioma stem-like cells (GSCs). In vitro proliferation and sphere-formation assays, along with in vivo orthotopic xenograft models, were used to evaluate tumor growth. Immunoprecipitation and AlphaFold3 structural prediction were performed to investigate the mechanistic interaction between QKI-5 and sterol regulatory element-binding protein 2 (SREBP2).

Results: GBM-induced QKI-5 interacts with SREBP2 to transcriptionally activate cholesterol metabolic enzymes, enhancing astrocyte-derived cholesterol production and promoting GBM growth. Knockdown of QKI-5 or inhibitors for SREBP2-driven signaling suppressed astrocyte-mediated tumor-supportive effects in vitro and in vivo.

Conclusion: QKI-5 drives astrocytic metabolic reprogramming via the QKI-5-SREBP2 axis, fostering a cholesterol-rich tumor microenvironment that supports GBM progression. Targeting this pathway offers a potential therapeutic strategy.

Isocitrate dehydrogenase (IDH) mutant gliomas represent a unique molecular subset of gliomas with distinct metabolic and microstructural characteristics. The recent approval of targeted IDH inhibitors marks a significant advancement in glioma therapy, thereby necessitating robust, quantitative methods for non-invasive assessment of treatment response. This review provides an overview of advanced multiparametric imaging techniques- including proton MR spectroscopy (1H-MRS), diffusion and perfusion MRI, amide proton transfer imaging (APT), and amino acid PET imaging-and their role in detecting IDH-mutations and monitoring therapeutic response to IDH inhibitors. Special emphasis is placed on metabolic imaging of the oncometabolite D-2-hydroxyglutarate (2-HG), a hallmark signature of IDH-mutant gliomas, and how its quantification serves as a surrogate biomarker for diagnosis and treatment monitoring. We also highlight the potential of advanced diffusion MRI based models, which capture microstructural alterations beyond conventional ADC metrics. Some limitations of these techniques in clinical translation are also considered, along with future directions to integrate them into prospective clinical trials.

Background: Sensorineural hearing loss (SNHL) is a common adverse treatment effect among pediatric brain tumor survivors. Neurocognitive functioning among children for whom radiation therapy (RT) is the primary SNHL risk factor has received limited attention. Accordingly, this study investigated neurocognitive outcomes as a function of SNHL among children treated for ependymoma with RT.

Methods: Prospective, serial, neurocognitive and audiology assessments were conducted with 145 children diagnosed with ependymoma and enrolled on a Phase II trial of conformal photon RT (NCT00187226; 53% female; 83% White; mean age at RT = 5.04 ± 4.47 years). SNHL was dichotomized as normal/mild-to-moderate or severe (Chang grade <2b vs. ≥2b). Cognitive risk was assessed for participants with severe SNHL in either ear who completed neurocognitive assessments at least one year after hearing loss (n = 50).

Results: At pre-RT baseline, full scale IQ (FSIQ), verbal learning, and communication were lower than normative expectations (p< .05), with a significant decline in FSIQ, estimated IQ (EIQ), reading, and communication over time. FSIQ and communication skills were worse among children with severe SNHL across all time points (p< .05). EIQ showed greater decline over time in those with severe SNHL (p< .0005), even after accounting for age at RT and pre-RT chemotherapy.

Conclusions: Severe SNHL was associated with worse intellectual functioning and communication skills across time points among pediatric ependymoma survivors. The decline in EIQ suggests increased risk related specifically to hearing loss. Severe SNHL following RT for ependymoma, even if only in one ear, is a cognitive risk factor requiring monitoring and intervention.

Background: Meningiomas are the most common adult brain tumors. While homozygous deletions of CDKN2A/B are linked to early recurrence and hence serve as CNS WHO grade 3 criterion, the clinical impact of hemizygous deletions remains unclear-especially since distinguishing between hemi- and homozygous losses can be technically challenging.

Methods: DNA methylation data, copy-number and mutation data were evaluated on a multicenter cohort of 970 meningiomas. Each sample's CDKN2A/B status was manually classified by visual inspection in relation to whole chromosomal losses and gains in the copy number profile generated from global methylation array in relation to other copy number events. Progression probabilities were determined using the Kaplan-Meier method.

Results: Among 970 meningiomas, n = 30 had homozygous, n = 114 hemizygous (n = 31 segmental; n = 83 focal) and n = 826 CDKN2A/B balanced status. In cases with hemizygous deletions in general, an association with increased progression risk compared to balanced cases was observed, although this did not reach statistical significance (log-rank p = 0.074; HR 1.36, 95% CI [0.97, 1.90]; p = 0.07). However, segmental hemizygous losses were linked to a significantly worse prognosis (log-rank p = 0.0023), but focal hemizygous deletions were not (log-rank p = 0.523). Segmental hemizygous CDKN2A/B deletions were more frequently associated with a higher amount of high-risk copy number variations (CNVs) than focal losses.

Conclusion: Our findings suggest that hemizygous CDKN2A/B deletions overall do not confer worse risks for progression in meningiomas. The signal for segmental deletions may not be locus-specific but just one representation of the generally instable genome of aggressive meningiomas.

Background: Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesised that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets.

Methods: We analysed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the tumor microenvironment. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease.

Results: We observed a shift in toward a heightened immunosuppressive tumor microenvironment at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance.

Conclusions: Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

Plexiform neurofibromas (PNs) are a hallmark of neurofibromatosis type 1 (NF1), affecting ∼50% of individuals with the condition. Originating from Schwann cells and other peripheral nerve sheath components, these tumors can cause significant morbidity, including functional impairment, diminished health-related quality of life, chronic pain, and malignant transformation. Managing NF1-PNs is challenging because of disease variability, differing growth rates, and age-related differences in clinical presentation and treatment tolerability. This review examines current therapeutic strategies, including surgery, medical therapies, and emerging treatments, emphasizing individualized care. Highlighted here is the need for age-specific treatment planning, particularly as disease progression, comorbidities, and side-effect profiles differ between pediatric and adult patients. Optimizing outcomes requires personalized surveillance and coordinated multidisciplinary management across all age groups. While MEK inhibitors (MEKi) provide therapeutic benefit, their long-term efficacy and safety, particularly in pediatric patients who may receive these agents for extended periods, warrant further investigation. Additionally, adult patients face unique comorbidities that may complicate therapy. Superficial PNs and potential MEK inhibitor resistance remain underexplored. Growing interest in combination therapies and adjuvant strategies may improve outcomes. Ongoing research is crucial to personalize treatment regimens, to identify effective combinations, and to refine surveillance protocols, ultimately enhancing long-term quality of life for individuals living with NF1-PN.

Background: IDH-wildtype Glioblastoma (GB) is the most prevalent primary malignant CNS tumour in adults. The standard treatment regimen involves radiotherapy, which can cause radionecrotic (postactinic) changes as a late-onset treatment complication. While radiation is thought to mainly affect resident brain tissue, progressive GB and radionecrotic changes can be challenging to differentiate, as they may present with similar symptoms and appear alike on MRI. Therefore, histopathological examination remains the gold standard of diagnostics.

Methods: The cohort comprised ten samples from nine patients diagnosed with GB, all of whom underwent first-line standard of care treatment including surgery, radio- and chemotherapy with temozolomide. Subsequent radiological examination identified tumour progression in all patients, thus necessitating a second surgery. Following histopathological examination of the material collected from the second surgery, four patients were histologically diagnosed with tumour recurrence, four exhibited no evidence of recurrence but manifested with radionecrotic changes, and one patient demonstrated both. The spatial single cell transcriptomic profiling of the samples was conducted using the Xenium platform.

Results: We generated a comprehensive spatial single cell transcriptomic atlas of progressive GB and brain tissue with radionecrotic changes. Tumour cells were detected in samples from both groups. The employment of the dataset revealed that progressive GB samples contained OPC/NPC-like and proliferating tumour cells with high EGFR expression. Conversely, in samples with radionecrotic changes, tumour cells downregulated their EGFR expression even in the presence of gene amplification and did not show proliferation markers. Additionally, border-associated macrophages infiltrated the tissue and might have promoted gliosis in samples with radionecrotic changes.

Conclusions: This study delineates a complex spatial architecture of brain tissue with post-treatment changes and its discrepancies from progressive GB, thus facilitating future research into novel treatment strategies.

Background: Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor affecting over 300 children annually in the United States. Chimeric antigen receptor (CAR) T cells are a targeted immune effector cell therapy with substantial clinical benefit against hematologic cancers. Against CNS tumors, CAR T cells targeting B7-H3, a protein highly expressed on DIPG, have rapidly advanced from preclinical studies to clinical trials. BrainChild-03 (NCT04185038), a phase 1 trial of repeatedly delivered intracerebroventricular (ICV) B7-H3-targeting CAR T cells (B7-H3 CAR T cells), demonstrated tolerability and potential efficacy for children and young adults with DIPG. However, clinical benefits were not uniformly seen, and multi-agent treatment strategies may be required against such an aggressive disease. Here, we combined B7-H3 CAR T cells with ONC206, an imipridone molecule also under clinical investigation.

Methods: We tested B7-H3 CAR T cells combined with ONC206 across multiple DIPG cell cultures and orthotopic xenograft mouse models.

Results: B7-H3 CAR T cell monotherapy induced robust cytotoxicity while ONC206 treatment resulted in significant mitochondrial dysfunction against DIPG cells. The combination of low effector-to-target ratios of B7-H3 CAR T cells and IC50 concentrations of ONC206 led to significantly enhanced cytotoxicity in vitro (p < 0.003) and increased IL-2, IL-29, VEGF-A, and Granzyme B levels. In vivo combinatorial studies of ONC206 and a single ICV dose of B7-H3 CAR T cells extended survival in DIPG xenograft mouse models.

Conclusions: B7-H3 CAR T cells combined with ONC206 is a feasible and efficacious multi-agent approach against multiple DIPG models.