Potential importance of early focal radiotherapy following gross total resection for long-term survival in children with embryonal tumors with multilayered rosettes (ETMR)
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PROVIDER: PRJNA674910 | ENA |
REPOSITORIES: ENA
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Project description:Embryonal tumors with multilayered rosettes (ETMR) are rare malignant embryonal brain tumors. The prognosis of ETMR is poor and novel therapeutic approaches are desperately needed. Comprehension of ETMR tumor biology is based on only few previous molecular studies, which mainly relied on the analyses of nucleic acids. In this study, we explored integrated ETMR proteomics with the aim to identify novel therapeutic vulnerabilities in these deadly tumors. Using mass spectrometry, proteome data were acquired from FFPE tissue of 40 embryonal brain tumors (16 ETMR, 9 atypical teratoid/rhabdoid tumors (AT/RT), 15 medulloblastomas (MB)) and integrated with case-matched global DNA methylation data, publicly available transcriptome data, and proteome data of further pediatric brain tumors. Proteome-based cluster analyses grouped ETMR samples according to histomorphology, separating neuropil-rich tumors with neuronal signatures from primitive tumors with signatures relating to stemness and chromosome organization. Microdissection analyses highlighted the close relationship of ETMR histomorphology and proteome profiles, regardless of intra- or intertumoral comparisons. Integrated proteomics showcased that ETMR harbor proteasome regulatory proteins in abundancy, implicating their strong dependency on the proteasome machinery to safeguard proteostasis. Respectively, in vitro cell culture viability assays using embryonal brain tumor cell lines BT183 (ETMR), BT16 (AT/RT), and D283 (MB) highlighted that ETMR cells were highly vulnerable towards treatment with the CNS penetrant proteasome inhibitor Marizomib. In summary, histomorphology stipulates the proteome signatures of ETMR. Pervasive and histomorphology-independent abundancy of proteasome regulatory proteins in ETMR indicates a strong proteasome dependency throughout these tumors. As validated in cell culture experiments, proteasome inhibition poses a promising therapeutic option in ETMR.
2024-01-08 | PXD045268 | Pride
Project description:We have generated DNA methylation profiles of 9 ETMR cases treated at the Medical University of Vienna
2020-11-06 | GSE160958 | GEO
Project description:Embryonal Tumors with Multilayered Rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh- and Wnt-signaling. Co-activation of these pathways in murine neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts based on histology and global gene expression analyses, and point to apical radial glia cells as the possible tumor cell-of-origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic Hedgehog (Shh)- and Wnt-signaling in these precursor cells through downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh-pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the Shh-inhibitor Arsenic trioxide (ATO). Our findings provide a novel mouse model to study this tumor type, demonstrate the driving role of Wnt- and Shh-activation in the growth of ETMRs and propose downstream inhibition of Shh-signaling as a therapeutic option for patients with ETMRs. Gene expression data of hGFAP-cre::Ctnnb1(ex3)Fl/+SmoM2Fl/+ , hGFAP-cre::SmoM2Fl/+ , hGFAP-cre::Ctnnb1(ex3)Fl/+ and Control mice
2017-09-11 | GSE103348 | GEO
Project description:Embryonal tumor with multilayered rosettes (ETMR) is a malignant pediatric brain tumor with a dismal prognosis. The proposed oncogenic driver is amplification and fusion of the chromosome 19 miRNA cluster (C19MC). However, the ramifications of this distinct genetic event as well as the complex tumor architecture and the interactions between malignant cell types in ETMR remain vastly understudied. Here, we have analyzed a cohort of 11 ETMR patients using single-cell transcriptomic and multiplexed spatial protein profiling. We reveal a common, spatially distinct cellular hierarchy, closely resembling normal development presenting as a highly proliferative neural stem cell-like population that gives rise to neuron-like cells. C19MC, which is predominantly expressed in the malignant stem-like population, controls a transcriptional network governing stemness and lineage commitment, indicated by high-resolution miRNA:mRNA analyses. Further, we show that FGF- and NOTCH-signaling, important for cell-cell interactions in ETMR, can be successfully targeted in preclinical ETMR models and ETMR patients. Taken together, our study provides unprecedented new insights into fundamental ETMR biology and a powerful rationale for more effective targeted therapies.
2024-12-31 | GSE231614 | GEO
Project description:Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the C19MC locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on nine consecutive patients and review the role of initiation/timing of radiotherapy on survival. Between 2006 and 2018, nine patients were diagnosed with ETMR. Diagnosis was confirmed histopathologically, immunohistochemically and molecularly. Median age was 25 months (5-38). Location was supratentorial in five, pineal in three, and brainstem in one. Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis. Chemotherapy augmented with intrathecal therapy started a median of 10 days (7-20) after surgery. Only two patients who after gross total resection received radiotherapy very early on (six weeks after diagnosis) are alive and in complete remission 56 and 50 months after diagnosis. All remaining patients for whom radiotherapy was deferred until the end of chemotherapy recurred, albeit none with leptomeningeal disease. A literature research identified 228 patients with ETMR. Including our patients only 26 (11%) of 237 patients survived >36 months with no evidence of disease at last follow-up. All but two long-term (>36 months) survivors received radiotherapy, ten of whom early on following gross total resection (GTR). GTR followed by early focal radiotherapy and intrathecal therapy to prevent leptomeningeal disease are potentially important to improve survival of ETMR in the absence of effective targeted therapies.
| S-EPMC7773839 | biostudies-literature
Project description:PurposeWe explored the use of intraventricular 131I-Omburtamab targeting B7-H3 in patients with ETMR.MethodsPatients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted.ResultsPatients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis).Conclusions131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.
| S-EPMC7416633 | biostudies-literature
Project description: Not available
| S-EPMC10506690 | biostudies-literature
Project description:Embryonal brain tumors (EBTs), arising during early brain development, present significant challenges in understanding pathogenesis and developing treatments. This study explores the efficacy of forebrain organoid models in replicating the complexities of the EBT microenvironment. We established an EBT-forebrain-organoid (EBT-FBO) model, incorporating embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid and rhabdoid tumor (ATRT), using a scalable liquid-handling-assisted coaggregation method. Comprehensive characterization, including wholemount immunostaining, immunohistochemistry, single-cell RNA sequencing, integration with existing datasets, and automated cell-type-specific drug screening, validated the EBT-FBO model. EBT-FBOs closely mimicked mid-gestational fetal brain environments, with EBTs reflecting intratumoral heterogeneity at both histological and transcriptomic levels. Drug screening on ETMR-FBOs identified promising treatment options, including anthracyclins and Triptolide, which demonstrated anti-tumoral effects with minimal neurotoxicity. Scalable EBT-FBO models that resemble immature neuronal microenvironments similar to ETMR or ATRT mark significant progress towards targeted therapy and personalized precision medicine that requires recapitulation of individual tumor heterogeneities.
2025-11-13 | GSE270018 | GEO
Project description:Embryonal brain tumors (EBTs), arising during early brain development, present significant challenges in understanding pathogenesis and developing treatments. This study explores the efficacy of forebrain organoid models in replicating the complexities of the EBT microenvironment. We established an EBT-forebrain-organoid (EBT-FBO) model, incorporating embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid and rhabdoid tumor (ATRT), using a scalable liquid-handling-assisted coaggregation method. Comprehensive characterization, including wholemount immunostaining, immunohistochemistry, single-cell RNA sequencing, integration with existing datasets, and automated cell-type-specific drug screening, validated the EBT-FBO model. EBT-FBOs closely mimicked mid-gestational fetal brain environments, with EBTs reflecting intratumoral heterogeneity at both histological and transcriptomic levels. Drug screening on ETMR-FBOs identified promising treatment options, including anthracyclins and Triptolide, which demonstrated anti-tumoral effects with minimal neurotoxicity. Scalable EBT-FBO models that resemble immature neuronal microenvironments similar to ETMR or ATRT mark significant progress towards targeted therapy and personalized precision medicine that requires recapitulation of individual tumor heterogeneities.
2025-11-13 | GSE270015 | GEO
Project description:Embryonal brain tumors (EBTs), arising during early brain development, present significant challenges in understanding pathogenesis and developing treatments. This study explores the efficacy of forebrain organoid models in replicating the complexities of the EBT microenvironment. We established an EBT-forebrain-organoid (EBT-FBO) model, incorporating embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid and rhabdoid tumor (ATRT), using a scalable liquid-handling-assisted coaggregation method. Comprehensive characterization, including wholemount immunostaining, immunohistochemistry, single-cell RNA sequencing, integration with existing datasets, and automated cell-type-specific drug screening, validated the EBT-FBO model. EBT-FBOs closely mimicked mid-gestational fetal brain environments, with EBTs reflecting intratumoral heterogeneity at both histological and transcriptomic levels. Drug screening on ETMR-FBOs identified promising treatment options, including anthracyclins and Triptolide, which demonstrated anti-tumoral effects with minimal neurotoxicity. Scalable EBT-FBO models that resemble immature neuronal microenvironments similar to ETMR or ATRT mark significant progress towards targeted therapy and personalized precision medicine that requires recapitulation of individual tumor heterogeneities.
2025-11-13 | GSE270070 | GEO