tbuckley/cabot-search huggingface dataset:
EPEN-06. IDENTIFICATION OF CSF MIRNA BIOMARKERS FOR THE EARLY DETECTION OF MEASURABLE RESIDUAL DISEASE IN PAEDIATRIC EPENDYMOMA: A BIOMECA STUDY
Authors: Rebecca J Chapman, Zachary G L Scurlock, Cinzia G Scarpini, Anbarasu A Lourdusamy, Timothy A Ritzmann, Matthew J Murray, Richard G Grundy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymoma (EPN) is the second most common malignant paediatric brain tumour. 50% of children relapse. Detection of Measurable Residual Disease (MRD) via MRI is difficult and lacks sensitivity for very early recurrence, necessitating an urgent need for identifying new, robust biomarkers for the early diagnosis, prognosis, and clinical management of disease progression in EPN. We hypothesise that microRNA (miRNA) quantification in the cerebrospinal fluid (CSF) will have clinical utility in the early detection of MRD in these patients. PATIENTS/METHODS A discovery cohort of EPN CSF samples (n=12) from patients enrolled on the SIOP Ependymoma II clinical trial (trials.gov identifier: NCT02265770) and control leukaemia CSF samples (n=8) underwent RNA-sequencing (QIAGEN) after total RNA extraction using QIAGEN miRNeasy Serum/Plasma kit. The EPN cohort consisted of infratentorial (IT; n=9), supratentorial (ST; n=1) and spinal (SP; n=2) cases taken prior to, or at, resection (primary/relapse). RESULTS Raw sequencing data entered a quality-control pipeline (Tally/Cutadapt), followed by alignment to miRBase-v22 (https://mirbase.org/) using Chimira (PMID:26093149). Two outlying (infratentorial) EPN samples were removed, leaving a 10 (IT+ST+SP) versus 8 comparison. Extracted raw counts were normalised across samples using DESeq2 (PMID:25516281) and 87 differentially-expressed miRNAs identified (adj-p&amp;lt;0.05). EPN samples completely segregated from controls on clustering/heatmap analysis. From these 87 miRNAs, a core set of 53 were overlapping in comparisons removing spinal (IT+ST remaining) and supratentorial (IT alone) samples. These miRNAs underwent combined ranking by adjusted-p and abundance (normalised count) values, and top-ranking candidates taken forward for confirmation using highly-sensitive Taqman PCR, prior to validation in additional samples. CONCLUSION Circulating miRNA quantification offers promise for EPN diagnosis and MRD detection. Further CSF study in larger patient cohorts, and serum/plasma analysis, are now warranted.
HGG-10. YAP1-MAML2 FUSION IN YOUNG CHILDREN WITH PEDIATRIC HIGH-GRADE GLIOMA: A CASE REPORT
Authors: Emily Jewels, Samuel Bergeron-Gravel, Simon Lagacé, Lili-Naz Hazrati, Stephen Saikali, Christopher Dunham, Sylvia Cheng
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade gliomas (HGG) in children are a heterogeneous group of central nervous system (CNS) tumors that are very aggressive and highly malignant. Few patients achieve long-term survival despite decades of clinical trials. International collaborations have sought to better describe and understand the genetic underpinnings of pediatric HGG in hopes to uncover more effective treatment options. We report two HGG cases of young children with a YAP1-MAML2 fusion. METHODS Clinical data was collected retrospectively, and pathology was reviewed to confirm the diagnosis. RNA sequencing was performed using the Illumina TruSight RNA Pan-cancer Next Generation Sequencing Panel. Methylation profiling was completed using the HumanMethylation450 BeadChip platform (Illumina, San Diego, CA). RESULTS Two children ages less than 5 years with HGG were identified to have the YAP1-MAML2 fusion. One child was diagnosed at age 4 years and had an additional somatic BRAF V600D mutation. The child was treated initially with surgical debulking and cisplatin-based chemotherapy but had rapid clinical and radiologic progression. Due to the BRAF V600D mutation, the child started Dabrafenib and Trametinib but continued to have rapid craniospinal dissemination and died within 8 weeks of presentation. The second child was diagnosed at age 2 years and had an additional oncogenic PTENpF341V mutation. DNA methylation profiling on this tumor did not show evidence of clustering with any known CNS tumor entity. This child was treated with surgical debulking, chemotherapy (Baby POG), focal radiation 5400cGy, and maintenance chemotherapy (lomustine and temozolomide as per COG ACNS 0423). This child continues to have stable residual disease 29 months from presentation. CONCLUSION We present two cases of HGG in young children with a unique YAP1-MAML2 fusion. Future studies are needed to further characterize the significance of how this new molecular alteration impacts treatment and long-term outcomes in pediatric HGG.
DIPG-39. ONCOHISTONE H3.3K27M-DRIVEN CREB5/ID1 AXIS DICTATES THE MALIGNANT CELL STATES OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Wei Zhou, Cheng Xu, Yujie Tang, Changcun Pan, Liwei Zhang, Qiaoran Xi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric cancer characterized by the presence of H3K27M-oncohistones, which drive relentless proliferation and differentiation arrest. This study focuses on the H3.3K27M DIPG subtype and investigates the role of the oncohistone-driven CREB5/ID1 axis in promoting malignancy. METHODS We employed a variety of biological in vitro assays and xenograft mouse models utilizing several H3.3K27M and H3.1K27M DIPG cell lines to evaluate the impact of the studied factors on the growth of DIPGs. Additionally, we employed methodologies in molecular biology, bioinformatics, drug screening, and biochemistry to elucidate the underlying mechanisms of tumorigenesis. RESULTS Through inhibition of ID1, this study explores the induction of cellular differentiation and apoptosis in H3.3K27M DIPG, shedding light on the oncogenic mechanisms at play. The intricate regulation of ID1, linked to CREB5—an oncogenic contributor independent of BMP signaling—is elucidated. The involvement of the SWI/SNF complex as a co-regulator of CREB5 is also examined. Moreover, our findings reveal that H3.3K27M-oncohistone triggers CREB5 overexpression, facilitating the formation of a super-enhancer promoter loop at the CREB5 locus. Disruption of this loop demonstrates potent anti-tumor efficacy in treating DIPG. Additionally, the combination of a compound targeting the CREB5/ID1 axis and a BRG1 inhibitor shows promise for DIPG treatment. CONCLUSIONS This research unveils key molecular pathways specific to the H3.3K27M DIPG subtype, offering valuable insights for potential therapeutic interventions against this lethal pediatric cancer. Inhibiting the CREB5/ID1 axis represents a promising strategy for inducing differentiation and apoptosis in DIPG cells, highlighting the potential for targeted therapies in combating this disease.
EPEN-10. INDUCING A SENESCENCE PHENOTYPE BY BROMODOMAIN INHIBITION IN HIGH-RISK EPENDYMOMA
Authors: Carola N Jaunecker, Julia Freund, Anna Laemmerer, Mieke Roosen, Dominik Kirchhofer, Antonia Otto, Sybille Madlener, Leah Mager, Katharina Bruckner, Natalia Stepien, Christine Pirker, Lisa Gabler, Daniel Senfter, Anne Jenseit, Peter Kuess, Franziska Eckert, Sabine Spiegl-Kreinecker, Cristian Dorfer, Mariella Filbin, Marcel Kool, Johannes Gojo, Walter Berger, Daniela Loetsch-Gojo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymomas (EPN) constitute 10% of pediatric brain tumors. WHO classification identified 10 molecular subtypes, with ZFTA fusion-driven supratentorial tumors (ST-ZFTA) and posterior fossa group A (PFA) being amongst the most aggressive ones. Current therapeutic success relies on local treatments, emphasizing the urgent need for novel targets. Epigenetic dysregulation is a major contributor to EPN aggressiveness. Bromodomain and extra-terminal domain (BET) proteins are transcriptional mediators involved in proto-oncogene transcription, thereby representing promising targets in cancer therapy. As the BET protein BRD4 co-regulates ZFTA-RELA fusion-mediated aberrant transcription, BET inhibitors emerge as novel targeted therapy approach in ST-ZFTA. METHODS Initial assessments encompassed primary, patient-derived (n=9) cell models representing ST-ZFTA and PFA EPN. RNA sequencing of two ZFTA-RELA models was performed, using DGE and GSEA analyses to discern altered pathways following BET-inhibition. On functional level, we investigated sensitivity towards BET-inhibition using cell viability, clone- and sphere formation assays, as well as Western blot and qPCR after treatment. Additionally, anti-tumor effects in genetically engineered cerebral organoids were assessed. RESULTS First investigations showed elevated BRD2 and BRD4 levels in ST-ZFTA compared to PFA models. Accordingly, treatment with BET inhibitors resulted in reduced survival and cell cycle arrest, evidenced by cell viability and clone formation assays, along with increased p21 and cleaved PARP levels in Western blot analyses. RNA sequencing revealed altered pathways associated with cell-cycle regulation and senescence following BET inhibition, supported by downregulation of the telomerase subunit TERT and genes of the senescence-associated secretory phenotype. Additionally, BET inhibitors exhibited synergistic effects with EZH2- and PARP inhibitors primarily in ZFTA-RELA cell lines, as well as decreased tumor volumes in ZFTA-RELA-driven cerebral organoids. CONCLUSIONS Summarizing, we show drastic effects of BET-inhibition in ZFTA-RELA EPN. Subsequently, the influence of Bromodomain inhibition on stemness and senescence, particularly combined with radio- and chemotherapy will be investigated.
DIPG-78. OSSEOUS METASTASIS IN DIFFUSE MIDLINE GLIOMA: A CASE REPORT AND REVIEW OF LITERATURE
Authors: Vibhuti Agarwal, Ramamoorthy Nagasubramanian, Rochelle Maxwell, Dorothea Douglas-Lindsay, Naren Ramakrishna, Laura Hayes, Tushar Chandra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG), H3K 27M-altered are uniformly fatal CNS tumors with 2-year overall survival of less than 10%. Neuroaxis dissemination with disease progression is well known. However, osseous metastasis is a rare occurrence. METHODS We report a patient with localized DMG at diagnosis with subsequent craniospinal and osseous metastasis. We also performed an updated literature review on DMG with extra-neural metastasis (ENM). RESULTS At 11 years of age, the patient presented with progressively worsening headache and vomiting and was found to have a tumor within the right thalamus with mild mass effect on the right lateral ventricle without hydrocephalus. The patient underwent stereotactic tumor biopsy with pathology consistent with DMG, H3K 27-altered. Whole exome sequencing revealed alterations in H3-3A, TP53 and PTPN11. Treatment consisted of upfront focal radiation therapy with subsequent stabilization of the thalamic lesion. However, within 1.5 months of completing radiotherapy, the patient developed drop metastasis, intracranial leptomeningeal dissemination, and diffuse osseous metastasis within the spine, bilateral iliac wings, and ribs. The patient died from disease progression within 2 months of metastatic progression, 6 months from initial diagnosis. Review of literature yielded 11 cases of ENM in pediatric patients with DMG, H3K 27M-altered. Four patients had ENM at diagnosis. The remaining seven patients developed extra CNS metastasis within 1-6 months of diagnosis. Eight patients received upfront radiotherapy with variation in adjuvant chemotherapy. All patients died with median overall survival of 9 months (range, 0.5-24) from diagnosis and 6 months (range, 0.5-22) from ENM occurrence. CONCLUSION ENM in DMG, H3K 27-altered is uncommon. Mechanisms for development of ENM in DMG is unclear. Biopsy and molecular testing for both primary site and ENM should be considered to help elucidate biologic mechanisms of ENM and potentially guide management.
STEM-07. CONSERVATION AND FAITHFUL REPRESENTATION OF CIRCULAR EXTRACHROMOSOMAL DNA IN ORTHOTOPIC PATIENT-DERIVED MEDULLOBLASTOMA XENOGRAFTS
Authors: Rishaan Kenkre, Owen Chapman, Jens Luebeck, Vineet Bafna, Robert J Wechsler-Reya, Jill Mesirov, Lukas Chavez
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Extrachromosomal DNA (ecDNA) drives tumor heterogeneity and correlates with poor survival across various cancer types. Patient-derived xenograft (PDX) models facilitate preclinical drug testing in vivo, enabling tumor growth analysis and molecular tumor profiling. These models, combined with single-cell profiling, offer insights into intratumoral heterogeneity under therapeutic pressure and the emergence of drug resistance. We investigate the abundance and conservation of ecDNA in PDX models to assess the faithful representation of ecDNA compared to their corresponding primary tumors. METHODS Whole-genome sequencing (WGS) was applied to 27 medulloblastoma (MB) PDX models and their tumors of origin using Amplicon Architect. ecDNA frequency in these models was also compared to that in the MB patient population. Optical genome mapping enabled accurate and reliable ecDNA sequence reconstructions. Multiome single-cell RNA and ATAC-sequencing of a PDX tumor enabled analysis of ecDNA conservation and intratumoral heterogeneity compared to similar data previously obtained from the primary tumor. RESULTS ecDNA is largely conserved in PDX models, emphasizing their relevance as faithful models of the primary tumors. MB PDX models exhibit significant higher ecDNA frequency (16 out of 27 tumors) as compared to their frequency in the overall patient population (~18%), suggesting ecDNA as a driver for successful establishment of MB PDX models. Single-cell analysis revealed that ecDNA is omnipresent in almost all PDX tumor cells, contrasting with only ~9% of tumor cells in the primary tumor. CONCLUSIONS ecDNA analysis in medulloblastoma primary tumors and in PDX models revealed that ecDNA is preserved in PDX models. These findings emphasize the relevance of PDX models in preclinical in vivo studies aimed at analyzing the role of ecDNA under therapeutic pressure and for analyzing clonal selection along with molecular evolution of ecDNA during the development of therapeutic resistance.
DIPG-80. IMAGING CHARACTERISTICS IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA AND OUTCOME: THE MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Lea M Stitzlein, Muhammad Baig, Jiasen He, Arnold Paulino, Debra N Yeboa, Susana Calle, Nazanin Majd, Susan McGovern, Wafik Zaky
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) occurs exclusively in children and, although rare, carries a poor prognosis with a median survival of approximately 10 months. Diagnosis is made on clinical and radiological appearance of the tumor. The treatment for DIPG is radiation therapy, but it is inadequate as most patients experience rapid progression and succumb to the disease. Our study sought to review radiological characteristics and survival outcomes in pediatric DIPG patients at MD Anderson Cancer Center to better understand imaging and improve current DIPG management. METHODS We performed a retrospective review of demographic and clinical data of patients with radiographic diagnosis of DIPG from 2006-2019, with IRB approval. The patients included in this study were treated at The University of Texas MD Anderson Cancer Center. Imaging findings upon diagnosis of DIPG, including the presence of hydrocephalus, intratumoral bleeding, contrast enhancement, and necrosis, were correlated with survival using Kaplan-Meier methods RESULTS This study included 25 patients diagnosed with DIPG via MRI imaging. The median OS was 13.7 months and median PFS was 10 months for this cohort. At diagnosis, if the patient had hydrocephalus or intratumoral bleeding, the median PFS were shorter compared with those who did not (8.5 and 5.4 months vs 12.2 and 10.8 months; Log-rank, P=0.019 and P=0.029, respectively). Other imaging findings, including contrast enhancement (CE) or presence of necrosis, are trending toward worse outcomes (CE vs no CE: PFS 7.9 vs 11.1 months, P=0.10; necrosis vs no necrosis: PFS 5.2 vs 10.5 months, P=0.78, respectively) CONCLUSION Imaging characteristics at diagnosis can be predictive of outcome. Hence, we propose to consider early interventions for these subgroups with worse outcomes to proceed with shunt placement and early enrollment for clinical trials as feasible. To further validate these findings, a large prospective study is required.
HGG-11. TRANS-SPECIES STUDY OF IDH-MUTANT REPLICATION-REPAIR DEFICIENT HIGH-GRADE GLIOMAS (RRD-HGG) AND RESPONSE TO COMBINED TARGETED AND IMMUNOTHERAPY: AN IRRDC STUDY
Authors: Anirban Das, Nicholas R Fernandez, Kevin J Bielamowicz, Gadi Abebe-Campino, Shani Caspi, Nyman Per, Richard T Graham, John Y Kim, Mari Wilhelmsson, Mette Jorgensen, Orli Michaeli, Maria Baro Fernández, Amanda Li, Adrian Levine, Zoya Aamir, Lucie Stengs, Logine Negm, Vanessa Bianchi, Melissa Edwards, Julie Bennett, Birgit Ertl-Wagner, Peter Dirks, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND IDH-mutant gliomas comprise &amp;lt;10% of HGG in children. RRD-HGG comprise 5-10% of childhood HGG, demonstrate high mutation burden (TMB) and respond to immune-checkpoint inhibition (ICI). The impact of RRD with childhood IDH-mutant gliomas, and effective therapeutic options for these patients are not well-established. METHODS Clinical and multi-omic analyses were performed on IDHmut-RRD-HGG registered to the IRRDC and the glioma taskforce. Tumor development and genomic data were studied from a novel IDHmut-RRD-HGG immunocompetent mouse model. Outcome following ICI and targeted therapy were evaluated. RESULTS IDH mut-RRD-HGG accounted for &amp;gt;60% of childhood IDH-mutant-HGG. Conversely, IDH1-mutations were detected in 20% of RRD-HGG. All patients (n=48) harboured germline mutations in MMR genes (CMMRD: 62%, Lynch syndrome: 38%). Contrary to sporadic IDH-mutant-gliomas, the majority (&amp;gt;90%) were high-grade. Diffuse/multifocal involvement, predominantly involving the frontal lobe, was frequent. TMB was lower than IDH-wildtype RRD-HGG (median: 28 mutations/Mb, p&amp;lt;0.05). Secondary POLE/POLD1 mutations were absent. TP53 and ATRX were frequent somatic hits. Copy number changes, particularly loss of CDKN2A/2B, were common. CD8-T-cell infiltration (immunohistochemistry) and tumor inflammation score (transcriptome) were lower than IDH-wildtype RRD-HGG (p&amp;lt;0.05). A novel mouse model (Olig2Cre+/Msh2LoxP/LSL-Idh1R132H) revealed similar lower TMB, diffuse cerebral involvement, slower growth, and low immune infiltrates as compared with IDH-wildtype RRD-HGG models. IDHmut-RRD-HGG demonstrated worse survival as compared to sporadic IDH-mutant-HGG (p&amp;lt;0.001). Within RRD-HGG, ICI monotherapy resulted in inferior survival in IDHmut-RRD-HGG vs IDH-wildtype RRD-HGG (p&amp;lt;0.05). Five patients developed metachronous IDHmut-RRD-HGG while on anti-PD1 treatment for IDH-wildtype RRD-HGG, suggesting intrinsic resistance. Interestingly, an IDH-inhibitor demonstrated objective response in 4/8 IDHmut-RRD-HGG. Furthermore, for IDHmut-RRD-HGG on ICI treatment, the addition of an IDH-inhibitor prolonged survival at 12-months in comparison to those without (p=0.01). CONCLUSION Hypermutant RRD-HGG with IDH1;p.R132H harbour unique immuno-biology and do not respond to anti-PD1 monotherapy. The addition of IDH-inhibition demonstrated favourable responses, supporting need for evaluation of the combination in clinical trials.
STEM-04. BIOBANKING PATIENT-DERIVED MODELS OFFERS A PRECISE SPATIAL AND EPIGENETIC APPROACH TO UNRAVEL THE INITIATION, PROGRESSION, AND THERAPEUTIC RESISTANCE OF PEDIATRIC BRAIN TUMORS
Authors: Marlene Deschuyter, Chinar Salmanli, Thibaut Wolf, Benoit Lhermitte, Damien Reita, Quentin Fuchs, Clémence Hubsch, Sophie Foppolo, Monique Dontenwill, Sophie Martin, Natacha Entz-Werlé
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Aggressive brain cancers represent the most lethal forms of tumors in pediatric population. Their molecular drivers and co-alterations are currently guiding therapeutic strategies. Due to heterogeneous nature of these tumors, they are quickly developing resistance to treatment. Recognizing intrinsic and extrinsic mechanisms underlying therapeutic resistance, international scientific community has recognized an urgent need to create precise models of brain tumors capable of predicting therapeutic responses. So far, patient-derived cell lines (PDCL) remain the most reliable model to estimate and mimic evolving scenarios. The primary challenges lie in derivation methods and in cellular and spatial validation. METHODS In the context of the PEDIAMODECAN program, we collected 105 fresh brain tumor samples, including 34 LGG, 24 HGG, 19 ependymomas, 19 medulloblastomas, and 9 other rare entities, to concurrently generate PDCLs and patient-derived xenografts (PDX). RESULTS Regarding the derivation process itself, we successfully maintained 80% of samples in 2D and 54% in PDX models. As anticipated, the LGG group showed the higher percentage of PDX failure (90%). Nevertheless, for high-grade subtypes, PDX generation rate increased to 85,7%. No correlation was found between derivation success and a shorter interval between surgical removal and dissociation processes. Histological analysis of PDXs models confirmed the similar microscopic features to those of primary tumors. Next-Generation Sequencing (NGS), methylome assays and spatial transcriptomic analyses of derived models matched those of the original patient tumors. Epigenetic approaches were proved to be the most effective methods for validating models, in addition to spatial transcriptomic analyses that highlighted similar inter-tumor heterogeneity between PDX models and primary tumor counterparts. CONCLUSIONS Establishing a systematic PDCL/PDX biobank for all pediatric brain tumors represents one of the most effective approaches to develop models capable of accurately reproducing tumoral heterogeneity, histological and molecular diversity, and facilitating the design predictive screenings for targeted therapies combined with irradiation.