bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOL-04. FROM MSWI/SNF’S ROLES IN PROTEIN SYNTHESIS TO NEW THERAPEUTIC OPPORTUNITIES
Authors: Van Rechem Capucine 
Published: June 2023

Abstract
The chromatin remodeler complexes mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) are altered in more than 40% of cancers and are involved in therapeutic resistance. In children, SMARCB1 is mutated in 95% of rhabdoid tumors, and the remaining 5% present mutations in SMARCA4. These tumors are typically identified in children younger than three years old and have a very poor prognosis with a survival under one year following diagnosis. SMARCB1 expression is also lost in more than 90% of epithelial sarcomas, a rare and aggressive tumor affecting young adults, and in 50% of pediatric chordomas. Additional mSWI/SNF subunits are also highly mutated in childhood cancers such as ARID1A and ARID1B in neuroblastomas, the most common solid tumor in children, and the ARID subunits and SMARCA4 in medulloblastomas, the most common brain cancer in children. To date, mSWI/SNF roles in normal and cancer cells are still largely undetermined and focus on nuclear functions. However, our assessment of genetic dependencies and drug sensitivity screens revealed that cancer cells mutated for mSWI/SNF are genetically dependent and exclusively sensitive to translation factors and translation pathway inhibitors. We demonstrate that mSWI/SNF complexes are extensively localized in the cytoplasm and that they interact with the translation initiation machinery. Furthermore, short-term inhibition, depletion and cancer mutations of specific subunits alter protein synthesis and increase sensitivity to translation inhibitors. Most mutations in these complexes being considered loss of function, these results suggest a potential therapeutic opportunity for diseases presenting mutations in these complexes. In conclusion, our work demonstrates the chromatin remodelers mSWI/SNF have direct roles in translation that will not only be relevant for the molecular understanding of cancer but also lead to new therapeutic opportunities.
BIOL-13. DEPLOYING NEW MODELS OF NF-1 MUTANT LOW GRADE GLIOMA TO ACCELERATE THERAPEUTIC DEVELOPMENT
Authors: Alaali Lujain , Xu Jinchong , Mumm Jeff , Yuan Ming , Eberhart Charles , Raabe Eric 
Published: June 2023

Abstract
Pediatric low grade glioma (pLGG) research is hampered by a paucity of genetically accurate cell line models and xenografts. To address this need, we have developed and characterized multiple in vivo and organoid models. We used cell reprogramming conditions (CRC) to establish and propagate JHH-NF1-PA1, a NF1-mutant line derived from a low grade optic pathway glioma of a patient with type 1 neurofibromatosis. JHH-NF1-PA1 cells persist and take up midline positions when xenografted into the brains of zebrafish, allowing testing of therapeutics in vivo. We developed a human iPSC-brain organoid system comprising of midline neurons, glia, and microglia, largely recapitulating the microenvironment of midline low grade glioma. Our JHH-NF1-PA1 cells incorporate into these brain organoids, allowing us to test potential therapeutics in an in vitro setting in which the tumor cells grow in the appropriate microenvironment. We have also further defined the mouse BL6 NF1 null glioma cell line 1810, which forms orthotopic xenografts in mice. This last model will be useful for therapeutic testing in a syngeneic BL6 background, allowing assessment of immune infiltration and signaling downstream of NF1 loss and potential immunotherapeutics. Together, these in vitro and in vivo models of NF1-driven low grade glioma make an important contribution to our understanding of the biology of low grade glioma.
BIOL-22. CHILDREN’S BRAIN TUMOR NETWORK PRECLINICAL TUMOR MODELS DEVELOPMENT AND SHARING PLATFORM: COLLABORATIVE MODEL EMPOWERING PEDIATRIC BRAIN TUMOR DISCOVERY AND GLOBAL RESEARCH
Authors: Hollawell Madison , Baubet Valerie , Beale David , Patterson Luke , Biluck Ian , Anthony Ciana , Goel Peeyush , Beck Christopher , Sonawane Poonam , Griffin Crystal , Stern Allison , Madsen Peter , Foster Jessica , Lilly Jena , Mason Jennifer , Trooskin Gerri , Sullivan Catherine , Gehrand Ashley , Morgan Allison , Frenkel Beth , Lehmann Kaitlin , Lopez Lina , Nguyen Thinh , Agbodza Ena , Lopez-gil Valeria , Helili Zeinab , Plisiewicz Alexa , Coleman Noel , Zhu Yuankun , Huang Xiaoyan , Patton Tatiana , Mcgrory Stephanie , Arya Kamnaa , Velasco Ryan , Santi Mariarita , Viaene Angela , Storm Phillip , Koptyra Mateusz , Resnick Adam 
Published: June 2023

Abstract
Pediatric brain tumor preclinical development has suffered from the lack of robust in vitro and in vivo models that span the large number of brain tumor histologies. Opportunities for precision medicine approaches for solid and brain tumors are expanding, including immunotherapies, so it is essential to maximize access to preclinical models for studies of specificity, efficacy, and safety of treatments in ways that align patient models to patient samples and their clinical course. The Children’s Brain Tumor Network (CBTN) seeks to accelerate pediatric brain tumor research and discovery through support of the tumor model development program paired with molecularly characterized patient samples and longitudinal clinical data. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide. Here we present currently available preclinical model resources comprising over 150 cell lines, organoids, and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the use of tumor tissue to generate a combination of cell lines, organoids and/or xenograft models grown in animals. To date, consortium-supported lines have been provided internationally to over 50 projects, encompassing basic biology and translational studies. Molecular data (whole genome sequencing and RNAseq) is currently available for over 80 models and a substantial portion of that cohort undergoes additional large-scale data generation and drug testing through collaborative work with Childhood Cancer Model Atlas, ProCan, and National Center for Advancing Translational Sciences. All models’ data are accompanied with patient molecular and clinical longitudinal information accessible through Kids First Data Resource, CAVATICA and PedcBio portals. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission – to accelerate therapeutic discovery for children suffering from brain tumors.
DIPG-04. TUMOR CELL-INTRINSIC TIM-3 PROMOTES DIFFUSE INTRINSIC PONTINE GLIOMA TUMORIGENESIS
Authors: Ausejo-Mauleon Iker , Laspidea Virginia , de la Nava Daniel , Nuin Sara , Palacios-Alonso Daniel , Marco-Sanz Javier , Becher Oren , Jiang Li , Filbon Mariella G , Pastor Fernando , Alonso Marta M 
Published: June 2023

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor and the leading cause of pediatric death caused by cancer. Despite great strides in the understanding of this disease, the median overall survival is still dismal. TIM-3 is emerging as an alternative to the classic immune checkpoints CTLA-4 and PD-1, and its expression regulates by various mechanisms the function of innate and adaptative immunity. In our work, we demonstrated that TIM-3 is expressed in murine and human DIPG tumor cell lines in vitro and in vivo. TIM-3 knockout using CRISPR/Cas9 was lethal in all human DIPG cell lines evaluated. However, a doxycycline-inducible shRNA-TIM-3 significantly reduced the proliferation of DIPG human cell lines (100% control vs. 25% shRNA TIM-3). Additionally, TIM-3KO murine cell lines displayed a significant decrease in clonogenicity, proliferation, and migration in vitro compared with parental DIPG murine cell lines. Interestingly, loss of TIM-3 expression did not result in cell death, as shown by the evaluation of apoptosis. In vivo evaluation of TIM-3KO cell lines tumorigenicity demonstrated that mice bearing TIM3-KO cells had an overall median survival (35 days) significantly higher than the ones bearing the control guide cells (16 days). RNAseq data indicated that TIM-3 plays a critical role in DIPG murine cells tumorigenesis and survival through the MAPK signaling pathway. Finally, single-cell sequencing and immunochemistry of human tumor samples uncovered TIM-3 expression in patients. TIM-3 expression in DIPG tumor cells correlated with genes positively involved in regulating ion transport, IL-6 production, and response to IFN-γ pathways. We also observed enrichment in genes regulating MAPK and ERK1/ERK2 cascades in these patients. Collectively, these data suggest that TIM-3 expression might have a role in the survival and tumorigenesis of DIPG cells.
DIPG-37. TRANSCRIPTIONAL, EPIGENETIC, AND IMMUNOLOGICAL FEATURES OF PAEDIATRIC-TYPE H3 K27-ALTERED DIFFUSE MIDLINE GLIOMAS ORIGINATING FROM DIFFERENT BRAIN LOCATIONS
Authors: Grabovska Yura , Mackay Alan , Pereira Rita , Sejdiu Drenusha , Burford Anna , Temelso Sara , Clarke Matt , Jones Chris 
Published: June 2023

Abstract
Diffuse midline gliomas (DMG) are highly aggressive brain tumours predominantly affecting young children. The main oncogenic driver is the substitution of lysine 27 to methionine (K27M) in histone 3 (H3) or overexpression of EZHIP resulting in global loss of H3K27me3. Recent single-cell (epi-)genomic studies have identified developmentally-restricted origins and cell states associated with tumour location and patient age, and we aimed to further explore the underlying biology of distinct subgroups of DMG using orthogonal data modalities. A retrospective reanalysis identified 242 patient genome-wide DNA methylation array profiles with a methylation classification of DMG_K27. H3 status was known for 168 cases (H3.3 K27M n=130, H3.1 K27M n=20, H3 WT n=18), with EZHIP overexpression or loss of H3K27me3 was confirmed in 13/18 H3 WT cases. Unsupervised clustering identified two distinct methylation subtypes, specific to brainstem (62/64) or thalamic (25/29) location, and highly enriched for gain of chromosome 1q or loss of 5q, respectively. Differential expression analysis from bulk RNA-Seq data recapitulated the recently-published overexpression of ZIC1/4 early development genes in thalamic tumours and an enrichment of HOX-cluster genes in those of brainstem origin. Within DMGs of the thalamus, we further observed a significant overexpression and hypomethylation of NR2E1, a regulator of bivalent promoters via LSD1-H3K4, and essential for stem cell renewal; and CD96, an immune checkpoint blockade target in NK/T-cells. We confirmed differential immune response expression between tumour location by GSEA as well as deconvolution by methylation CIBERSORT from bulk samples, which we were able to characterise further by by single-cell RNA-sequencing. We report unique copy-number and differentially methylated loci as well as differential expression that recapitulates previously reported single-cell metaprogrammes. We also highlight involvement of neural stem cell development programme in thalamus-type tumours as well as evidence of these tumours as being potential targets for immune therapeutic targeting.
DIPG-38. PATIENT-DERIVED THREE-DIMENSIONAL AVATARS REVEAL CELL-AUTONOMOUS MECHANISMS DRIVING INVASION AND METASTATIC PROGRESSION IN DIFFUSE MIDLINE GLIOMAS
Authors: Bruschi Marco , Midjek Lilia , Ajlil Yassine , Vairy Stephanie , Lancien Manon , Ghermaoui Samia , Kergrohen Thomas , Verreault Maïté , Idbaih Ahmed , Beccaria Kévin , Blauwblomme Thomas , Puget Stéphanie , Tauziede-Espariat Arnault , Varlet Pascale , Dangouloff-Ros Volodia , Boddaert Nathalie , Teuff Gwenael Le , Grill Jacques , Montagnac Guillaume , Elkhatib Nadia , Debily Marie-Anne , Castel David 
Published: June 2023

Abstract
Diffuse midline gliomas H3K27-altered are pediatric tumors associated with dismal survival after diagnosis that are characterized by their ability to infiltrate the entire central nervous system. We show that the extent of tumor invasion and metastatic progression represent critical adverse prognostic factors affecting the survival of DMG patients. Yet, no genetic alterations associate to the tumor progression patterns. We therefore used glioma stem cells collected at diagnosis to create patient-specific 3D avatars. We found that their invasive behaviour faithfully predicts metastatic relapse in patients, thus proving DMG spread is mainly an autonomous ability of tumor cells. This relevant modelling strategy revealed the existence of phenotypic entities associated with distinct migration modalities and capacities. Using transcriptomics of both organoids and primary tumors, we identified the biological programs associated with variable invasiveness. Importantly, we show that Bone Morphogenetic Protein 7 (BMP7) signalling is a crucial tumour-autonomous regulator of DMG invasiveness via the control of a phenotypic switch. We further deciphered effectors downstream of BMP7 stimulation as actionable targets to reduce invasion.
These findings have two possible therapeutic applications. First, glioma stem cell 3D models represent a tool for tumor phenotypic stratification to rapidly predict patients with exacerbated invasiveness and increased risk of metastatic progression. This may allow to propose whole-brain or cranio-spinal irradiation within weeks after diagnosis to prevent the appearance of distant foci. Second, targeting autocrine and short-range BMP7-related signalling may become a useful adjunct to the current therapeutics, which are mainly directed to control the disease locally.
DIPG-47. DISCOVERING A MOLECULAR BASIS FOR VULNERABILITY OF H3K27M-DMG TO HISTONE DEACETYLASE INHIBITORS
Authors: Paine Danyelle , Hao Yue , Tang Nanyun , Biery Matt , Vitanza Nicholas , Berens Michael 
Published: June 2023

Abstract
Using two H3K27M-DMG treatment-naive preclinical models (PBT22 and PBT29), we detected a 20-fold differential response to the histone deacetylase inhibitor, Quisinostat. PBT-22 harbors mutations in H3F3A, TP53, and ASXL2, while PBT-29 has mutations in H3F3A, TP53, PIK3CA and FGFR1. Acetylation and deacetylation of wtH3 alter chromatin structure as part of normal regulation of gene expression. The methionine substitution for Lysine in H3K27M removes this histone from participating in acetylation/deacetylation regulated gene expression. Concomitantly, H3K27M induces a marked reduction in global acetylation of histone tails on wtH3. In the native state of H3K27M DMG with hypoacetylated H3, we posit that the specific pattern of nucleosome integration with genes responsible for cell survival/death underlies the differential vulnerability of DMGs to HDACi. Additionally, the nucleosome integration pattern with cell survival/death genes may be based on the relative abundance of wtH3wt versus H3K27M- histones. Following Quis treatment (48 hrs) in both preclinical models, total wtH3ac protein abundance increased 3-fold, suggesting HDACi stabilizes or impedes K27 acetylated H3 histone turnover. Comparison of differentially expressed genes (DEGs) from control and Quis-treated PBT22 and PBT29 will seed gene ontology analysis focusing on chromatin remodeling, cell death, and growth arrest pathways accounting for differential vulnerability. Findings will be validated by measuring transcripts and proteins (qRT-PCR and ELISA or mass spectrometry) from analytes from a larger panel of DMG cell lines. The data depicts DMG preclinical models with large differential sensitivity to Quis. The long-term goal is to discover a molecular profile of DMGs predictive of the vulnerability to HDACi. The discovery exercise is also likely to yield insight into the development of resistance to HDAC inhibitors.
EPEN-10. SPINAL EPENDYMOMA WITH MYCN-AMPLIFICATION – A DISEASE OF CHILDHOOD AND YOUNG ADULTHOOD WITH DISMAL PROGNOSIS
Authors: Ghasemi David R , Sill Martin , Okonechnikov Konstantin , Shatara Margaret , Yip Stephen , Reisz Zita , Plate Karl-Heinz , Scheie David , Hasselbalch Benedikte , Dohmen Hildegard , Chaouch Amel , Jabado Nada , den Dunnen Wilfred F A , Wesseling Pieter , Fröhling Stefan , Donson Andrew , Capper David , Schüller Ulrich , Pfister Stefan M , Reuss David E , Pajtler Kristian W 
Published: June 2023

Abstract
Spinal ependymoma (EPN) with MYCN-amplification (SP-EPN-MYCN) was recently recognized as a distinct tumor type within the 2021 WHO classification of CNS tumors. To date, information about the epidemiological, clinical, and biological features of SP-EPN-MYCN remain sparse. Using DNA-methylation profiling, we collected a cohort of n = 71 (54 primaries, 17 relapses) SP-EPN-MYCNs. Based on the Heidelberg Methylation Brain Tumor Classifier V12.5, 95.6% (68/71) reached a classifier score of ≥ 0.9. In 68/71 cases, focal amplifications of MYCN were detected by copy number variation (CNV) analysis. Two tumors of pediatric patients harbored MYC-amplifications. Other repeated CNVs amongst the primary cases included gains of chromosomes 5 (5/54) and 18 (5/54), loss of chromosome 10 (14/51), and combined 17p loss and 17q gain (5/54). FISH (n = 17) and immunohistochemistry (n = 19) provided positive results for the detection of the MYCN-amplification. Epidemiological data was available for 63% (34/54) of all patients, showing an even sex distribution (17 female patients). Twenty-four percent (8/34) were children and adolescents younger than 20 years. The rest of the cohort consisted of an AYA-population with an overall median age of 31.5 years. Primary lesions were predominantly located in the thoracic (72%) and/or cervical (55%) spinal cord. Two patients showed extra-CNS metastasis to the humerus and the paraspinal musculature, respectively. At the point of analysis, 38% (10/26) of all patients had died, and 10/16 alive patients had already developed disseminated disease. Of patients with available information, 90% (18/20) had relapsed, whereas 10% (2/20) showed stable disease with leptomeningeal spread. Median PFS (n = 17) and OS (n = 25) were 15,5 (12 – 34) and 85 (61 – NA) months. In summary, SP-EPN-MYCN is a disease with dismal prognosis that can disseminate outside of the CNS and affects mainly children and AYA. Currently, comprehensive multi-omics analyses are ongoing.
METB-01. EXTRACHROMOSOMAL DNA IS ASSOCIATED WITH ONCOGENE AMPLIFICATION AND POOR SURVIVAL ACROSS MULTIPLE PEDIATRIC CANCER TYPES
Authors: Sridhar Sunita , Chapman Owen , Dutta Aditi , Wang Shanqing , Chavez Lukas 
Published: June 2023

Abstract
Circular extrachromosomal DNA (ecDNA) is an important driver of aggressive cancers. Its frequency and impact on the spectrum of pediatric cancers has yet to be fully described. To determine the ecDNA prevalence in various pediatric cancer types, we accessed whole genome sequencing (WGS) data in the Children’s Brain Tumor Network (CBTN) and St. Jude cancer cloud genomics platforms and utilized the bioinformatics tools Amplicon Architect (AA) and Amplicon Classifier (AC) to reconstruct ecDNA sequence structures. We then identified which genes were amplified on the ecDNA and the association of ecDNA with survival using Kaplan Meier curves. In total, we analyzed a retrospective cohort of over 1600 tumor biopsies from 1400 different patients, spanning 69 different tumor types. We identified ecDNA in 14 tumor types. The incidence of ecDNA within these 14 tumors was 16% with the highest percentage in osteosarcoma (47%), pineoblastoma (40%) and rhabdomyosarcoma (40%). The overall incidence of ecDNA across the patient cohort was 10%. In analyzing matched diagnostic/relapse and relapse/progression pairs, ecDNA was noted to evolve over time with progression of disease. Across the cohort, ecDNA was found to be significantly associated with poor survival. Our preliminary results demonstrate that ecDNA is prevalent in pediatric cancer, can contain known and potentially novel oncogenes and can be associated with poorer outcomes across many different pediatric cancer types.
HGG-12. INFANT HEMISPHERIC GLIOMA: CLINICAL AND MOLECULAR CHARACTERISTICS AND RESULTS OF TARGETED THERAPY
Authors: Papusha Ludmila , Druy Alexander , Zaytseva Margarita , Salnikova Ekaterina , Panferova Agnesa , Samarin Alexey , Novichkova Galina , Hwang Eugene , Packer Roger 
Published: June 2023

Abstract
We analyzed an infant cohort consisting of 14 patientswith hemispheric gliomas (hHGG, n=10 and DIGG, n=4) diagnosed at D. Rogachev Center between 2017and 2022.
The hHGG cohort included nine females and one male ranging in age from one week to 22 months. RTK-fusions were detected in all (ROS1 - 4, ALK - 2,NTRK1 – 2, NTRK3 - 1, and EGFR - 1). In one of thesecases, the diagnosis was made retrospectively in a patient initially diagnosed with anaplastic ependymoma who died during treatment. Out of the nine remaining hHGG patients, four (ROS1 - 3, NTRK3-1) experienced rapid progressive disease (PD) duringconventional chemotherapy and one pt (ROS1) after RT. These five pts received targeted therapy with entrectinib with initial good responses in all cases (CR-2, PR-3); one of these patients (ROS1) experienced PD after 7 months of targeted therapy and died of disease. Molecular genetic analysis after the second operationin this case revealed an acquired ROS1 G2032R mutation. Treatment-related adverse events on entrectinib therapy were detected in two patients and included bone fractures and neutrophil count decrease in one case and decrease left ventricular ejection fraction in another patient. Median duration of targeted therapy was 7 months (range, 3-33). From those pts who received only chemotherapy – 2 pts are alive with CR and 1 pt died from complication of CT.
All patients with DIGG are alive without signs of progression after surgery alone. Median follow-up time is 19 months (range, 5-64). Molecular genetic analysis revealed MAPK-pathway alterations in each case (rearrangements of NTRK1-1, ROS-1, RAF1-1, BRAF-1), respectively.
Patients with infant hHGG demonstrate an aggressive course on conventional therapy, especially in cases with ROS1-positive tumors. Targeted therapy may be an effective treatment option but required close monitoring for toxicity and resistance.