bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-17. TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA USING ALLELE-SPECIFIC SIRNA TARGETING H3.3 K27M MUTANT HISTONE
Authors: Wentworth Simon , Batista Ana Rita , Alterman Julia , Khvorova Anastasia , Sena-Esteves Miguel 
Published: June 2023

Abstract
In recent years CNS tumors have surpassed leukemia and lymphoma as the deadliest forms of pediatric cancer, yet many of these tumors remain resistant to treatment. Understanding of the molecular pathology of a particularly fatal pediatric glioma, diffuse intrinsic pontine glioma (DIPG), has improved dramatically over the past decade. However, this knowledge has not yet yielded new targeted therapeutics or advances in treatment. The majority of DIPG tumors (~70-80%) harbor a K27M mutation in the histone H3.3 gene resulting in significant epigenetic changes which drive tumorigenesis. We are utilizing cutting edge siRNA chemistries to develop a therapeutic specifically targeting this oncohistone H3.3 K27M. It has been shown by others that ex vivo disruption of the H3.3 K27M mutant significantly delays tumor development in orthotopic xenograft models and could be a promising target for treatment of disease. New siRNA chemistries allow broad distribution and silencing throughout the brain with durable silencing for months. Utilizing this technology, we have engineered siRNA compounds that can discriminate between wild-type (WT) and K27M mutant H3.3 alleles. Our first-generation compounds achieved &gt;95% silencing of K27M mutant with only 40% silencing of WT H3.3. We have developed second-generation compounds to improve the discrimination between the two alleles. These compounds allow us to selectively knockdown the mutant driver of DIPG tumorigenesis and we hypothesize that silencing of this oncohistone will revert the epigenetic landscape of DIPG to a more wild-type form detrimentally impacting tumor growth and progression. Together the in vivo potency of the new siRNA chemistries combined with the precision allele-specific targeting of mutant K27M oncohistone may be a promising path towards development of an effective and safe therapy for DIPG.
DIPG-55. DIRECT BRAIN-TO-BRAIN WORKFLOW ENABLES THE PRECLINICAL MODELING OF PEDIATRIC GLIOMAS
Authors: Tum Hong , Tse Christopher , Salinas Jennifer , Bayley Nicholas , Zhu Henan , Cloughesy Timothy , Liau Linda , Graeber Thomas , Nathanson David 
Published: June 2023

Abstract
Pediatric high-grade gliomas (pHGG) are one of the leading causes of brain cancer deaths in children. Progress towards the characterization of molecular and genetic features in adult high-grade gliomas and subsequent therapies has not yielded similar results in pHGG patients. pHGGs do not readily establish in culture and there has also been a lack of preclinical models to identify new therapeutic targets. Here, we employ a direct brain-to-brain workflow enabling the establishment of rare pediatric tumors including Atypical Teratoid/Rhabdoid Tumor (ATRT), H3_K27ALT diffuse midline gliomas, and H3_G34MUT diffuse hemispheric xenograft models. These Direct, Patient-Derived Orthotopic Xenografts (DPDOX) models recapitulate the clinical, genomic, and transcriptomic landscape of that of the parental tumors. Moreover, we have incorporated each tumor with a secreted gaussia luciferase reporter enabling the minimally-invasive tracking of intracranial tumor burden over time in response to drug perturbations. Taken together, we present a novel approach to establish pHGG models and evaluate new therapeutics.
DIPG-56. PEDIATRIC GLIOMAS EXHIBIT A UNIQUE LIPID METABOLIC PHENOTYPE DISTINCT FROM ADULT GBMS
Authors: Salinas Jennifer , Minami Jenna , Bayley Nicholas , Tse Christopher , Zhu Henan , Tum Hong , Cloughesy Timothy , Liau Linda , Graber Thomas , Nathanson David 
Published: June 2023

Abstract
Pediatric and adult IDH-wildtype gliomas (GBM) differ in both their clinical and molecular characteristics. However, whether distinct metabolic vulnerabilities exist between these two types of malignant brain tumors is unknown. Here, we performed integrated molecular and lipidomic profiling of both adult IDHwt and pediatric gliomas to identify distinguishable lipid phenotypes and consequent vulnerabilities. This analysis revealed IDHwt gliomas have heightened de novo lipid biosynthetic programs with an elevated abundance of triacylglycerides (TAGs). By contrast, pediatric gliomas exhibited lower lipid biosynthetic capacity and contained a higher enrichment for phospholipids. As a consequence of this unique metabolic program, pediatric gliomas relied of uptake of environmental complex fatty acids derived from normal resident brain cells for growth. Accordingly, therapeutic abrogation of lipid scavenging pathways selectively inhibited proliferation of pediatric gliomas compared to adult IDHwt counterparts. Together, these studies identify distinct metabolic programs among adult and pediatric gliomas, revealing new therapeutically actionable targets to slow pediatric glioma growth.
EPEN-01. ZFTA-RELA FUSION PROGRAMS CONVERGE ON YAP PATHWAY ACTIVATION IN EPENDYMOMA
Authors: Stuckert Austin , Varadharajan Srinidhi , Mack Stephen 
Published: June 2023

Abstract
Approximately two thirds of supratentorial ependymoma are driven by the ZFTA-RELA gene fusion. ZFTA is a recently described gene with a role in DNA binding and transcriptional regulation, while RELA (p65) is a known principal mediator of the canonical NFkB pathway, a pathway activated many human malignancies. The underlying mechanism of NFkB pathway protein interaction with the ZFTA-RELA fusion to drive tumorgenesis has not yet been described. In this study, we utilized our autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain to explore these questions. Using rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) targeting HA-tagged ZFTA-RELA fusion in our IUE model, we demonstrate that both canonical and non-canonical NFkB proteins interact with ZFTA-RELA protein in ZFTA-RELA fusion ependymoma. Focusing on select key NFkB proteins, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) targeting p50/NFkB1, a protein that partners with RELA/p65 in the canonical NFkB pathway, revealing that p50/NFkB1 regulatory programs define active genes that are both distinct from and shared with the ZFTA-RELA fusion protein. Functionally, we performed CRISPR-CAS9 knock out (KO) of p50/NFkB1 and identified no phenotypic effect, as KO lines demonstrated no growth impairment. Furthermore, NFkB targeting drugs did not impair tumor growth. Given these findings, suggesting redundant transcriptional programing, we identified that ZFTA and RELA intersect with TEAD transcription factor programs to activate YAP signaling and that p50 localizes to YAP-TEAD pathway members. Targeting TEAD 1 and 4 with ChIP-Seq, we found that TEAD 1 and 4 co-regulate p50/NFkB1 and ZFTA-RELA target genes. Finally, we demonstrate YAP pathway activation across all supratentorial ependymoma, including ZFTA-RELA ependymoma. Our pathway analysis consistently converged on YAP/TEAD pathways, suggesting collaboration of ZFTA-RELA fusion with YAP/TEAD in transcriptional regulation for these tumors. Targeting YAP/TEAD may therefore represent a promising therapeutic strategy for ZFTA-RELA fusion ependymoma.
EPEN-07. A MULTICENTER STUDY OF POOR PROGNOSIS CHROMOSOME 1Q GAIN AND/OR 6Q LOSS IN POSTERIOR FOSSA A EPENDYMOMA SHOWS INCREASED PREVALENCE FROM 20% AT DIAGNOSIS TO 60% AT FIRST RECURRENCE
Authors: Donson Andrew , Bertrand Kelsey , Riemondy Kent , Gao Dexiang , Sanford Bridget , Norris Gregory , Fu Rui , Willard Nicholas , Griesinger Andrea , Amani Vladimir , Grimaldo Enrique , Hankinson Todd , Booker Ffyona , Grundy Richard , Pajtler Kristian , Ellison David , Ritzmann Timothy 
Published: June 2023

Abstract
Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN types. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA EPN remains largely unknown, which hinders clinical advances. In this longitudinal large multicenter study, we examined matched samples of primary and recurrent disease from PFA EPN patients (n=95) to investigate the biology of recurrence. DNA methylomic data was used to measure copy number variants (CNVs), revealing progressive large scale chromosome gains and losses in successive recurrences. These CNV changes were dominated by chromosome 1q gain and/or 6q loss (1q+/6q-), both previously identified as high-risk factors in PFA EPN, which were present in ~20% at presentation but increased to ~60% at 1st recurrence. Because 6q testing is not routinely performed, this very high incidence at recurrence has not been previously reported. Evolution of chromosomal aberrations was further explored using CNV analysis of single-nuclei RNAseq on approximately 46,000 PFA EPN cells from 6 matched pairs of primary and 1st relapse tumors that harbored CNV changes at recurrence. No evidence of rare subclones in primary tumors was observed, suggesting that chromosomal rearrangement events occur after initial presentation. Cellular and molecular characteristics associated with CNVs were examined by single-nuclei RNAseq, bulk transcriptomic analysis and immunohistochemistry, revealing that 1q+/6q- PFA have a significantly higher mitotic index, increased proportions of proliferative epithelial progenitors and decreased differentiated neoplastic subpopulations. Multivariate survival analyses showed that cases with 1q gain or 6q loss at 1st recurrence were significantly more likely to recur than cases with no 1q or 6q change. The high prevalence of 1q+/6q- at recurrence and the associated shortened survival, suggest that both these abnormalities should be routinely tested for, and used for trial stratification.
METB-10. EXPLAINABLE ARTIFICIAL INTELLIGENCE REVEALS DNA METHYLATION PATTERNS UNDERLYING BRAIN TUMOR CLASSIFICATION
Authors: Benfatto Salvatore , Hovestadt Volker 
Published: June 2023

Abstract
Over 100 different molecular classes of brain tumors are recognized across histopathological grades and age groups. Their precise diagnosis is crucial for prognostication and appropriate treatment decisions, particularly in pediatric patients. Recently, a random forest-based classifier trained on genome-wide DNA methylation profiles has been developed to guide the accurate classification of these tumors. Over recent years, this classifier has been applied to tens-of-thousands of patient tumors all over the world. Clinical and basic neuro-oncology research would benefit greatly from a detailed understanding of the underlying artificial intelligence decision process. However, why the algorithm arrives at a certain prediction remains unclear. Here, we develop an interpretable framework to explain the model’s decisions and to uncover DNA methylation patterns distinguishing different tumor classes. Using this approach, we demonstrate both global and local differences across epigenetic landscapes. For instance, the model frequently uses DNA methylation probes in CpG islands to distinguish IDH mutant gliomas from other tumor classes. Tumor classes associated with global hypomethylation are distinguished by probes located in broad heterochromatic domains. At the level of individual genes, we find hundreds of promoter and gene body regions specifically methylated or unmethylated in specific classes. In general, we detect a high degree of redundant information in the dataset, with multiple genes across the genome distinguishing individual tumor classes, and many CpG probes representing each gene. These findings explain the technical robustness of the array-based classifier, and provide a starting point for the design of more compact point of care assays. The results of our approach are provided to the research community via an interactive web interface. We hope that this resource will help to build up trust in the machine learning-based classifier in clinical settings, foster biomarker discovery, and enable cancer epigenome research in the context of the central nervous system tumors.
METB-13. A SINGLE-CELL GENETIC IN VIVO LINEAGE-TRACING PLATFORM FOR MEDULLOBLASTOMA
Authors: Jung Jangham , Yu Bohyeon , Hoare Owen , Diaz Aaron 
Published: June 2023

Abstract
Comparative single-cell studies of group 3/4 medulloblastomas (MBs) and fetal brain have identified a common hierarchy of glutamatergic-lineage cell types and an apparent cell-of-origin in the rhombic lip. An increased understanding of the genetic regulators of stem-cell maintenance and differentiation in MB would clearly be of therapeutic benefit. There is a significant need for lineage-tracing systems to model MB malignant transformation, progression, and response to therapy. We developed in vivo and in organoid genetic lineage-tracing systems with a single-cell readout. A high-complexity lentiviral library expressing heritable polyadenylated molecular barcodes was transduced into D283 and D425 patient-derived cell lines. Barcoded cells were injected into the brains of immunocompromised mice. Both preimplantation barcoded cultures and the resulting mature tumors were profiled by single-cell RNA-sequencing (scRNA-seq). This captured both endogenous RNA and barcode transcripts. While only minimal barcode clash was detected in the preimplantation cultures, we observed a clonal expansion of barcodes in mature tumors which aligned with phylogenetics analysis of expressed mutations in endogenous RNA. Methods for assessing lineage coupling between transcriptional clusters and inferring their lineage relationship were developed. Ongoing efforts to recover barcodes from tumor sections via spatial transcriptomics will be presented. These studies fill a gap in status quo models of MB which are needed to leverage recent findings derived from single-cell analysis of human tumors.
OUTC-10. SELF-REPORTED RACE AND ETHNICITY AND GENETIC ANCESTRY GROUPS SHOW DISTINCT PREVALENCE AND OUTCOMES ACROSS PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Corbett Ryan , Plisiewicz Alexa , McHugh Sean , Drake Emmett , Brown Miguel A , Zhang Bo , Zhong Chuwei , Kaur Charnpreet , Storm Philip B , Resnick Adam , Waszak Sebastian , Mueller Sabine , Rokita Jo Lynne , Kline Cassie 
Published: June 2023

Abstract

BACKGROUND
Race and ethnicity disparities have been identified in survival of pediatric central nervous system (CNS) tumors. No prior studies have investigated the comparative effects of self-identified race and ethnicity versus genetic ancestry on tumor prevalence and outcome. We examine these contributions in a retrospective analysis of pediatric patients with CNS tumors.

METHODS
Patients from Children’s Brain Tumor Network (CBTN; n=646) and Pacific Pediatric Neuro-Oncology Consortium (PNOC; n=35) with available clinical data and whole genome sequencing were included. Ancestry groups were predicted with somalier and genetic markers from reference individuals of known ancestry that participated in the 1000 Genomes Project: sub-Saharan African (AFR), admixed American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS). Independence of predicted ancestry and self-reported race and ethnicity was assessed with chi-squared tests. Effects of predicted ancestry on survival were estimated using multivariate Cox models with molecular subtype and extent of tumor resection as covariates.

RESULTS
Predicted ancestry groups were highly concordant with self-reported race (χ2=897, p&lt;0.001) and ethnicity (χ2=340, p&lt;0.001). Patients from AFR ancestry were significantly enriched within ATRT (n=26; p=0.001) and neurofibroma plexiform (n=11; p=0.005) and patients with AMR ancestry were enriched within DMG (n=53; p&lt;0.001). Patients diagnosed with H3 wildtype high-grade glioma (n=39) with non-EUR ancestry trended towards worse overall survival (OS; HR=2.0, p=0.07). Patients with ATRT (n=19) with AMR ancestry trended towards worse OS compared to AFRs (HR=4.1, p=0.09) and AFR patients with MB (n=78) trended toward worse OS compared to EUR patients (HR=3.7, p=0.07), including Group 4 MBs (n=39; HR=3.9, p=0.08). Patients with LGG (n=182) with non-EUR ancestry were more likely to have less than gross total/near total resection compared to patients with EUR ancestry (p=0.02).

CONCLUSIONS
Differences in ancestry are seen across pediatric CNS tumor entities and outcomes. Analyses are underway in an additional ~800 patients.
HGG-03. HIGH-GRADE GLIOMA IN YOUNG CHILDREN IS HISTOLOGICALLY, MOLECULARLY, AND CLINICALLY DIVERSE—RESULTS FROM THE SJYC07 TRIAL AND INSTITUTIONAL EXPERIENCE
Authors: Chiang Jason , Bagchi Aditi , Li Xiaoyu , Dhanda Sandeep K , Huang Jie , Pinto Soniya N , Sioson Edgar , Partap Sonia , Fisher Paul G , Bowers Daniel C , Hassall Timothy E G , Lu Congyu , Zaldivar-Peraza Airen , Wright Karen D , Sabin Noah D , Orr Brent A , Onar-Thomas Arzu , Zhou Xin , Ellison David W , Gajjar Amar , Robinson Giles W 
Published: June 2023

Abstract

BACKGROUND
High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies have broadened our understanding of tumor biology, prospective data regarding outcomes and molecular predictors is lacking.

METHODS
Young children (0-5 years) histologically diagnosed with HGG and enrolled on the SJYC07 trial or treated at St Jude Children’s Research Hospital from November 2007 to December 2020 were included. DNA methylation, whole genome (WGS), whole exome (WES), and RNA (RNA-seq) sequencing were performed on available samples and these data were integrated with standard histopathological tests to yield a diagnosis. Clinical characteristics and pre-operative imaging were analyzed.

RESULTS
Fifty-six children (0.0-4.4 years) were identified. Integrated molecular and histopathological analysis split the tumors into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors (i.e., CNS embryonal tumors, CNS sarcomas, neuroepithelial tumors). IHG was the most prevalent (N=22), occurred in the youngest patients (median age 0.4 years; 0-4.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95% CI: 35.52 -79.47) and 90.91% (95%CI: 79.66-100.00) vs. 0.0% and 16.67% (95% CI: 2.78-99.74%) for HGG (p= 0.0043, 0.00013). EFS and OS were not different between IHG and LGG (p=0.95, 0.43). Imaging review of HGG, LGG , IHG and Other CNS tumors showed that IHGs are associated with circumscribed margins (p=0.0047), hemispheric location (p=0.0010), and hemorrhage (p=0.0149).

CONCLUSIONS
HGG in young children is not a single-entity and is best defined by an integrated histopathological and molecular diagnosis. While patients with IHGs display good survival, as compared to other pediatric HGGs, they still suffer severe treatment-related morbidities. Therefore, prompt consideration for reduced adjuvant and molecularly targeted therapies is warranted.
HGG-20. NOVEL PAEDIATRIC CASE OF A SPINAL HIGH-GRADE ASTROCYTOMA WITH PILOID FEATURES IN A PATIENT WITH NOONAN SYNDROME
Authors: Staunton Jordan , Robertson Pamela Ajuyah , Harris Angela , Mayoh Chelsea , Wong Marie , Rumford Megan , Fuentes-Bolanos Noemi , Cowley Mark , Lau Loretta , Ziegler David S , Barahona Paulette , Manoharan Neevika 
Published: June 2023

Abstract
Noonan Syndrome (NS) is a genetic condition, known to be associated with low grade central nervous system tumours in children but only very rarely associated with high-grade gliomas. Here we describe the first reported case of a spinal high-grade astrocytoma with piloid features (HGAP) in a child with NS. This case presented as a diagnostic and treatment dilemma, prior to comprehensive molecular profiling with whole-genome germline and tumour sequencing, tumour transcriptome sequencing and DNA methylation analysis. The methylation profile was a strong match for HGAP and was critical to establish this child’s diagnosis, as this is an essential diagnostic criteria for confirmation of this relatively new tumour group. Sequencing results identified activation of the MAPK signalling pathway with somatic variants in FGFR1 and NF1 and the previously known germline pathogenic variant in PTPN11. The somatic molecular profile was consistent with those previously reported in other HGAP case series and reports, whereas the germline finding has not been previously described in individuals with this tumour type. This patient’s molecular profile adds to the small group of paediatric cases reported in the literature, continuing to expand our understanding of this new WHO diagnostic category. Confirmation of this rare diagnosis was critical to this child’s management and targetable aberrations were identified, providing alternative therapeutic options. The therapeutic targets included known drivers within the MAPK pathway, but also changes not previously associated with HGAP such as differential expression of VEGFA and PD-L1. Together this case underscores the power of precision medicine from a diagnostic, therapeutic and clinical management perspective, and describes an association between HGAP and NS which has not previously been reported.
IMG-04. POTENTIAL TARGETS FOR THERANOSTICS IN PEDIATRIC HIGH-GRADE CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Plasschaert Sabine , Tolboom Nelleke , Kester Lennart , Tops Bastiaan , Hoving Eelco , Poot Alex , Wesseling Pieter , Kranendonk Mariëtte 
Published: June 2023

Abstract
Theranostics refers to the combination of a radioactive drug to identify (diagnose) and another radioactive drug to deliver therapy to cancer. In adult cancer several radiopharmaceuticals with specificity for receptors like cx-chemokine-receptor type 4 (CXCR-4), prostate-membrane specific antigen (PSMA), and somatostatine receptor (SSTR2a) are used. Especially PSMA for prostate cancer and SSTR2a ligands for neuro-endocrine tumors have proven their value. Moreover, novel promising targets like B7-H3 are upcoming. In children the potential of such theranostic drugs have been minimally explored.
AIM of this study is to explore the expression of theranostic markers CXCR-4, PSMA, SSTR2a and B7-H3 in a broad cohort of high-grade pediatric CNS tumors to determine the potential of these imaging ligands in this cohort.
METHODS The expression of CXCR-4, PSMA, SSTR2a and B7-H3 were examined both by RNA (by bulk RNAsequencing) and protein level (by immunohistochemistry (IHC)) (RNA n=161/IHC n=52) in pediatric high-grade CNS tumors: ependymomas (n=33/11), atypical teratoid rhabdoid tumors (ATRT) (n=9/7), medulloblastomas (n=51/11), diffuse midline gliomas H3K27-altered (n=27/9) and other high-grade gliomas (n=41/15).
RESULTS mRNA expression of CXCR-4 was present but low in most tumor types, with the highest expression in medulloblastoma. Immunohistochemistry showed variable CXCR-4 expression, with the highest expression in some medulloblastomas, ependymomas and ATRTs. PSMA (FOLH1) mRNA and protein expression was generally very low. As expected SSTR2a showed a very high mRNA and protein expression only in medulloblastoma samples. Remarkably, B7-H3 (CD276) showed a relatively high expression in all high-grade pediatric CNS tumor types, both on RNA and protein level.
CONCLUSION Of the four potential theranostic targets tested, SSTR2a is an interesting antigen in medulloblastoma. CXCR-4 could be of interest for individual patients with medulloblastoma, ATRT or ependymoma. Finally, B7-H3 is widely but variably expressed on all different tumor types, and seems a promising novel target for theranostics in pediatric CNS tumors.