bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-15. HIGH-GRADE GLIOMAS OCCURRING IN TEENAGERS AND YOUNG ADULT PATIENTS COMPRISE NOVEL MOLECULAR SUBGROUPS
Authors: Clarke Matthew , Pereira Rita , Mackay Alan , Grabovska Yura , Clarke Amelia , Nicoll James , Procter John , Moore Andrew , Schagen Joanna , Walker Liam , Roncaroli Federico , Ogunbigi Olumide , Jacques Thomas , Marshall Lynley , Carceller Fernando , Reisz Zita , Al-Sarraj Safa , Vinci Maria , Kurian Kathreena , Ng H K , Brandner Sebastian , Jones Chris 
Published: June 2023

Abstract
High-grade gliomas (HGG) arise in any central nervous system location, in adults and children, with a poor prognosis. HGGs in teenagers and young adults (TYA) are understudied; this project aimed to characterise these tumours and identify potential therapeutic targets. HGG samples (n=195, FFPE/FF, 13-30 years) were collected, excluding well-characterised entities (histone/IDH-mutant). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package), n=195) classified cases against a reference cohort. Calibrated scores guided workflows to characterise mutational landscapes including RNA-based ArcherDx fusion panel (n=112), whole exome sequencing (n=84), and histological reviews in parallel. Well-characterised entities (n=50, including IDH-mutant tumours (n=18), PXA (n=12)) were excluded. Of the cases scoring &gt;0.6, 64% classified as paediatric-type subgroups (pedHGG-RTK1A/B/C (30%), pedHGG-MYCN (10%), pedHGG-A/B (7%), pedHGG-RTK2A (6%)). 29% classified as subgroups more frequently seen in adults (GBM-MES (12%), GBM-RTK1/2 (3%)). 54% classified with a score &lt;0.6. 38% cases were assigned to novel, recently identified, poorly-characterised subgroups with distinct methylation profiles and molecular features (HGG-B, HGG-E, ANTCON, GBM-CBM). Frequency comparisons to publicly available methylation data showed GBM-MES-ATYP tumours are TYA age-specific, in contrast to adult age-specific GBM-MES-TYP. Copy number profiling identified frequent changes across the cohort, including chromosomal gains (chr1q (54%), chr2 (22%), chr7 (41%)) and losses (chr10 (40%), chr13 (64%)). Focal amplifications included PDGFRA (12%), CDK4 (7%), MYCN/ID2 (3%), MYC (2%) and EGFR (0.7%) and the most common focal deletion was CDKN2A/p16 (12%). The most frequent glioma-associated somatic variants included TP53, PDGFRA, EGFR, and NF1. BCOR alterations were enriched compared to adult and paediatric reference cohorts. 10% cases showed a hypermutator phenotype, enriched in HGG-E. CDK4 amplifications were recurrent in GBM-RTK1 and GBM-CBM. Histology showed variable cytological and architectural features within novel subgroups. TYA HGG comprise novel subgroups with distinct methylation profiles and molecular characteristics, representing opportunities to refine future treatment.
IMMU-06. SYSTEMIC MRNA VACCINES RESET IMMUNOGENICITY AGAINST DIFFUSE MIDLINE GLIOMA
Authors: McGuiness James , Weidert Frances , DeVries Anna , Ligon John , Zhang Dingpeng , Von Roemeling Christina , Grippin Adam , Karachi Aida , Qdaisat Sadeem , Thomas Nagheme , Castillo Paul , Huang Jianping , Silver Natalie , Rahman Maryam , Hwang Eugene , Mitchell Duane , Mendez-Gomez Hector , Sayour Elias 
Published: June 2023

Abstract

BACKGROUND
DIPG remains a uniformly fatal disease in dire need of new therapies. There are currently no systemic therapies with proven efficacy against these tumors. To overcome these barriers, we developed a systemic mRNA lipid particle (LP) vaccine that localizes to tumors and reticuloendothelial (RE) organs to modulate both innate and adaptive immunity against poorly immunogenic tumors like DIPG.

OBJECTIVE
We sought to assess whether RNA-LPs encoding for model antigens (e.g. H3K27M) would reprogram innate immunity and simultaneously elicit sustained adaptive immunity against diffuse midline glioma (DMG).

RESULTS
RNA-LP encoding for model antigens elicit massive recruitment of nearly all monocytes and lymphocytes to RE organs secondary to a danger response mediated by release of orchestrated cytokines (IL-12, TNF-α, IFN-α) and chemokines (CCL2, CCL4, CXCL9-10). This corresponds to increases in absolute numbers of activated DCs and T cells in the RE organs of mice and reprogramming the glioma tumor microenvironment in canines (pet dogs with spontaneous disease). In neonatal mice inoculated midline with established murine K2 gliomas, we observed that RNA-LP vaccines encoding for H3K27M (beginning at ~day 30) elicit significant long-term survivorship, which appears curative in the bulk of animals treated. While H3K27M specific constructs appeared superior, we observed improved survivorship with irrelevant mRNA species (i.e. pp65 and GFP) suggesting these tumors to be particularly sensitive to innate immune modulation. In mice with DMGs, we observed clinical symptomatology of edema/hydrocephalus followed by improvement in many animals suggesting pseudoprogression from intratumoral inflammation and remodeling.

CONCLUSION
RNA-LPs reprogram the tumor microenvironment of poorly immunogenic tumors in effect making them ‘hot.’ Treatment responses in murine models of advanced DMGs are encouraging. We are advancing a final RNA-LP formulation for FDA-IND submission and early phase clinical trials for DIPG through multi-institutional consortia.
IMMU-07. TACEDINALINE (CI994), A CLASS I HDAC INHIBITOR, TARGETS INTRINSIC TUMOR GROWTH AND LEPTOMENINGEAL DISSEMINATION IN MYC-DRIVEN MEDULLOBLASTOMA WHILE MAKING THEM SUSCEPTIBLE TO ANTI-CD47 INDUCED MACROPHAGE PHAGOCYTOSIS VIA NF-KB-TGM2 DRIVEN TUMOR INFLAMMATION
Authors: Marquardt Viktoria , Theruvath Johanna , Qin Nan , Picard Daniel , Vibhakar Rajeev , Venkararaman Sujatha , Remke Marc , Mitra Siddhartha 
Published: June 2023

Abstract

BACKGROUND
While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified medulloblastoma, which sensitizes them to macrophage-mediated phagocytosis upon targeting the CD47-SIRPa innate checkpoint pathway.

METHODS
We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), medulloblastoma (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven medulloblastoma. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven medulloblastoma, with little to no activity in non-MYC-driven medulloblastoma, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting Class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in-vitro phagocytosis assays and in-vivo orthotopic xenograft models.

RESULTS
CI-994 displayed anti-tumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven medulloblastoma. Furthermore, RNA sequencing revealed NFκB pathway induction as a response to CI-994 treatment, followed by TGM2 expression, which enhanced inflammatory cytokine secretion. We further show interferon-gamma (IFN-g) release and cell surface expression of engulfment (“eat-me”) signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPa phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice.

CONCLUSION
Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC-amplified medulloblastoma and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
LGG-14. TREATMENT OF TWO PEDIATRIC FGFR-ALTERED LOW-GRADE GLIONEURONAL TUMORS WITH MEK INHIBITION
Authors: Lazow Margot , Thomas Diana , Cottrell Catherine , Kobolt Daniel , Ramadesikan Swetha , Salloum Ralph , Shaikhouni Ammar , Mardis Elaine , Jones Jeremy , Leonard Jeffrey , Boué Daniel , Fouladi Maryam , Schieffer Kathleen 
Published: June 2023

Abstract
Somatic alterations in the fibroblast growth factor receptor (FGFR) gene family (FGFR1/2/3) have been implicated in tumorigenesis across pediatric low-grade glioneuronal neoplasms and represent a potential therapeutic target. FGFR rearrangements and internal tandem duplication (ITD) cause constitutive receptor tyrosine kinase activation, thereby promoting tumor cell growth, differentiation, and survival through complex downstream signaling, including via the mitogen activated protein kinase (MAPK) pathway. With increasing safety and efficacy data in pediatric neuro-oncology, MEK inhibitors may be considered to target MAPK pathway activation in FGFR-altered low-grade glioneuronal tumors, although clinical evidence within this specific molecular subgroup is lacking. Herein, we describe two cases of pediatric low-grade glioneuronal tumors harboring FGFR aberrations with encouraging clinical and radiographic response to MEK inhibition. The first patient has a multiply recurrent left parietal dysembryoplastic neuroepithelial tumor (DNET) with an FGFR1 ITD, diagnosed at eight years of age after presenting with seizures. Despite two surgical resections (with identical pathology), his disease slowly progressed. Oral MEK inhibitor therapy with trametinib was initiated, which he has remained on for the past 9+ months, with stable residual tumor without continued radiographic progression. The second patient was diagnosed at three years of age with focal epilepsy, prompting imaging demonstrating an infiltrative T2/FLAIR-hyperintense right temporal mass. Subtotal resection was performed, with pathology consistent with pediatric-type diffuse low-grade glioma. Molecular profiling identified an FGFR3-TACC3 fusion, with suspected enrichment for MAPK-pathway activation by preliminary RNA-sequencing analyses. Adjuvant therapy with trametinib was started, with small reduction in residual disease burden observed radiographically three months into treatment. Both patients continue on MEK inhibitor therapy with minimal toxicity and adequate control of underlying seizures. Though further research in larger, prospective cohorts with comprehensive biology data is necessary, oral MEK inhibitors represent a feasible and rational treatment consideration for pediatric FGFR-altered low-grade glioneuronal tumors.
LGG-20. LANDSCAPE OF FGFR ALTERATIONS IN PEDIATRIC AND AYA GLIOMAS
Authors: Nobre Liana , Sait Sameer Farouk , Bennet Julie , Larsen Alexandra Gianyini , Ho I-Chen , Gianno Francesca , Lin Andrew , Mellinghoff Ingo , Miller Alexandra , Siddaway Robert , Karijannis Matthias , Tabori Uri , Bale Tejus , Hawkins Cynthia 
Published: June 2023

Abstract
FGFR alterations including single nucleotide variants (SNV) and rearrangements represent common oncogenic alterations found in pediatric low-grade gliomas. From a population-based cohort of over 1800 pediatric and AYA (adolescent and young adult) gliomas, FGFR mutations were found in 6% of pediatric low-grade gliomas (LGG) and 16 % of IDH-WT AYA gliomas. Given the frequency of FGFR driver alterations, we assembled a large cohort of 370 FGFR mutated glioma across all ages (6 months to 87 years) 53% of which were LGG. In the pediatric patients, most (87%) of FGFR altered gliomas were low-grade; while in AYA patients only 67%. Fusions were more frequent in pediatric LGG (60%), while SNVs were more common in AYA LGG (57%). The rearranged genes also differed; pediatric LGG: 26% FGFR1 ITD, 20% FGFR1 fusions, 15% FGFR2 fusions. AYA LGG had equal frequency of FGFR1 and FGFR2 fusions (30%). In adults, high grade gliomas were more common (73%), and frequently had additional oncogenic drivers. In general, additional oncogenic drivers were more common with increasing age and grade. In contrast to pediatric and AYA LGG, FGFR3-TACC3 fusions represented 40% of adult cases. Interestingly, this fusion was also found in 10% of FGFR LGGs overall. Although analysis of clinical outcomes are still ongoing, in our preliminary data 18 patients with FGFR altered low grade gliomas were treated with targeted agents; 3 stopped due to toxicity and were not evaluated for response. From patients on MAPKi 1/6 had a minor response and 3/6 stable disease; while 6/9 on FGFRi had partial or minor responses with additional 3 patients recently initiated on the drug. FGFR alterations are frequently encountered in AYA and pediatric population, molecular characterization is important in guiding prognosis and therapy. Although encouraging, further studies are needed to assess the benefit of FGFR inhibition in these patients.
MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS
Authors: Badodi Sara , Marino Silvia 
Published: June 2023

Abstract
Medulloblastoma (MB) is the most common paediatric malignant brain tumour and is classified into four distinct molecular subgroups (WNT, SHH, G3 and G4), each of them further divided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes play an essential role in MB, particularly in the G4 subgroup. A BMI1High;CHD7Low molecular signature identifies patients with poor survival. We have shown that BMI1High;CHD7Low sustains MB growth through regulation of MAPK/ERK signalling and via epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display over-activation of MAPK/ERK and AKT/mTOR pathways leading to energetic rewiring characterised by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration and significantly extends survival in an in vivo pre-clinical model. Additionally, we identify a synergistic vulnerability of G4 MB to a combination treatment with BMI1 and MAPK/ERK inhibitors that overcomes the acquired resistance induced by single drug therapies. Importantly, we have now analysed recurrent G4 MB and found that the BMI1High;CHD7Low signature is maintained at recurrence and it continues to predict the pharmacological vulnerabilities we previously described. Finally, we extended the analysis to other paediatric brain tumours, including histone mutant gliomas and ependymomas, and identified molecularly defined subgroups that exhibit differential response to the compounds predicted to be effective by the BMI1High;CHD7Low signature, hence expanding the spectrum of tumour potentially amenable to these novel pharmacological approaches.
MDB-26. CDK8 IS AN ONCOGENE IN GROUP 3 MEDULLOBLASTOMA THAT IMPACTS PROTEIN TRANSLATION BY REGULATING THE TRANSCRIPTIONAL ACTIVITY OF RIBOSOMAL GENES
Authors: Wang Dong , Veo Bethany , Pierce Angela , Ritz Caitlin , Vibhakar Rajeev 
Published: June 2023

Abstract
Medulloblastoma (MB) is one of the most common malignant childhood brain tumors. Single-cell RNA-seq analysis of human medulloblastoma patients revealed that Group 3 MBs are dominated by undifferentiated progenitor-like cells with elevated expression of ribosomal genes, suggesting that overactive ribosome biogenesis is a hallmark of Group 3 MB. Using CRISPR-Cas9 screen, we found that Cyclin-dependent kinase 8 (CDK8) is an essential gene for MYC MB viability. We showed that CDK8 facilitates MYC-driven transcriptional programs and is necessary for sustaining expression of MYC. Furthermore, the loss of CDK8 resulted in a reduction in the phosphorylation of RNA polymerase II CTD and caused significant changes in genome transcription. Using cut&run, we found CDK8 directly regulated ribosomal gene transcription activity. CDK8 inhibition impaired ribosome biosynthesis suppressed protein translation and led to a striking reduction in phospho-Pol II binding at the promoter regions and gene bodies of SE-associated genes. The combination of an mTOR inhibitor with CDK8 inhibitors showed remarkable synergy in suppressing ribosome biogenesis, decreasing cell viability and attenuating tumor growth in vitro and in multiple models of MB. This proposal outlines the mechanistic consequences of CDK8 inhibition on ribosome biogenesis and provides pre-clinical validation of CDK8 inhibitor treatment as a novel therapeutic approach in MYC MB.
MDB-27. A PRO-DRUG OF TRIPTOLIDE IN CLINICAL DEVELOPMENT ATTENUATES HIGH-RISK MEDULLOBLASTOMA GROWTH
Authors: Rodriguez-Blanco Jezabel , Salvador April , Suter Robert , Palomo-Caturla Isabel , Viera Megan , Nienhius Ashley Metts , Ayad Nagi , Robbins David 
Published: June 2023

Abstract
Medulloblastoma (MB), the most common malignant brain tumor of childhood, is currently classified in four major subgroups. A natural compound used in Chinese medicine for centuries, triptolide, has been shown to have a potent antitumor activity, and the efficacy of one of its derivatives is being evaluated in the clinic. However, to date no preclinical data supports the use of triptolide for the treatment of patients with MB. Here, we performed bioinformatic analyses to predict which subgroup of medulloblastoma patients would more likely benefit from the use of triptolide, and validated its efficacy in series of ex vivo and in vivo mouse and human derived MB models. Correlation analyses identified Group 3 (G3) MB patients as the most prone to respond to triptolide treatment. Consistent with this prediction, triptolide attenuated the growth of G3 MB at lower doses than those classified as SHH subgroup, increasing symptom-free survival in G3 mouse MB models. Transcriptomic analyses revealed MYC signaling as the key downstream target of triptolide in MB cells. Importantly, a pro-drug of triptolide in clinical development, minnelide, similarly showed efficacy in mouse and human derived G3 in vivo MB models. Our findings highlight the potential of repurposing Minnelide to treat G3 MB patients. Due to their dismal prognosis, inclusion of G3 MB patients in future minnelide clinical trials should be considered.
MDB-39. ASSESSMENT OF MEDULLOBLASTOMA PATIENTS THROUGH MONITORING EXTRACELLULAR VESICLES VIA SURFACE-ENHANCED RAMAN SPECTROSCOPY COMBINED WITH MACHINE LEARNING
Authors: Mata Carolina del Real , Lu Yao , Jalali Mahsa , Montermini Laura , Khatami Marjan , Danieau Geoffroy , Orozco Ana Castillo , Rak Janusz , Garzia Livia , Mahshid Sara 
Published: June 2023

Abstract
Medulloblastoma (MB) is the most common brain pediatric tumor associated with considerable morbidity. While MB is treated with multimodal approaches, including surgery, the currently available technologies fail to provide non-invasive access for continuous assessment of disease progression and therapy efficacy. There is a need to develop monitoring systems for frequent use with minimum invasiveness that provides actionable information incorporating the heterogeneous nature of MB. Liquid biopsy is a non-invasive approach using circulating biomarkers, including nano-sized extracellular vesicles (EVs). EVs are secreted by all cells, even cancerous ones. Molecular composition of cancer EVs contains fingerprints of their parental cell, reflective of salient features of the underlying disease. We used 54 pediatric plasma samples of MB patients to determine feasibility of assessing disease progression through EVs analysis. EVs were isolated from plasma using size exclusion chromatography prior to loading onto unique MoSERS chip. MoSERS platform contains nanostructured capture element for single EV detection capable of profiling liquid biopsy samples for surface-enhanced Raman Spectroscopy. A total of 54 datasets were generated, each comprised of EV spectra collected with the MoSERS chip at a single EV resolution. A spectral library was integrated with the datasets of patients with confirmed MB diagnosis (n=34) and healthy controls (n=20), required to train and test a machine-learning implementation. The combination of MoSERS with robust machine learning algorithm provides a strong analysis and a simple interpretation of the patient’s health status. We optimized a pipeline for the data collection and analysis, demonstrating the feasibility of the MoSERS platform for pediatric cancer indication and need for less than 10 μl of sample to generate each unique dataset. Preliminary results demonstrate that MoSERS performance correlates with the results of clinical standards, providing a proof-of-concept for its implementation as a non-invasive and accessible alternative to monitor the health status of MB patients.
MDB-40. TRANSCRIPTOME-BASED DRUG REPURPOSING IN GROUP 3 MEDULLOBLASTOMA
Authors: Doss David , Kanchan Ranjana , Perumal Naveenkumar , Batra Surinder , Mahapatra Sidharth 
Published: June 2023

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is divided into four molecular subgroups (SHH, WNT, Group 3 [G3], and Group 4 [G4]), each defined by unique genetic and molecular features. G3MB is the most aggressive subgroup, with the lowest five-year survival. Features conferring high risk to G3MB include frequent metastases at diagnosis, MYC amplification, and chromosome i17q. Outcomes for G3MB patients remain dismal, partly due to a lack of G3MB-specific therapies, defining an important gap in MB research. To address this gap, we employed a strategy of comparing the G3MB transcriptomic signature against a repository of chemical perturbagens (LINCS) to identify FDA-approved, blood-brain barrier penetrant drugs capable of reverting the disease signature to a more normal cerebellum-like state. Following preliminary in silico and in vitro screening, we identified four drugs - fluoxetine, sertraline, simvastatin, and nortriptyline - that passed screening criteria and demonstrated cytotoxicity against HDMB03 cells at low micromolar doses. Each compound also inhibited clonogenicity, impaired wound healing, and impeded cell migration and invasion. Further, each compound induced apoptosis as evidenced by annexin V and propidium iodide staining. Western blotting confirmed both dose- and time-dependent increases in the expression of key apoptotic markers. Since nortriptyline possessed the best cytotoxicity profile against HDMB03 cells, we interrogated the transcriptome of HDMB03 cells treated with nortriptyline to identify cancer-related pathways inhibited by drug treatment. Our data revealed strong inhibition of E2F transcription factors, which are critical to cancer cell cycle progression and proliferation. Notably, five of the six E2F transcription factors as well as a panel of E2F target genes (HN1, KIF4A, CDCA3, CDCA8, and SSRP1) are all specifically upregulated in G3MB. This study highlights the promise of drug discovery and repurposing using subgroup-specific transcriptomes, which may deliver effective treatments expeditiously to high-risk patients.