tbuckley/cabot-search huggingface dataset:
PATH-37. A NEW SUBTYPE OF DIFFUSE MIDLINE GLIOMA, H3 K27 AND BRAF/FGFR1 CO-ALTERED, EXHIBITS SPECIFIC BIOLOGICAL CHARACTERISTICS AND NEW THERAPEUTIC VULNERABILITIES
Authors: Lucie Auffret, Clémentine Barry, Yassine Ajlil, Arnault Tauziède-Espariat, Lisa Mayr, Marie Simbozel, Thomas Kergrohen, Chloé Puiseux, Laurent Riffaud, Pascale Blouin, Anne-Isabelle Bertozzi, Pierre Leblond, Klas Blomgren, Sébastien Froelich, Alberto Picca, Mehdi Touat, Marc Sanson, Kevin Beccaria, Thomas Blauwblomme, Volodia Dangouloff-Ros, Nathalie Boddaert, Johannes Gojo, Mariella Filbin, Pascale Varlet, Marie-Anne Debily, Jacques Grill, David Castel
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumor type is classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System tumors. However, we recently identified a new subtype of DMG by assembling a retrospective cohort of 60 adult and pediatric DMG cases harboring BRAF or FGFR1 mutations in addition to the H3K27M mutation or EZHIP overexpression. Comprehensive clinical, histological, radiological, and genomic, analyses allowed to identify distinct genotype-phenotype characteristics. Contrary to other DMG, these tumors occur more frequently in the thalamus (27% vs. 70% for BRAFV600E or 58% for FGFR1MUT), and in adults in the case of FGFRMUT tumors. Importantly, these patients display a longer overall survival with a median above three years. Unsupervised analysis of DNA methylation profiles regrouped these MAPK-altered DMG in a methylation cluster distinct from other DMG H3K27, but also lower-grade midline tumors driven by FGFR1 or BRAF mutations Additionally, this new DMG subtype harbors atypical radiological and histopathological profiles with calcification and/or a solid tumor component both for BRAFV600E and FGFR1MUT cases that can suggest this differential diagnosis. Further analyses of the transcriptome of these tumors compared to canonical DMG H3K27-altered showed an expression signature of senescence with activation of a TP53/CDKN1A axis, together with a strong upregulation of the PI3K/AKT/MTOR pathway. Our current modelling of the drug response using patient-derived models of these specific DMG will permit to rapidly prioritize treatment strategies. Additionally, our clinical experience in treating these patients suggests a higher response to everolimus and imipridone ONC201 in this specific subtype. In conclusion, DMG H3 K27 and BRAF/FGFR1 co-altered, represent a new subtype of DMG with distinct specific characteristics compared to canonical DMG H3K27 and data accumulated strongly support their separate stratification in clinical trials and specific therapeutic managements.
BIOM-38. OPPOSING EFFECTS OF LINKED CX3CR1 GERMLINE VARIANTS ON INCIDENCE, SURVIVAL, AND IMMUNE ACTIVATION IN GLIOMA
Authors: A Basit Khan, Malcolm McDonald, Rachel Curry, Sungho Lee, Yuhui Yang, Khatri Latha, Benjamin Deneen, Akdes Harmanci, Ganesh Rao
Journal: Neuro-Oncology (2024)

Abstract Linkage-disequilibrium connects CX3CR1 V249I and T280M single-nucleotide polymorphisms; V249I occurs as a single-variant (SV) and T280M exclusively as a double-variant (DV) concurrent with V249I. The effect of these combined haplotypes remains unexplored in glioma. We identified CX3CR1 haplotypes in internal LGG and TCGA GBM cohorts and analyzed median overall survival (mOS). The proportion of each haplotype in glioma and normal patients was assessed via meta-analysis. Bulk RNAseq analysis was conducted in TCGA and internal GBM cohorts and scRNAseq in internal IDH mutant gliomas. In LGG, SV improved mOS (n=14, 21.03yrs) by twofold compared to WT (n=45, 9.41yrs) and DV (n=31, 10.49yrs; p=0.037). In TCGA GBM, SV (n=69, 15.65mo) improved mOS over DV (n=106, mOS 11.74mo; p=0.044). In combined meta-analysis, SV patients had increased risk for glioma development (OR 1.11, 1.03-1.19 p = 0.006) and the WT genotype was protective (OR 0.95, p=0.048). Collagen genes associated with increased immunosuppression (COL6A3: log2FC=2.33, p-adj=0.004; COL6A2: log2FC=1.55, p-adj=.059) were reduced in SV. MME, an endopeptidase associated with radiation resistance, was downregulated in SV (log2FC=3.29, p-adj=2.53e-6). MN1, associated with improved glioma survival, was upregulated in SV (log2FC=-1.76, p-adj=0.001). CCL18, an immunosuppressive chemokine associated with M2 macrophage polarization was reduced in SV (log2FC=2.36, p-adj=0.014). Thus, concomitant with its improved survival, SV is biologically distinct from DV and WT. Using scRNAseq, myeloid-derived cells (microglia/macrophages; 7758 cells) were re-clustered, identifying fourteen clusters. Cells clustered by CX3CR1 status, with 58.2% of SV cells in cluster five and 84.9% of DV cells in clusters six or seven. Cluster five over-expressed IL1B (average-log2FC 3.16), a tumor-suppressive M1 macrophage marker. Clusters six and seven were characterized by IFIT genes (IFIT3 average-log2FC 2.72 and 2.16 respectively), which corresponds to glioma associated microglia from recent scRNAseq microglial atlases. We demonstrate that CX3CR1 SV has improved survival and reduced immunosuppression over wildtype and this is lost with in the linked CX3CR1 DV genotype.
NIMG-30. DEUTERIUM METABOLIC IMAGING (DMI) SHOWS A STRONG RELATION BETWEEN TUMOR GRADE AND GLUCOSE METABOLISM IN PRIMARY BRAIN TUMORS
Authors: Serena Thaw-Poon, Nicholas A Blondin, Yanning Liu, Zachary A Corbin, Joachim Baehring, Antonio Omuro, Jennifer Moliterno, Sacit Bulent Omay, Robert K Fulbright, Robin A de Graaf, Henk M De Feyter
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Metabolic imaging using FDG-PET is a key component of disease management in many cancers outside of the brain, but in brain tumors, it often shows low tumor-to-brain contrast because of high background signal from normal brain. Deuterium metabolic imaging (DMI) is a new 2H magnetic resonance spectroscopic imaging-based technique that when combined with administration of 2H-labeled glucose can provide high tumor-to-brain image contrast because it can detect downstream metabolism instead of only glucose uptake. In this observational study, DMI of glucose metabolism was performed in 22 patients with primary brain tumors of different grades, and at different disease stages. METHODS DMI data were acquired using a 4 tesla MRI scanner after oral administration of 0.75g/kg of [6,6’-2H2]-glucose in water. Metabolic maps were generated of 2H-labeled glucose, glutamate+glutamine (Glx), lactate (Lac), and Lac/(Lac+Glx), a proxy for the metabolic shift observed in many cancers known as the Warburg effect. Volumes of interest (VOI) based on contrast-enhancing and non-enhancing tumor regions were created using clinical MRIs and combined with DMI maps to generate tumor-specific values for Lac/(Lac+Glx). Eta-squared was calculated using tumor grade and Lac/(Lac+Glx) as independent and dependent variables; data are reported as mean±SD. Results – Tumor-to-brain image contrast for Lac/(Lac+Glx) was 2.57±0.93 for grade 4 (n=14), 1.74±0.75 for grade 3 (n=6) and 0.94±0.28 for grade 2 lesions (n=3). Lac/(Lac+Glx) was 0.36±0.13 for grade 4; 0.19±0.049 for grade 3; 0.09±0.042 for grade 2 lesions; and 0.14±0.043 for normal brain. Eta-squared between tumor grade and Lac/(Lac+Glx) was 0.52. CONCLUSIONS VOI-based analysis showed a high dependence of metabolism-specific image contrast to tumor grade. The apparent relation between lesion grade and Lac/(Lac+Glx) indicates the potential of DMI to complement anatomical MRI and possibly provide a valuable biomarker indicating active tumor tissue and could improve evaluating disease progression.
EPCO-49. SEX-SPECIFIC CHROMATIN REMODELING DRIVES TUMORIGENESIS IN GLIOBLASTOMA
Authors: Adham Halaoui, Najla Kfoury-Beaumont, Thomas Beaumont
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most prevalent primary malignant brain cancer and has higher incidence and lower survival in males compared to females. The SWI/SNF chromatin remodeling complexes, including canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), play a critical role in multiple cancers including gliomas. However, their role in gliomagenesis and progression remains largely unknown. We analyzed 18 human glioma specimens for BAF complex mRNA expression by CNS WHO grade and used these data to guide CRISPRi knockdown of BAF components in syngeneic murine male and female GBM astrocytes. BAF complex knockdown revealed marked sex-specific differences in proliferation. Specifically, Smarce1 or Smarcb1 knockdown (cBAF &amp; PBAF) resulted in increased growth in male astrocytes but decreased growth in females. Brd7 (PBAF) knockdown enhanced growth in both sexes, while Brd9 (ncBAF) had minimal impact. We utilized extreme limiting dilution analysis (ELDA) to assess the clonogenic potential of GBM cells with depleted BAF components. Notably, cells with BRD7 knockdown displayed enhanced sphere-forming capacity in both male and female cells. Male cells with Smarce1or Smarcb1 knockdown showed increased clonogenic frequency, whereas females with Smarce1 knockdown had a marked reduction in sphere formation. Brd9 knockdown did not affect the sphere-forming capacity in male or female cells, in part due to compensatory plasticity of an alternate BAF complex. Epitranscriptomic analysis is ongoing and demonstrates sex-specific differences in chromatin accessibility and downstream gene expression programs based on BAF complex knockdown. Immunoprecipitation coupled with mass spectrometry was performed to elucidate the structure and assembly of the BAF complex in GBM cells. Understanding sex-specific mechanisms of BAF chromatin remodeling complex in glioma pathogenesis may yield critical insights for the development of precision therapeutics that have the potential to improve patient outcomes.
IMMU-15. CD74/MIF SIGNALING AXIS DISRUPTION IN BONE MARROW-DERIVED MYELOID CELLS DELAYS MALIGNANT PROGRESSION IN A PRECLINICAL MODEL OF GLIOMA
Authors: Alessandro Canella, Sakthi Rajendran, Matthew Nazzaro, Claire Schmitt, Daniel Kreatsoulas, Wesley Wang, Prajwal Rajappa
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION CD74, a chaperone associated with the major histocompatibility complex class II (MHC-II), plays a crucial role in assembling and transporting MHC-II molecules on the cellular surface. Beyond its physiological function in antigen presentation, CD74 is a negative regulator of inflammation, and its dysregulation is associated with inflammatory disorders and cancer. Notably, tumor stem cells release macrophage migration inhibitory factor (MIF) to trigger CD74 immunosuppressive signaling in tumor-infiltrating immune cells, thereby abrogating CD8+ T cell activation and promoting angiogenesis. While CD74 expression is known in dendritic cells, macrophages and B cells, our recent findings reveal its upregulation in immunosuppressive macrophages within the low-grade glioma (LGG) tumor microenvironment, and its negative correlation with the survival of adolescent and young adult patients with LGG. HYPOTHESIS. We hypothesize that inhibiting CD74/MIF in immunosuppressive myeloid cells may affect tumor progression and prevent malignant transformation (MT) to high-grade glioma (HGG). METHODS To test our hypothesis, we isolated bone marrow cells from immunocompetent RCAS n/tv-a LGG bearing animals, differentiated them into bone marrow-derived myeloid cells (BMDMs), silenced CD74 expression, and co-cultured them with primary CD8+T cells. Moreover, we inhibited CD74/MIF signaling in vivo. RESULTS. Deconvolution analysis of tumor-infiltrating immune cells revealed upregulation of CD74 and its network in myeloid cells during LGG compared to HGG. Silencing CD74 in LGG BMDMs in vitro resulted in the downregulation of genes associated with migration, proliferation, and immunosuppression. The co-culture of LGG CD74KD-BMDMs with CD8+ T cells increased the expression of T cell activation genes. In vivo treatment of LGG mice with MIF inhibitors significantly decreased myeloid cell infiltration in the tumor microenvironment (TME) and prolonged survival. CONCLUSIONS These preclinical studies highlight a role for the CD74/MIF signaling axis in glioma and present a novel immunotherapeutic target to modulate the activity of immunosuppressive myeloid cells in order to delay MT.
EPID-04. VESTIBULAR SCHWANNOMA IN PREGNANCY: A SYSTEMATIC REVIEW
Authors: Mason Bartman, Carole Barake
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Vestibular Schwannomas (VS) are intracranial tumors of the nervous system originating from peripherally myelinating Schwann cells. There are sparse reports of this tumor presenting in pregnant patients but many of the cardinal symptoms of pregnancy overlap with the presentation of VS. For this reason, we systematically reviewed reports of VS in pregnant patients to identify the most specific clinical symptoms to aid diagnosis of and address management considerations for this population. METHODS Our systematic review was performed according to PRISMA guidelines. The data extracted includes study characteristics, symptom presence and onset relative to tumor diagnosis, tumor size, treatment modality, complications, and maternal/fetal health outcomes. This data was analyzed for overlap with commonly presenting symptoms and current management trends. RESULTS Sixteen papers between 1967 and 2018 reported a total of 26 pregnant patients who met criteria for inclusion. The most common presenting symptoms were hearing loss (76.9%), ataxia (42.3%), headache (38.5%), and vomiting (38.5%). The symptoms that presented with the longest duration were dizziness/vertigo (145.33 weeks), tinnitus (155 weeks), and hearing loss (145.67 weeks). The most common complications were post-op facial paralysis (46.2%), hydrocephalus (23.1%), and post-op hearing loss (19.2%). CONCLUSIONS A heightened clinical suspicion for VS in pregnant patients is needed due to the large overlap of cardinal symptoms of pregnancy and VS presentation. The way pregnancy changes patients’ normal physiology should be considered when determining optimal management. We hope that this review will improve diagnostic accuracy and prevent complications in pregnant patients with VS.
EXTH-39. A BENCH-TOP MODEL FOR THE OPTIMIZATION OF ULTRASOUND PARAMETERS FOR SONODYNAMIC THERAPY OF GLIOBLASTOMA
Authors: Robert Hovey, Roberto Diaz
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In-vitro studies have demonstrated that low frequency sound waves can interact with hemo-porphyrin molecule to induce the production of reactive oxygen species. This biophysical phenomenon can induce tumour cell death in glioblastoma cells in-vitro. The purpose of this study was to evaluate the production of reactive oxygen species and expression of apoptotic markers in glioblastoma cells in response to varying total treatment time and ultrasound power using a bench-top focused ultrasound (FUS) device. METHODS U251 cells were exposed to 5-Aminolevulenic Acid (5-ALA) at varying concentrations for up to 24 hours. The time point with peak proto-porphyrin IX (PPIX) fluorescence was established using fluorescence activated cell sorting (FACS). A transducer utilized at 0.91MHz was placed on an inverted stage with the focus targeted to the bottom of a standard 96-well cell culture plate. Pressure wave delivery was confirmed using a hydrophone. GBM cells were treated with 5-ALA alone, FUS alone, or 5-ALA + FUS and the cells were incubated for 24 hours prior to measuring ROS induction and cell death. ROS was measured using FACS with the CellROX Green Kit for Oxidative Stress Detection and Annexin-V was measured using the Dead Cell Stain Kit. RESULTS Peak fluorescence intensity for PPIX in the U251 cell line was found to be induced through incubation with 5-ALA for 24 hours with a concentration 200mg/mL. The fluorescence intensity of PPIX was found to be 313% greater in the treated group compared to the control group. Peak ROS was observed using a 0.91MHz transducer frequency for a total time of 120s with 6W average power. ROS was 61% and 66% greater in the SDT group compared to the FUS and 5-ALA group respectively. CONCLUSION Using this bench-top set up we successfully induced ROS and apoptosis in U251 cells. Establishing a reliable in-vitro model will allow us to further investigate the effects of other sonication parameters such as burst length.
EPID-05. THE INCREASED RISK OF MENINGIOMA AMONG INDIVIDUALS WHO ARE NON-HISPANIC BLACK IS MAGNIFIED AMONG MALES AND AMONG THOSE DIAGNOSED WITH GRADE 2-3 TUMORS
Authors: Kyle Walsh, Mackenzie Price, David R Raleigh, Carol Kruchko, Jill S Barnholtz-Sloan, Quinn T Ostrom
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Demographic factors associated with elevated meningioma incidence include older age, female sex, and Black race. There are limited data exploring how meningioma risk in Black persons varies across the lifespan, interacts with sex, and differs by tumor grade. METHODS The Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry combining data from the CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology and End Results Program, covering the entire U.S. population. Meningioma diagnoses from CBTRUS (2004-2019) were used to calculate incidence rate ratios (IRRs) for non-Hispanic Black individuals (NHB) as compared to non-Hispanic White individuals (NHW) across 10-year age intervals, and stratified by sex and WHO tumor grade (grade 1 versus grades 2/3, combined). RESULTS From 2004-2019, a total of 53,890 NHB individuals and 322,373 NHW individuals were diagnosed with a primary meningioma. The NHB to NHW IRR was elevated, beginning in the third decade of life (IRR=1.19; 95%CI: 1.11-1.28), peaking in the seventh decade (IRR=1.29; 95%CI: 1.26-1.31), and persisting throughout the lifespan. The IRR peaked in the seventh decade of life across strata of tumor grade, but, within this age group, NHB race/ethnicity was associated with substantially higher risk of grade 2/3 tumors (IRR=1.59; 95%CI: 1.48-1.70) than grade 1 tumors (IRR=1.27; 95%CI: 1.24-1.29). Meningioma risk was elevated in NHB females compared to NHW females (IRR=1.16; 95%CI: 1.15-1.18) and among NHB males compared to NHW males (IRR=1.22; 95%CI: 1.19-1.25), revealing synergistic interaction between NHB race/ethnicity and male sex (PInteraction=0.001). CONCLUSIONS This study identifies an elevated risk of meningioma in NHB relative to NHW, beginning shortly after puberty and continuing across the lifespan. NHB race/ethnicity conferred higher risk of meningioma among men than among women, and higher risk of developing WHO grade 2/3 than grade 1 tumors. These results highlight meningioma as a major potential source of racial disparities in neuro-oncology.
EXTH-31. TARGETING<i>MIR-19B</i>/PPP2R5E REGULATORY AXIS TO MAXIMISE ALKYLATING AGENT EFFICACY: A NEW AVENUE TO COUNTERACT TEMOZOLOMIDE RESISTANCE IN RECURRENT GLIOBLASTOMAS
Authors: Elham Kashani, Kristyna Hlavackova, Martin Sadowski, Theoni Maragkou, Philippe Krebs, Erik Vassella
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma, IDH-wildtype (GBM), notorious for its inevitable recurrence despite aggressive multi-modal standard of care, presents a pressing need for novel treatment paradigms. The extensive DNA damage caused by the frontline DNA alkylating agent, temozolomide (TMZ) is counteracted by intricate or acquired survival mechanisms. Through functional microRNA screens we identified miR-19b-overexpressing clones possessing extra fitness in presence of escalating doses of TMZ. Our study uncovers a previously unrecognized TMZ resistance mechanism governed by miR-19b. Notably, miR-19b attenuation intensified DNA damage response and CHEK1 and CHEK2 phosphorylation, instigating persistent DNA lesions and consequently priming GBM cells for heightened TMZ cytotoxicity. Mechanistically, we showed that miR-19b exerts its function by targeting PPP2R5E, a subunit of protein phosphatase PP2A, frequently downregulated in GBM. We uncovered that the elevated DNA damage response in the miR-19b-attenuated cells was a consequence of enhanced nuclear and mitochondrial ROS production. This in turn, induced ROS-mediated senescence, and an intriguing susceptibility to ferroptosis, possibly due to increased ROS-mediated lipid peroxidation. Of note, all these phenotypes were reversed in GBM cells with concomitant miR-19b and PPP2R5E attenuation, demonstrating that miR-19b exerts its role in TMZ resistance by targeting PPP2R5E. In line with this finding, an orthotopic human-derived glioblastoma stem cell xenograft model confirmed that PPP2R5E attenuation not only decreases TMZ cytotoxicity in the brain, but also at the spinal metastatic location. Consistently, treating cells with the PP2A-activating drug FTY720 or knocking down endogenous PP2A-inhibiting proteins mirrored the effects of miR-19b attenuation in enhancing TMZ cytotoxicity. This intricate interplay between miR-19b and PPP2R5E underscores a novel strategy to modulate the TMZ response, highlighting promising results in our pre-clinical models. In conclusion, our findings advocate for the therapeutic targeting of the miR-19b/PPP2R5E regulatory axis as a potential novel strategy in the pursuit of effective therapeutic interventions for the formidable recurrent GBM tumours.
EPCO-27. CHROMATIN REMODELING REPROGRAMS THE TRANSCRIPTION NETWORK IN GLIOBLASTOMA
Authors: Xueqin Sherine Sun, Alea Mills
Journal: Neuro-Oncology (2024)

Abstract Fundamentally, cancer arises from genetic and epigenetic alterations that interplay to reprogram gene expression networks, leading to unrestrained proliferation. Glioblastoma (GBM) is the most prevalent and aggressive primary brain cancer, with a median survival of approximately one year and a 5-year survival rate of just 5%. The standard care for GBM patients has remained unchanged for decades, underscoring the need for a better understanding of GBM biology to develop more effective therapies. The relatively low genetic mutation burden in GBM highlights the significant role of epigenetic mechanisms in its pathogenesis. Our recent work shows that chromatin remodeling plays pivotal roles in GBM pathogenesis. The BRD8-driven EP400 chromatin remodeling complex maintains GBM by crippling p53-mediated tumor suppression in an unprecedented way through hijacking the histone variant H2AZ at p53 target loci, enforcing a repressive chromatin state that prevents p53-mediated transactivation. Targeting BRD8 in TP53WT GBM, which makes up ~71% of all GBM cases, enhances chromatin accessibility by evicting H2AZ. This restores p53-mediated transactivation of its targets, reestablishes cell cycle arrest, inhibits gliomagenesis, and prolongs survival in xenograft models of TP53WT GBM. Conversely, the NuRD chromatin remodeling complex driven by CHD5 governs the MYC-mediated oncogenic network to prevent gliomagenesis. Mechanistically, CHD5 forms a CHD3-containing but CHD4-independent NuRD complex that directly binds to the MYC promoter and super enhancers. Chd5 loss triggers the remodeling of chromatin, enhances chromatin accessibility at Myc loci, augments Myc expression, significantly impairs NSCs differentiation while promotes proliferation, transformation, and gliomagenesis in vivo. Furthermore, reactivating CHD5 in human GBM xenograft models significantly extends survival. Thus, our findings reveal previously unappreciated epigenetic mechanisms by which GBM cells reprogram both tumor-suppressive and oncogenic transcription networks to facilitate their outgrowth. This sheds new light on our understanding of GBM malignancy and provides promising therapeutic opportunities for treating patients with this devastating malignancy.