tbuckley/cabot-search huggingface dataset:
EPEN-15. TRANSCRIPTOMIC AND METABOLOMIC INTEGRATION REVEAL INTRA-TUMOUR HETEROGENEITY AND IDENTIFY DISULFIRAM AND COPPER AS A SYNERGISTIC THERAPY IN PAEDIATRIC EPENDYMOMA
Authors: Alina Pandele, Alison Whitby, Sophie J Lankford, Donald Macarthur, Ian Kamaly-Asl, David Barrett, Richard Grundy, Dong-Hyun Kim, Ruman Rahman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymoma (EPN) is the second most malignant paediatric brain tumour. The PF-A subgroup, associated with a hypoxic microenvironment, has a dismal survival rate of 50% with clinical trials failing to demonstrate a significant survival advantage from chemotherapy to date. As the lack of genomic alterations makes it difficult to uncover novel therapeutic targets, we present a multi-omic integration investigating whether spatially-distinct tumour microenvironments represent targetable metabolic niches in PF-A EPN. METHODS Surgical sampling of spatially-distinct regions was performed on eight PF-A EPN patients. Metabolites and RNA were simultaneously extracted from the same cellular population and analysed using liquid chromatography-mass spectrometry (LC-MS) and RNAseq. Multi-omic integration was performed using Metscape3 and functional assays evaluating proliferation, invasion and siRNA-mediated knockdown were performed in 2D and 3D models of intra-tumour region patient-derived cell lines. Selected single and drug combination therapy was performed in normoxia and hypoxia, and synergy assessed using the Chou-Talalay method. RESULTS Multi-omic integration revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites with the largest number of interactions occurring in the gluconeogenesis pathway. Each anatomical region also presented at least one unique gene-metabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. Four selected drug targets (Disulfiram, Vandetanib, Mildronate and FBP1 inhibitor) based on metabolically relevant genes (ALDH3A1, FMO3, BBOX1, FBP1) showed impairment of metabolic viability in vitro, with limited chemosensitivity observed in control human cerebellar astrocytes. The addition of Cu2+ significantly sensitised cells to Disulfiram, particularly under hypoxic conditions. This synergistic combination significantly impaired invasion in both normoxia and hypoxia. CONCLUSION This is the first instance where multi-omic data integration and intra-tumour heterogeneity has been investigated for paediatric EPN revealing novel therapeutic targets in the context of gene-metabolite correlations. Drug tolerability will be further assessed in vivo using the previously characterised PF-A EPN orthotopic mouse xenograft MAF-928.
IMMU-08. OUTCOME OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND EPENDYMOMA TREATED WITH PEMBROLIZUMAB, AN IMMUNE CHECKPOINT INHIBITOR: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)
Authors: Eugene I Hwang, Lindsay B Kilburn, Duane A Mitchell, Tong Lin, Tina Young-Poussaint, Giles Robinson, Amar Gajjar, Alicia Lenzen, Kathleen Dorris, Nathan Robison, Jason R Fangusaro, Maryam Fouladi, Arzu Onar-Thomas, Ira J Dunkel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children with recurrent medulloblastoma and ependymoma typically have a dismal prognosis. Immune checkpoint blockade has revolutionized treatment of some resistant cancers. PBTC045 is a safety and preliminary efficacy study of pembrolizumab, a PD-1 inhibitor, in children with recurrent/progressive brain tumors. Here we present the strata that included children with recurrent/progressive ependymoma and medulloblastoma. METHODS Eligibility included patients aged 1-21 years old with recurrent/progressive ependymoma or medulloblastoma and with functional scores &amp;gt;70, no greater than physiologic steroid usage and standard washout periods, among other eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available) and serum were collected for correlative studies. Primary endpoints included toxicity and response, and two stages were planned requiring objective responses for potential expansion. RESULTS Patients with progressive ependymoma (Stratum D, n=13) or medulloblastoma (Stratum E, n=14, one ineligible) were enrolled. The median age at diagnosis was 3.37 years (range, 1-12.7) and 7 years (range, 2.2-13.1), respectively. The median age at study entry was 8.5 and 11.4 years, respectively. There were no first-stage objective responses in either stratum, and thus the expansion arms were not initiated. Grade 3 or greater treatment-related adverse events included rash (n=1), anemia (n=1) and neutropenia (n=2), with no dose-limiting toxicities. The median progression-free survival (PFS) for ependymoma and medulloblastoma were 1.38 months (range, 1.08-1.51) and 1.41 months (range, 1.22-3.45), respectively. Immune correlative analyses are ongoing. CONCLUSIONS Immune checkpoint inhibition holds potential for CNS cancer treatment, and as a single agent, is well tolerated. However, in the current study, checkpoint inhibition monotherapy does not appear to significantly prolong survival or induce radiographic responses in children with recurrent/progressive ependymoma or medulloblastoma. Potential incorporation of checkpoint inhibitors into treatment for these patients will likely require combinatorial approaches that may be informed by the correlative science.
OTHR-29. A SINGLE INSTITUTION REVIEW REGARDING TRENDS IN THE MOLECULAR ANALYSIS OF PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS AND GERMLINE ANALYSIS BETWEEN 2019 – 2023, EMPHASIZING THE IMPORTANCE OF EASY ACCESS TO COMPREHENSIVE TESTING
Authors: Anne E Bendel, Mary M Skrypek, Allison M Galkowski, Dinel A Pond, Damon R Olson, Samuel A Roiko
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Molecular characterization of pediatric CNS tumors improves diagnostic accuracy and guides treatment. Germline analysis is also important to uncover cancer predisposition syndromes, which influence the approach to treatment and tumor surveillance. The options for molecular assessment are influenced by availability, including access through a trial or insurance approval. METHODS A retrospective review of the molecular workup performed on all CNS tumors biopsied/resected at Children’s Minnesota from 2019 – 2023 was undertaken to look at trends in the specific tests performed over time and how the molecular results guided treatment. RESULTS Between 2019 – 2023, 220 patients at Children’s Minnesota were diagnosed with a CNS tumor. A total of 191 underwent surgery and 162 (85%) had sufficient tissue for molecular analysis. There was no apparent difference in the percentage of patients who underwent IHC/FISH/NGS between 2019 - 2023, but methylation profiling frequency increased over time (2019 2%, 2020 and 2021 10%, 2022 58% and 2023 71%). Frequency of germline analysis also increased (2019-2021 29%, 2022-52% and 2023-63%). Easy availability of comprehensive molecular and germline analysis for patients enrolled on COG-APEC14B1 is credited for these improving trends. Molecular analysis confirmed (59%) or supported (36%) the diagnosis, and guided treatment in 30% of cases (stratification of treatment in 89% of medulloblastoma and targeted treatment in 63% of high-grade glioma, 9% of medulloblastoma and 6% of low-grade glioma). Methylation profiling alone accurately diagnosed 79% of cases, including subtyping tumors. Germline analysis detected a pathogenic germline alteration in 14% of CNS tumor patients (NF1 5%; TP53 and BRIP1 1%; PALB1, NF2, TS2, SMARCB1, biallelic PMS2, CHEK2, FANCA, ORICH1 and SDHA 0.5%). CONCLUSION These findings demonstrate the importance of easy access to comprehensive molecular and germline analysis with quick turnaround time to provide the best diagnosis, prognosis and treatment options for pediatric CNS tumor patients.
ETMR-29. PRIMARY CNS SARCOMAS IN CHILDREN AND ADOLESCENTS: EXPERIENCE OF AN INSTITUTION
Authors: Milena Reis Santos de Oliveira, Jessica Benigno Rodrigues, Daniela Barbosa Almeida, Sergio Cavalheiro, Patricia Dastoli, Marcos Devanir, Frederico Silva, Maria Teresa Seixas, Silvia Toledo, Fernanda Teresa Lima, Andrea Maria Cappellano, Nasjla Saba Silva
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Soft tissue sarcomas represent 6% of childhood cancers, less than 0.2% of CNS tumors are primary intracranial sarcomas. Their origin is pluripotential primitive mesenchymal cells. OBJECTIVE to evaluate clinical and genetic characteristics and report the experience of a rare CNS tumor. METHODS review of CNS tumors database at IOP/GRAACC/UNIFESP for the period 2008-2024, searching for all types of sarcomas that involved the CNS. RESULTS case series included 7 male, 2 female patients; average age at diagnosis 11.3 years. Supratentorial was the most common site of occurrence (66.6%), posterior fossa and intramedulary (2 and 1 cases, respectively) were found. One PF sarcoma presented as a second neoplasm after 2 years finished treatment for medulloblastoma, the other was diagnosed just after metilation. The presenting symptoms varied with tumor location, specially hemiparesis, seizure and headache. Gross total resection was achieved in 7 cases (77.7%), 1 after second look surgery. Histology and immunohistochemistry studies revealed: spinocellular sarcoma, fusocellular and myxoid sarcoma, gliosarcoma, meningeal sarcoma, Ewing sarcoma, condrosarcoma and synovial sarcoma. Work-up excluded other primary tumor origin outside CNS. Analyses for genetic characteristics were performed by Next Generation Sequencing in 6 patients (66.6%) and the following alterations were found: NRAS, TP53, JAK3, NF2, C11orf95-RELA fusion, PDGFRA. Some of these, by now, with no significant meaning for the disease. All patients underwent multimodal treatment. Chemotherapy involved mainly ICE Protocol (55.5%), but also Head Start Protocol and Ewing Sarcoma Protocol. Follow-up ranged from 13 months to 12 years, 90% of patients are alive, 2 (28.5%) dealing with endocrinal issues after focal radiotherapy. The mean overall survival was 61.4 months. CONCLUSION CNS primary sarcomas were mostly observed in the supratentorial region and in older children, with male predilection. Multimodal treatment seems to benefit patients’ outcomes. More patients and longer follow-up periods are needed to further elucidate the biological features of these tumors.
BIOM-12. LIQUID BIOPSIES IN CNS TUMORS: A COMBINED APPROACH TO PROFILING CSF
Authors: Liana Nobre, Yoshiko Nakano, Ian Burns, Monique Johnson, Javal Sheth, Mansuba Rana, Richard Yuditskiy, Logine Negm, Michal Zapotocky, Ana Stucklin, Craig Erker, Chantel Cacciotti, Adam Fleming, Sylvia Cheng, Annie Huang, Andrew Bondoc, MaryJane Lim Fat, Anirban Das, Vanan Magimairajan, Julie Bennet, Robert Siddaway, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2024)

Abstract In precision medicine, molecular profiling of pediatric tumors is crucial for diagnosis, prognosis, and therapeutic decision-making. Traditional biopsy methods, often invasive, have inherent risks and may not capture a tumor’s heterogeneity. Liquid biopsy, however, offers a minimally invasive and comprehensive alternative. We demonstrate its utility in diagnosing and monitoring brain tumors using cell-free DNA (cfDNA) from cerebrospinal fluid (CSF), where conventional cfDNA plasma analysis has shown low sensitivity. Through digital droplet PCR, we analyzed 23 plasma samples from patients with BRAFV600E or H3K27M gliomas, detecting H3K27M in a single case. Conversely, CSF samples revealed 8 positives out of 9 for these mutations, underscoring CSF’s diagnostic value. We advanced our methodology by developing a 21-gene hybrid-capture panel paired with low-pass whole-genome sequencing to pinpoint copy number variations. In our reference sample set, the panel achieved a detection limit with variant allele frequencies as low as 0.5%. With 10ng of cfDNA, we reached 83% sensitivity and 100% specificity, which increased to 100% sensitivity with a 30ng input. Using this assay, we profiled 141 CSF samples from 119 patients, achieving 70% positivity rate in active disease cases in a validation cohort—ranging from 50% in low-grade gliomas to 84% in high-grade gliomas and 75% in medulloblastomas. Intriguingly, of 14 queried tumor samples lacking biopsy confirmation, half showed positive ctDNA results using the panel and/or low-pass whole-genome sequencing. This approach allowed for differential diagnoses in suspected medulloblastoma relapses, tailored therapeutic interventions based on CSF profiles, and effective treatment response monitoring. In summary, our integrated liquid biopsy strategy showcases a powerful, clinically applicable tool that significantly enhances patient care in pediatric neuro-oncology.
TRLS-05. A PILOT STUDY TO ASSESS THE SAFETY, FEASIBILITY, AND PRELIMINARY EFFICACY OF A NEOEPITOPE-BASED PERSONALIZED DNA VACCINE APPROACH IN PEDIATRIC PATIENTS WITH RECURRENT BRAIN TUMORS
Authors: Margaret Shatara, Abbey Rocco, Mary Beck, Michele McHugh, Ashley Lampe, Ashley Meyer, Andrea Ogle, Nicole M Brossier, Andrew Cluster, Joshua B Rubin, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain tumors present a heterogeneous group of neoplasms with limited treatment options, especially at relapse. Hence, innovative therapeutic strategies are imperative. Immunotherapy, specifically immunogenomics, utilizing personalized vaccines based on tumor-specific neoantigens, has emerged as a promising option in other tumors. However, the feasibility of this approach in pediatric brain tumors remain largely unexplored. METHODS This single institution feasibility study focuses on sequencing analyses of pediatric brain tumors to identify mutant tumor-specific antigens. The study employs tumor/normal exome sequencing and cDNA-capture sequencing to identify and confirm mutant antigens, respectively. An epitope prediction algorithm prioritizes these antigens with subsequent confirmation of binding to HLA class I molecules. The neoantigen DNA vaccine strategy, utilizing a polyepitope DNA vaccine, is designed to target up to 20 prioritized antigens. The TDS-IM v2.0 device facilitates the administration of the vaccine. The primary objective of the study is to determine the feasibility of adjuvant personalized neoantigen DNA vaccine administration in patients with recurrent or refractory pediatric brain tumors. RESULTS We anticipate the identification of actionable neoantigens in pediatric brain tumors to support the potential efficacy of personalized DNA vaccines. The proposed sequencing strategies, epitope prediction algorithm, and in vitrobinding studies aim to establish a comprehensive methodology for neoantigen identification and prioritization. During the meeting, we will present the study background, rationale, detailed methodology, and design to inform the brain tumor community of this study. CONCLUSION This feasibility study is poised to provide essential insights into the development of personalized neoantigen DNA vaccines for recurrent or refractory pediatric brain tumors and aims to demonstrate safety, feasibility, and potential efficacy in targeting mutant tumor-specific antigens. The findings from this study will lay the groundwork for future clinical trials, evaluating the impact of personalized immunotherapy on progression-free and overall survival rates in this challenging patient population.
OTHR-21. DEVELOPING A NEURO-ONCOLOGY PROGRAM FOR ADOLESCENTS AND YOUNG ADULTS IN CANADA – THE CANON EXPERIENCE
Authors: Julie Bennett, Seth Climans, Sunit Das, Derek S Tsang, Natalie Massey, Uri Tabori, Cynthia Hawkins, Mary Jane Lim-Fat
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain tumors are the leading cause of cancer-related death in adolescents and young adults (AYA). These tumors possess both pediatric-type and adult-type qualities, with up to 30% of gliomas harboring pediatric-type alterations. Specialized expertise and significant collaboration between pediatric and adult providers is needed to guide therapy for AYAs. To address this, we have developed the Canadian Adolescent and Young Adult Neuro-Oncology Network (CANON). METHODS In April 2021, we established a national virtual AYA tumor board integrating comprehensive molecular analysis of available tumors. Rounds included representatives from both pediatric and adult neuro-oncology, radiation oncology, neurosurgery, neuropathology and neuroradiology. We collected clinical data and recommendations from rounds. RESULTS In the first 2 years of rounds through CANON, 156 cases have been reviewed. Gliomas (108) accounted for most cases followed by medulloblastoma (18) and ependymoma (7). Sequencing was available in 47% of cases. Of those with molecular data available, the majority (36) had a pediatric-type alteration, followed by IDH mutation (10). Additional molecular analysis was recommended in 29% of cases presented. Of those with sequencing data available, 35% had a potentially targetable alteration identified. Despite this, only 8% were eligible for a clinical trial based on their diagnosis and age. Recurrent clinical questions included access to molecular analysis, use of “off-label” targeted agents, lack of clinical trial options for AYA patients and the practice variation in treatment of AYA tumors typically seen in childhood such as medulloblastoma and germ cell tumor. DISCUSSION Dedicated AYA rounds have highlighted many inequities in care of these patients, highlighting a need for inclusion of AYAs in clinical trials and further study of tumor biology and clinical outcomes of this cohort. AYAs with pediatric-type tumors would also benefit from management by dedicated physicians with expertise in these complex tumors.
MDB-10. DIVERGENT MEDULLOBLASTOMA CHROMATIN STATES DISCLOSE KDM2B AS A NOVEL ONCOGENIC DEPENDENCY
Authors: Ran Tao, Serap Erkek, Yurika Matsui, Beisi Xu, Kyle S Smith, Qingsong Gao, Yiran Li, Nadhir Djekidel, Emily Darrow, Rahul Kumar, Leena Paul, Hong Lin, Jennifer Hadley, Melissa Batts, Natarajan V Bhanu, Lena Kutscher, Benjamin A Garcia, Xin Zhou, Brent A Orr, Giles W Robinson, Gang Wu, Jan O Korbel, Jamy Peng, Stefan M Pfister, Paul A Northcott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is a highly malignant childhood cerebellar tumor comprising a collection of molecularly and clinically distinct entities. Group 3 and Group 4-MB subgroups originate from overlapping progenitor pools of the developing rhombic lip when neuronal differentiation hierarchies are subverted through somatic alterations. Mutations suspected to deregulate the activity of chromatin-modifying genes are pervasive in Group 3 and Group 4-MB. However, the molecular consequences of these alterations remain largely undefined. METHODS We characterized the chromatin landscape of fifty-two primary MBs using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for six histone modifications and performed multi-modal integration with sample-matched somatic lesions, genome-wide DNA methylation, and transcriptomic profiles. RESULTS Analysis of differential chromatin states across MB subgroups using a Hidden Markov Model revealed a significant enrichment of the bivalent enhancer state (EnhBiv; marked by coincident H3K4me1 and H3K27me3) in Group 4-MB which localized to promoters of neurodevelopmental genes and transcription factors. To functionally dissect the pathogenetic significance of the enriched EnhBiv state in Group 4-MB, we sought to identify key regulators that confer this state. Integrative bioinformatics coupled with CUT&amp;RUN analysis revealed significant enrichment of KDM2B, a histone lysine demethylase overexpressed in Group 4-MB, in gene promoters marked by the EnhBiv state. CRISPR gene targeting or targeted protein degradation of KDM2B selectively suppressed growth of Group 3 and Group 4-MB models in vitro and in vivo. Mechanistically, inhibition of KDM2B disrupted chromatin bivalency by blocking PRC2 complex recruitment and reducing H3K27me3 deposition, profoundly derepressing PRC2 targets involved in neuronal differentiation. CONCLUSIONS Our comprehensive characterization of the MB chromatin landscape in a large cohort of primary tumors provides unprecedented insights into the epigenetic basis of MB subgroups, implicating novel mechanisms of tumorigenesis, and nominating KDM2B as a selective dependency in Group 3/4-MB that should be prioritized as an attractive therapeutic target.
MDB-16. CLINICAL AND MOLECULAR CHARACTERISTICS OF JAPANESE MEDULLOBLASTOMA, WNT-ACTIVATED
Authors: Kohichi Go, Asako Katsuma, Yasuhide Makino, Etsuko Yamamoto, Ema Yoshioka, Tomoko Shofuda, Daisuke Kanematsu, Yukinori Terada, Noritaka Sano, Masahiro Tanji, Yohei Mineharu, Yoshinori Kodama, Masayuki Mano, Koichi Ichimura, Atsushi Sasaki, Junko Hirato, Takeshi Inoue, Ryo Nishikawa, Isao Date, Masahiro Nonaka, Motoo Nagane, Yoshiki Arakawa, Yonehiro Kanemura
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastomas are at least classified into four core subgroups, including WNT-activated, SHH-activated, group 3 and group 4. These molecular subgroups have been introduced in the latest WHO classification, which has become fundamental and indispensable. Medulloblastoma, WNT-activated (WNT-MB) accounts for about 10% of all medulloblastomas, and their prognosis is excellent, and it is desired to ensure that patients with WNT-MBs are diagnosed exactly. In this study, we have summarized results of molecular analysis of Japanese MBs collected by Japanese Pediatric Molecular Neuro-oncology Group (JPMNG) study, and analyzed clinical and molecular characteristics of WNT-MBs. METHODS We enrolled 267 cases of medulloblastoma from 44 centers participating in the JPMNG study since 2012.Central histopathological diagnosis was performed by three neuropathologists, and molecular genetic diagnosis was performed using molecular subgrouping, DNA sequencing (CTNNB1), and copy number analysis. RESULTS A total of 244 cases were finally analyzed, and the 4-subgroup classification was WNT: 39 (16%), SHH: 61 (25%), group3: 42 (17%), and group4: 102 (41.8%), respectively. The age at diagnosis was 3 years or older (6-40 years) in all cases, with no cases occurring in infants, the majority being children (6-18 years) (31/39: 79.5%), and 8 cases (8/39: 20.5%) in adults older than 18 years. Histological features were classic (CMB) in the majority of cases and large cell (LCA) type in only 2 cases. The positivity rate of nuclear β-catenin by Immunological staining was 9 out of 12 (75%) of the cases examined. While, CTNNB1mutation was positive in 39 of 39 cases (100%) and monosomy 6 was also positive in 35 of 35 cases (100%), respectively. The 5-year survival rate was 91.9%. CONCLUSIONS Clinical characteristics of Japanese WBT-MB were almost similar to those reported in other countries, which showed excellent prognosis, and their molecular genetic status were also identical with results from other ethnics.