tbuckley/cabot-search huggingface dataset:
MDB-07. A SUICIDE GENE THERAPY TARGETING SOX9-POSITIVE THERAPY-RESISTANT MEDULLOBLASTOMA CELLS
Authors: Tong Lin, Sonja Hutter, Elin Vikström, Miao Zhao, Karl O Holmberg, Gabriela Rosén, Tobias Bergström, Geraldine Giraud, Fredrik J Swartling
Journal: Neuro-Oncology (2024)

Abstract The transcription factor SOX9 is a stem cell factor and a glial fate marker in the developing brain. SOX9 levels correlate with worse prognosis and relapse in Group 3 medulloblastoma, a malignant pediatric brain tumor with poor survival. SOX9 activation promotes epidermal to mesenchymal transition and leptomeningeal spread. It is also upregulated by and facilitates cisplatin resistance in medulloblastoma cells. Direct SOX9 inhibition has proven difficult and few targeted substances have emerged from drug screening efforts. SOX9 acts as a selective and potent activator of a minimal collagen type II alpha 1 enhancer element. We here show that cells with SOX9 activity can be efficiently and specifically labeled when this SOX9 response element is coupled to a minimal promoter (S9RE-minP) driving GFP or luciferase. We further show that S9RE-minP construct can be used to drive herpes simplex virus thymidine kinase (TK) in a suicide gene construct that can convert ganciclovir to a cytotoxic drug in mitotic SOX9-positive cells. The gene therapy worked efficiently together with cisplatin to eradicate SOX9-positive medulloblastoma cells in vitro and could be safely combined and synergize with fractionated radiation in vivo. We suggest that this could be an attractive approach to target therapy-resistant cells in malignant pediatric brain tumors.
EPEN-17.<i>IN VITRO</i> MODELLING OF PEDIATRIC SUPRATENTORIAL EPENDYMOMAS USING CEREBRAL ORGANOIDS
Authors: Mieke Roosen, Julie Morscio, Phylicia Stathi, Norman Mack, Benjamin Schwalm, Panagiotis A Polychronopoulos, Mariëtte E G Kranendonk, Eelco Hoving, Jens Bunt, Marcel Kool
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Ependymomas (EPN) are glial tumors of the central nervous system occurring in children and adults. ZFTA-fusion positive and YAP1-fusion positive EPN are the main supratentorial (ST) subgroups in children. While most ST-EPN-YAP1 patients survive, only 50% of ZFTA positive patients survive longer than 5 years. Improving survival of ST-EPN patients requires a better understanding of tumor biology. Human embryonal stem cell-derived (hESC) brain organoids provide a novel opportunity to model ST-EPN and study the impact of oncogenic fusions on tumor development within a healthy brain environment. METHODS hESC-derived cerebral organoids were genetically modified with YAP1 or ZFTA fusion genes and histologically and molecularly analyzed using antibody stainings, bulk and single cell RNA sequencing. RESULTS scRNA-seq analyses showed that our cerebral organoids mimic embryonal brain development and that radial glia, the presumed cell-of-origin of ST-EPN are abundant in 11-day old organoids. At this timepoint, electroporation of oncogenic ZFTA-RELA or YAP1-MAMLD1/YAP1-FAM118B fusions led to ectopic tumor outgrowth. Histological and molecular analyses showed that ZFTA and YAP1 EPN tumor organoids displayed different phenotypes and fusion-specific gene signatures, closely resembling human ZFTA and YAP1 EPN patient samples. ScRNA-seq data of organoid tumors showed a skewed differentiation compared to normal development with ZFTA tumors being more neuronal and YAP1 tumors having a more extracellular matrix-like phenotype. Analysis of the healthy compartment showed that YAP1 tumors influence the differentiation of the healthy cells and in both subtypes a new cell cluster was identified with high expression of tumor associated markers. Intercellular interactions revealed potential targetable tumor(specific) interactions such as YBX1-NOTCH1 in ZFTA or GNAI2-CAV1 in YAP1 tumor organoid models, as well as CD99-CD81 in both. CONCLUSIONS These models contribute to a better molecular and biological understanding of ependymomas and can be used to identify targeted therapies, especially those targeting the tumor microenvironment.
DIPG-93. OVERALL EXPERIENCE OF TWO PHASE I CLINICAL TRIALS WITH FOCUSED ULTRASOUND-MEDIATED BLOOD BRAIN BARRIER OPENING IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH PROGRESSIVE DIPG/DMG USING A NEURONAVIGATION-BASED DEVICE
Authors: Luca Szalontay, Jessica Fino, Xander Berg, Jennifer Lipina, Matthew Gallitto, Genesis Los De Santos, Nina Yoh, Robyn Gartrell, Jovana Pavisic, James Garvin, Angela Lignelli, William Gomes, Neil Feldstein, Elisa E Konofagou, Stergios Zacharoulis, Cheng-Chia Wu
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVES DIPG/DMG is a fatal brain tumor developing in delicate areas of the brain with a median overall survival of 1 year. The dismal outcome is partly due to the blood-brain barrier (BBB) which poses a major challenge to delivering effective therapeutic agents. Over the past 4 years we opened two Phase I clinical trials using Delsona focused ultrasound (FUS) device developed at Columbia University to treat pediatric and AYA patients with relapsed DMG. In the first study, we delivered FUS with concomitant panobinostat and during the second study we gave oral etoposide. Here we present our experience of delivering neuronavigation based FUS for pediatric patients with progressive DMG. METHODS Pediatric and AYA patients with biopsy proven DIPG/DMG at disease progression were enrolled (FUS with oral panobinostat: NCT04804709 and FUS with oral etoposide: NCT05762419). Patients were allowed to have prior therapies, including radiation and reirradiation. FUS was delivered over the course of six or four cycles respectively. MRI was performed to validate BBB-opening and closure. RESULTS During the FUS-panobinostat study, we treated 3 patients. The study was closed prematurely when panobinostat was taken off the US market. In the FUS-etoposide study, we have already treated 2 patients (the study is currently open). For the two trials combined, we delivered over twenty-five FUS treatments. Four of the five patients treated had achieved BBB-opening. Two patients in the FUS and panobinostat study showed improvement in their neurological symptoms. The average time for FUS-delivery was approximately 47 minutes. All treatments were performed in the outpatient settings in the Department of Radiation Oncology. Side effects from FUS was limited to one grade 1 dermatological toxicity. CONCLUSION FUS-mediated BBB-opening delivered as an outpatient procedure is feasible, to date, in children with relapsed DIPG/DMG. Further studies are needed to assess for efficacy.
ETMR-02. CNS EMBRYONAL TUMOR WITH BRD4–LEUTX FUSION POTENTIAL NEW MOLECULAR SUBTYPE OF EMBRYONAL TUMORS IN THE FUTURE WHO CLASSIFICATION OF TUMORS OF THE CENTRAL NERVOUS SYSTEM
Authors: Nahla Aly Mobarak, Ayman Al Banyan, Basma Alyamnai, Wafa Al Shakweer, Sadeq Al-Dandan, Musa Alharbi
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Central Nervous System (CNS) embryonal tumors previously called Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are highly malignant tumors that predominantly affect Yonge children. CNS World Health Organization (WHO) 2021classification includes new embryonal tumor subtypes: CNS neuroblastoma, FOXR2-activated, CNS tumor with BCOR internal tandem duplication (ITD), and cribriform neuroepithelial tumor CRINET.CNS-embryonal tumors which cannot be classified into a specific subgroup, considered as ‘‘CNS embryonal tumors, NOS.’’ METHOD We report a 2-year girl previously healthy presented with 2 weeks HX of vomiting, progressive lower limb weakness, and nystagmus. Radiological diagnosis was suggestive of metastatic ATRT with Brain and spine MRI showed a large left interventricular tumor (10.2 x 7.7 x 7.6 cm) centered in the posterior horn of the left lateral ventricle with extensive intracranial and spinal leptomeningeal CSF seeding metastasis she had Partial tumor resection LT-sided external ventricular drain EVD Insertion The tumor showed very aggressive behavior with rapid tumor recurrence/progression post-surgical resection the patient was treated with Palliative chemotherapy due to clinical and neurological deterioration the patient and died 2 months after diagnosis. RESULT Pathological examination showed Embryonal tumor (WHO Grade 4) with Medulloblastoma-like cells Immunohistochemistry: Synaptophysin: Positive Beta-catenin, P53: Negative and INI-1: Retained. NGS molecular testing was positive for BRD4–LEUTX fusion. Tumor DNA- -methylation profiling (DKFZ CNS v12.5) confirmed the diagnosis “CNS embryonal tumor with BRD4–LEUTX fusion” This rare very aggressive/uncurable tumor may show pathological features similarities with Medulloblastoma. Also, BRD4–LEUTX fusion was reported in pediatric epithelioid malignant peripheral nerve sheath tumor and an alveolar rhabdomyosarcoma CONCLUSION CNS tumor with BRD4– LEUTX fusion” A rare tumor has been described in the literatures in infant and young children and may be integrated in the CNS WHO classification as a new highly aggressive subgroup of CNS embryonal tumor.
LMIC-11. OUTCOMES OF INFANTS WITH CNS TUMORS: REPORT OF 85 CASES FROM 6 MEXICAN HOSPITALS
Authors: Alma Edith Benito-Reséndiz, Regina Navarro-Martín del Campo, Francisco Pantoja-Guillén, Gabriela Escamilla-Asiain, Atzin Ángeles-Romero, Beatriz García-Robles, Rafael Ruvalcaba-Sanchez, Melisa Nájera-Castillo, Isidoro Tejocote-Romero, Daniela Arce-Cabrera, Elsa Echevarria-Valenzuela, Mariana Ortiz-Azpilcueta, Farina Arreguín González, San Juanita Sandoval-de Jesús, Jeannie García-Ramos, Imelda Zapata-Sosa, Daniel Moreira
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Reports on central nervous system (CNS) tumors in infants from low- and middle-income countries are scarce. This is a high-risk population, we sought to analyze their outcomes in Mexico. METHODS Patients &amp;lt;36 months diagnosed CNS tumors between January 2014 to December 2023 from 6 hospitals in Mexico were included. Demographic, treatment, and outcomes were collected. RESULTS In total, 85 patients with a median age of 21 months were included. Of these, 51 (60%) were male. Diagnoses included low-grade glioma (LGG) in 26 (33%), medulloblastoma (MB) in 19 (22%), other embryonal tumors in 12 (14%), ependymoma (EPN) in 11 (13%), high-grade glioma (HGG) in 6 (7%), and other tumors in 11 (13%). Regarding surgery, a near or gross total resection was achieved in 22 patients (26%). For LGG it was 23%, while it was 37% for for MB, 36% for for EPN, and 17% for HGG. Ten patients (12%) died from postoperative complications. Overall, 12 (14%) patients, including 4 patients with MB, had metastasis at diagnosis. In total, 19 (22%) patients received radiotherapy, including 10 patients who received CSI (average age 35 months) and 9 who received focal radiotherapy, including 6 with EPN, 2 with LGG, and 1 with ATRT. Of patients with MB, 18 (95%) received chemotherapy, including 1 with autologous stem cell transplant and 3 with intraventricular chemotherapy. The 5-year event-free survival was 38±11%, while the 5-year overall survival (OS) was 52±10%. The 5-year OS were: 84±10% for LGG, 43±21% for MB, 55±23% for EPN, 9±25% for other embryonal tumors, and 17±35% for HGG. CONCLUSIONS These data show low survival rates, associated with very poor surgical outcomes. A fraction of patients received CSI radiotherapy, showing deviation from international standards. Further analyses are needed to identify factors that lead to better prognosis.
PATH-02. THE IMPACT OF EVOLVING DIAGNOSTIC METHODOLOGY ON THE CLASSIFICATION AND OUTCOME OF CENTRAL NERVOUS SYSTEM TUMOURS IN CHILDHOOD: A RETROSPECTIVE COHORT STUDY
Authors: Maria L Kirby, Jordan R Hansford
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Central nervous system tumours are the second most common childhood tumours and the largest cause of childhood cancer death in Australia. Tumours arise from many cell types within the developing and mature CNS, leading to a wide spectrum of clinical behaviour despite overlapping histological appearances. Emerging molecular testing methods allow more precise determination of cell lineage as well as genetic and epigenetic changes driving tumour development. Particularly since 2016, molecular findings have been incorporated into international classification schema, potentially impacting the frequency of individual diagnoses and their observed prognosis. METHODS We performed a retrospective cohort study including patients with newly diagnosed CNS tumours at Royal Children’s Hospital, Melbourne between 2011 and 2020 (total 473). The first and last 100 eligible patients in the data set were reviewed for diagnosis, survival and recorded use of molecular testing. Reviewed patients were assigned to one of two cohorts, Cohort 1 2011-2013 (pre-2016 WHO revision) or Cohort 2 2018-2020 (post-2016 WHO revision). RESULTS The frequency of diagnoses on biopsy rather than imaging alone was stable (81% Cohort 1 vs 83% Cohort 2). Molecular testing utilization increased markedly over time (10 molecular investigations in Cohort 1 vs 348 in Cohort 2). The incidence of astrocytic and oligodendroglial diagnoses was stable. The incidence of embryonal and neuronal/ mixed glial neuronal diagnoses increased in Cohort 2, and the incidence of ependymal diagnoses decreased (p=0.0122). There were no event free or overall survival differences between the whole of Cohorts 1 and 2, with numbers of individual diagnoses too small for meaningful comparisons over time. CONCLUSIONS Access to molecular testing has impacted on the pattern of reported diagnoses of central nervous system tumours in children. Although outcomes have not changed, it is hoped that over time, improved molecular understanding will lead to more effective therapy selection.
DIPG-74. TARGETING TRANSCRIPTIONAL DYSREGULATION IN DMG THROUGH CDK9 AND HDAC INHIBITOR COMBINATION THERAPY
Authors: Brittany R Eberl, Rebecca L Murdaugh, Adanze N Nnyagu, Rosemary U Richard, Benjamin Deneen, Kwanha Yu, Jamie N Anastas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND With no successful treatment options available, diffuse midline glioma (DMG) are fatal brain tumors with a median survival of ∼12 months. DMG are characterized by transcriptional dysregulation induced by the H3K27M driver mutations. Since these histone mutations cannot yet be directly targeted pharmacologically, our goal is to identify druggable targets of aberrant transcription in DMG. Previous studies identified RNA polymerase 2 (Pol2)-targeting cyclin-dependent kinase 9 inhibitors (CDK9i) and histone deacetylase inhibitors (HDACi) as potential DMG therapeutics, and CDK9i and HDACi are under investigation in ongoing glioma clinical trials. This study aims to develop CDK9i+HDACi combination therapies for DMG. METHODS We determined the consequences of CDK9i+HDACi combination treatment in DMG using in vitro dose curve analyses, orthotopic xenograft models, and molecular profiling through immunofluorescence imaging, Western blotting, flow cytometry and RNA-seq analysis. RESULTS We find that CDK9i+HDACi combination therapy synergistically reduces DMG growth in vitro and alters DMG protein post-translational modifications associated with gene regulation by reducing phos-Pol2-Ser2 and increasing histone acetylation. Further RNA-seq analysis identified unique transcriptional changes induced by CDK9i+HDACi, including the downregulation of genes associated with mitochondrial function, cell division, and DNA repair. In line with these gene expression changes, additional studies suggest that CDK9i+HDACi treatment induces DNA damage and cell cycle defects. Finally, preliminary pre-clinical studies using an orthotopic DMG xenograft model reveal that CDK9i and HDACi treatment reduces DMG tumor growth as measured by bioluminescent imaging. CONCLUSIONS Together, these studies suggest that CDK9i and HDACi co-treatment alters DMG protein modifications and gene expression leading to cell cycle defects, DNA damage, and reduced tumor growth. In view of the proposed synergistic role of CDK9i and HDACi in DMG, additional ongoing studies are examining if this combination may represent a novel approach for the treatment of DMG.
EPEN-16. BULK AND SINGLE-CELL SPATIAL CHARACTERIZATION OF THE TUMOR IMMUNE MICROENVIRONMENT OF POSTERIOR FOSSA GROUP A EPENDYMOMAS
Authors: Julie A S Lammers, Mariëtte E G Kranendonk, Friso G Calkoen, Thijs J M van den Broek, Aniello Federico, Marcel Kool, Eelco W Hoving, Pieter Wesseling, Lennart A Kester, Jasper van der Lugt
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite advancements in molecular classification of ependymomas, the tumor immune microenvironment of posterior fossa group A (PFA) ependymomas and the spatial interplay between tumor and immune cells have not been elucidated. Here, we aim to comprehensively characterize the tumor immune microenvironment of pediatric PFA ependymomas, which could ultimately uncover leads for immunotherapy for these children. METHODS We collected bulk RNA-sequencing data of 28 PFA ependymoma samples and defined two subgroups based on the expression of immune-related genes (n = 716). Furthermore, we analyzed single-cell RNA-sequencing data of PFA ependymomas to dissect myeloid and lymphocyte heterogeneity, which we subsequently used to deconvolute bulk data. Lastly, we performed both high-dimensional cyclical immunofluorescence of 20 protein markers on a tissue microarray containing 60 cores from 20 tumor samples and immunohistochemistry on whole tissue slides. RESULTS Unsupervised hierarchical clustering of bulk RNA expression of immune-related genes revealed the presence of an immune-enriched subgroup. Furthermore, analysis of single-cell RNA-sequencing data identified multiple distinct myeloid cell subpopulations, with gene expression signatures reflective of inflammation, angiogenesis/hypoxia response and proliferation. Deconvolution of the bulk RNA-sequencing data using the newly annotated single-cell data as a reference showed enrichment of both myeloid cells and lymphocytes in the immune-enriched subgroup. Lastly, spatial immune profiling enabled detailed mapping of the organization of the tumor immune microenvironment and unveiled a heterogeneous presence of myeloid cells, with enrichment of infiltrating myeloid and T-cells in peri-necrotic areas compared to areas with high tumor cell density. CONCLUSIONS Our multi-faceted approach has shed unprecedented light on the cellular and spatial heterogeneity within the PFA ependymoma immune microenvironment. Further studies are warranted to unravel the functional differences between the two subgroups and the potential impact on response to future immunotherapeutic approaches/interventions.
LMIC-09. CRADLE TO CRAYON: THE IMPACT OF COLLABORATION ON PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN GHANA
Authors: Ernestina N B Schandorf, Mary-Ann Dadzie Quarcoopome, Hafisatu Gbadamosi, Lorna A Renner, Eric Bouffet, Patrick E Bankah
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND A multidisciplinary team (MDT) approach is essential for quality care, especially in paediatric oncology. In developing countries like Ghana, paediatric neuro-oncology is a relatively young subspecialty and requires a multidisciplinary team approach. The St Jude Global Academy Neuro-Oncology Training Seminar in 2022 saw a significant milestone in this MDT journey. Four MDT members benefited from the training, with a profound impact. This study aims to study the effect of neuro-oncology training on the number of CNS cases reviewed at MDT meetings. METHODS A retrospective review of case announcements made on the Pediatric Oncology MDT WhatsApp group page were collated spanning the period August 1, 2022, to July 31, 2023. Tumour distribution of cases discussed at MDT was compared 4 months pre- and 4- and 8-months post-St Jude Global Academy Neuro-Oncology Training Seminar (NOTS) completion in November 2022. A T-test was used to calculate for statistical significance of the difference in the number of cases discussed over the period. RESULTS A total of 208 cases were discussed after 52 MDT Zoom meetings. The number of cases discussed at MDT increased from 40 recorded in the first four months (August -November 2022) to 89 cases in the last four months (April- July 2023). There was a significant increase in the number of CNS cases discussed by 3.9% (p=0.012) at 4 months and 6.6% (p=0.023) at 8 months after NOTS. The complexity of CNS tumours discussed also increased. CONCLUSIONS The St Jude Global NOTS positively influenced the number of CNS cases discussed at MDT. Multidisciplinary team discussions allow for collations of ideas from all specialists with a patient-centred approach which is particularly invaluable to the care of neuro-oncology patients. Further studies on the effect on time of plan implementation, and client satisfaction will be beneficial to evaluate the effectiveness of our MDTs.
TRLS-06. PHASE 1 STUDY OF THE CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M (SOTIGALIMAB) IN PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH RECURRENT OR PROGRESSIVE CNS TUMORS AND NEWLY DIAGNOSED BRAIN STEM GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC-051; NCT03389802)
Authors: Holly B Lindsay, Catherine Billups, Patricia Baxter, Eugene Hwang, Alicia Lenzen, Tobey MacDonald, Ian F Pollack, Nathan Robison, Anna Vinitsky, Tina Young Poussaint, Arzu Onar-Thomas, Jason Fangusaro, Ira J Dunkel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND CD40 is a co-stimulatory receptor present on antigen-presenting cells. CD40 agonists are hypothesized to reverse cancer-induced immune suppression and induce tumor cell killing. The PBTC completed a first-in-pediatrics phase 1 study (PBTC-051) of the CD40 agonistic monoclonal antibody APX005M (sotigalimab). METHODS Patients 1-21.99 years old with recurrent/progressive/refractory malignant non-brainstem central nervous system (CNS) tumors were eligible for stratum 1, and those with post-radiation pre-progression diffuse intrinsic pontine glioma (DIPG) for stratum 2. Patients received APX005M (sotigalimab) via IV on day 1 of each 21 day cycle. A 3 + 3 statistical design was used for dose escalation through 3 planned dose levels (DL). Patients could receive APX005M (sotigalimab) for 36 cycles or until disease progression, unacceptable toxicity, or death. RESULTS 31 eligible patients enrolled (20 on stratum 1, 11 on stratum 2) between 2018-2023; 29 were evaluable for dose finding. The most common diagnosis in stratum 1 was ependymoma (35%). DL3 (0.6 mg/kg) was the recommended phase 2 dose (RP2D) for stratum 1 and DL2 (0.3 mg/kg) for stratum 2. Five patients had dose limiting toxicities—two stratum 1 patients at DL3 and three stratum 2 patients at DL3. The most common grade 3+ adverse events at least possibly attributable to APX005M (sotigalimab) were lymphopenia, neutropenia, leukopenia, and increased ALT. Median number of cycles was 2 (1-36) for stratum 1 and 3 (1-19) for stratum 2. No patients had an objective response to APX005M. 6 month progression-free survival (PFS) for stratum 2 patients (calculated from start of treatment) was 30.7±12.8%; median PFS was 3.7 months. CONCLUSIONS APX005M was well-tolerated in pediatric patients with both recurrent/refractory/progressive CNS tumors and post-radiation pre-progression DIPG. A RP2D was established for both populations. Future studies of this agent in pediatric neuro-oncology patients should prioritize combination therapy.