tbuckley/cabot-search huggingface dataset:
LGG-14. INTEGRATED MULTI-OMICS EXPLORATION OF MAPK PATHWAY INHIBITION IN PEDIATRIC PILOCYTIC ASTROCYTOMA
Authors: Romain Sigaud, Anja Stefanski, Florian Selt, Diren Usta, Daniela Kocher, Daniel Picard, Isabel Büdenbender, Marc Remke, Stefan M Pfister, David T W Jones, Tilman Brummer, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2024)

Abstract Pilocytic astrocytomas (PA), the most common pediatric brain tumors, exhibit MAPK pathway alterations leading to its constitutive activation. They are also associated with low proliferation index due to the oncogene-induced senescence (OIS), sustained by senescence-associated secretory phenotype (SASP) factors. Little is known about the downstream consequences of MAPK activation leading to OIS-SASP, and of the molecular implications of MAPK pathway inhibition in senescent PA cells. Senescent DKFZ-BT66 cells derived from a primary KIAA::BRAF-fusion positive PA were used to generate RNA-sequencing and phospho-/proteomic datasets, before and after treatment with the MEK inhibitor (MEKi) trametinib for different time-spans. A multi-omics factor analysis tool (MEFISTO) and single sample gene set enrichment analysis (ssGSEA) were used to identify key OIS effectors and differentially regulated pathways upon MAPK inhibition. Trametinib treatment inhibited OIS and SASP signatures across all omics levels in the senescent DKFZ-BT66 cells, associated with reduced sensitivity towards senolytics drugs, indicating inhibition of senescence features upon MEKi. MEFISTO analysis identified key effectors involved in MAPK-induced OIS in the senescent PA cells. We built a pathway network using a prior knowledge network approach allowing to map the direct downstream effectors of MAPK leading to OIS-SASP. We identified several parallel pathways (JAK/STAT, p38, GSK3B) potentially involved in OIS and under the control of the MAPK pathway. In addition, ssGSEA showed that pathways related to upstream MAPK activators (SOS1, CK2, several RTKs) were predicted to be upregulated upon treatment, highlighting putative targets to be further investigated. Our data suggest that MAPKi reverses OIS signaling in senescent PA cells, while inducing the activation of MAPK upstream regulators, identifying putative co-targets for the treatment of PA. Further validation of the targetability of these pathways is pending. Furthermore, the identification of the MAPK-related OIS-SASP genes provides insight into the regulation of OIS-SASP by the MAPK pathway.
LGG-09. REBOUND GROWTH AFTER MAPKI WITHDRAWAL INVOLVES RAPID MAPK REACTIVATION AND CYTOKINE-MEDIATED MICROGLIA RECRUITMENT IN PEDIATRIC LOW-GRADE GLIOMA MODEL
Authors: Daniela Kocher, Lei Cao, Romain Guiho, Melanie Langhammer, Yun-Lu Lai, Pauline Becker, Dennis Friedel, Florian Selt, David Vonhören, Julia Zaman, Gintvile Valinciute, Sonja Herter, Johanna Rettenmeier, Kendra K Maass, Kristian W Pajtler, Andreas von Deimling, Stefan Pusch, Stefan M Pfister, Ina Oehme, David T W Jones, Sebastian Halbach, Tilman Brummer, Juan Pedro Martinez-Barbera, Olaf Witt, Till Milde, Romain Sigaud
Journal: Neuro-Oncology (2024)

Abstract Patients with pediatric low-grade gliomas (pLGG), the most common primary brain tumor in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. Four patient-derived pLGG models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset of the rebound model encompassing different MAPKi withdrawal timepoints was generated using RNA sequencing and LC-MS/MS based phospho-/proteomics to investigate possible driving mechanisms of rebound growth. Following in vitro validation, putative rebound driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. Of the tested models, BT-40 (BRAFV600E, CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal, characterized by faster cell regrowth after MAPKi withdrawal compared to standard-of-care chemotherapy. Using this model, we observed MAPK pathway reactivation within hours after withdrawal, associated with a transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels. Additionally, we observed increased expression and secretion of cytokines (in particular CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal (at least until 24 h). While increased cytokine expression did not affect response to MAPKi or rebound growth upon withdrawal in an autocrine manner, increased attraction of microglia cells mediated by these cytokines was observed. MAPK pathway reactivation during rebound growth and increased expression of CX3CL1 and CXCL10 induced by MAPKi treatment could further be confirmed in vivo. Taken together, these data indicate a rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound driving mechanism. Furthermore, increased microglia recruitment during MAPKi treatment and withdrawal, mediated by cytokines, may play a role in response to MAPKi treatment and rebound growth upon withdrawal, warranting further evaluation.
LGG-12. INTEGRATED CLINICAL AND MOLECULAR CHARACTERIZATION OF 200 DISSEMINATED PEDIATRIC LOW-GRADE GLIOMAS
Authors: Adrian Levine, Julie Bennett, Cyril Li, Mansuba Rana, Richard Yuditskiy, I-Chen Ho, Joseline Haizel-Cobbina, Jordan Hansford, Amanda Luck, Louise Ludlow, David Eisenstat, Helen Toledano, Roaya Masoud, Kohei Fukuoka, Kai Yamasaki, Yoshiko Nakano, Naureen Mushtaq, Khurram Minhas, Syed Ibrahim Bukhari, Ana Guerreiro Stuecklin, Annette Weiser, Filip Jadrijevic-Cvilje, Adam Fleming, Shawde Campbell, Chantel Cacciotti, Craig Erker, Frank van Landeghem, Bev Wilson, Karina Black, Mary MacNeil, Sylvia Cheng, Chris Dunham, Valerie Larouche, Panagiota Giannakouros, Adriana Fonseca, Lane Williamson, Ashley Plant-Fox, Jean Mulcahy Levy, Samantha DeMarsh, José Velázquez Vega, Prabhumallikarjun Patil, MacLean Nasrallah, Mariarita Santi-Vicini, Ernest Nelson, Richard Graham, Scott Raskin, Igor Fernandes, Michael Dewan, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2024)

Abstract Pediatric low-grade gliomas (PLGG) have excellent outcomes overall but are a major clinical challenge when disseminated. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a recognised entity both clinically and pathologically, however many disseminated LGG (DLGG) fall outside this diagnosis. To better understand the clinical and molecular features of DLGG as well as risk factors for dissemination, we assembled an international consortium of 30 sites, contributing over 200 patients with clinical annotation, along with genomic and methylation profiling. DLGG have worse progression-free (PFS) and overall survival (OS) than PLGG overall (p&amp;lt;0.0001). Seventy (35%) presented with a localized mass and secondary dissemination, including some with initial gross-total resection. The most common growth pattern observed (n=77, 40%) is a dominant suprasellar/optic pathway tumor with leptomeningeal drop-metastases involving the brainstem and spinal cord. Only 27 (14%) patients had diffuse tumors (without an identifiable dominant mass), and these had significantly worse OS (p=0.03). The most common pathologic diagnosis was pilocytic/pilomyxoid astrocytoma (n=92; 53%). DLGNT comprised a minority of cases (n=23, 14%), with a trend (p=0.056) towards worse survival compared to other diagnoses. The most frequent molecular alteration was BRAF fusion (78/151 with molecular testing; 52%), followed by FGFR mutations or fusions (18/151; 12%). BRAF V600E was underrepresented (14/151; 9%). 1p deletion was rare (17 patients) but highly associated with DLGNT. Methylation classification (n=70) was highly concordant with histologic diagnoses rather than clinical behavior. Importantly, patients who received upfront targeted therapies (TT; BRAF and/or MEK inhibition, n=9) had better PFS compared to those receiving chemotherapy (n=146, p=0.05). Furthermore, patients who were treated sequentially with chemo then TT had longer PFS on TT (p=0.011). This study presents the largest cohort of DLGG to date, expanding our understanding of the clinical, pathologic, and molecular features of this disease and supports the use of upfront targeted therapy.
LMIC-24. ASSESSING THE TREATMENT OUTCOMES OF PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA UNDER A U.S.-MEXICO CROSS-BORDER NEURO-ONCOLOGY PROGRAM
Authors: John R Crawford, Alexander Tenorio, Michael Brandel, John Adams, Nikhil Kumar, Rebeca Rivera Gomez, David Gonda, Michael L Levy, Paula Aristizabal
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Treating pediatric brain tumors in low-income countries is associated with worse outcomes, likely due to requiring a highly trained interdisciplinary team with ample resources. The Cross-Border Neuro-Oncology Program (CBNP) between Rady Children’s Hospital, San Diego (RCHSD), and Hospital General, Tijuana (HGT), was established to provide comprehensive care for children with brain tumors diagnosed at HGT. Given the most common malignant pediatric brain tumor is medulloblastoma, assessing treatment outcomes for this tumor is essential to establish this program’s validity. METHODS Pediatric patients with medulloblastoma were recruited from 2012-2021 as part of CBNP and risk-stratified into one of two treatment protocols (low - (K) versus high-risk (Y)). Patients underwent surgical resection and chemotherapy, which included cisplatin, etoposide, vincristine, and cyclophosphamide; patients with higher risk additionally received radiation therapy and higher-dose chemotherapy. Clinicopathologic profiles, extent of resection, methylation status and protocol type were analyzed and compared to known prognostic values for pediatric medulloblastoma. RESULTS Seventeen patients with medulloblastoma (age at diagnosis=6.8±5.0 years) were treated as part of CBNP during the study period. Patients were admitted to HGT, underwent resection at RCHSD, and returned to HGT for collaborative management. The mean symptom duration preceding diagnosis was 72.1±99.2 days. Gross total resection was achieved in 53% of cases and 5-year overall survival was 53% (9/17). Eight (47%) patients had residual post-treatment cerebellar signs. Survival data correlated with protocol type and methylation status will be presented. CONCLUSION Our cohort demonstrated a 5-year overall survival of 53%, moderately lower than the reported average 5-year overall survival of ~70% for pediatric medulloblastoma, with the majority of our cohort comprising of higher risk subtype and pathology. This indicates that this twinning model is a valid archetype for treating pediatric patients with brain tumors in low-income countries.
MDB-26. GENE REGULATORY NETWORK LANDSCAPE OF GROUP 3/4 MEDULLOBLASTOMA
Authors: Piyush Joshi, Tamina Stelzer, Konstantin Okonechnikov, Ioannis Sarropoulos, Mari Sepp, Mischan V Pour-Jamnani, Anne Rademacher, Tetsuya Yamada-Saito, Céline Schneider, Julia Schmidt, Philipp Schäfer, Kevin Leiss, Michele Bortolomeazzi, Jan-Philipp Mallm, Patricia B G da Silva, Britta Statz, Andrea Wittmann, Kathrin Schramm, Mirjam Blattner-Johnson, Petra Fiesel, Barbara Jones, Till Milde, Kristian Pajtler, Cornelis M van Tilburg, Olaf Witt, Karsten Rippe, Andrey Korshunov, David T W Jones, Volker Hovestadt, Paul A Northcott, Supat Thongjuea, Natalie Jäger, Henrik Kaessmann, Stefan M Pfister, Lena M Kutscher
Journal: Neuro-Oncology (2024)

Abstract Intra-tumor heterogeneity in brain cancers contributes to therapy resistance and relapse through positive selection of resistant tumor cell populations. Resolving the molecular mechanisms driving intra-tumor heterogeneity will uncover tumor-specific vulnerabilities and advance effective treatment strategies. Group 3/4 medulloblastomas, the most common embryonal cerebellar tumor subgroup, are highly heterogeneous tumors with high frequency of relapse which are almost certainly fatal. Here, we generated and analyzed a comprehensive single-cell multi-omic Group 3/4 medulloblastoma atlas, comprising 355,295 cells from 38 tumor patients representing eight Group 3/4 molecular subtypes. We identified transcription factor gene regulatory networks driving intra- and inter-tumor heterogeneity in Group 3/4 medulloblastoma, and determined the common regulatory framework that drives this heterogeneity. We show that Group 3/4 tumor diversity stems from differential enrichment of cell-states along four molecular identity axes: photoreceptor, MYC, precursor, and unipolar brush cell-like. Further, we show that intermediate subtype I/VII tumors exhibit a unique biology where a tumor exhibits dual Group 3 and Group 4-like tumor cell-states in a single tumor, and for a subset of these tumors, we identified a potential role of PAX6 in driving the observed dual trajectory. Altogether, our study demonstrates how oncogenic events together with key lineage determinants hijack normal developmental programs and drive Group 3/4 tumor identity away from the normal cerebellar unipolar brush cell-lineage.
IMMU-17. A PHASE I STUDY OF INTRATUMORAL/PERITUMORAL HERPES SIMPLEX VIRUS-1 MUTANT HSV1716 IN PATIENTS WITH REFRACTORY OF RECURRENT HIGH-GRADE GLIOMAS: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY
Authors: Aaron Y Mochizuki, Trent R Hummel, Timothy Cripe, Maryam Fouladi, Charles B Stevenson, Ian Pollack, Duane Mitchell, Tina Young Poussaint, Arzu Onar-Thomas, Mariko DeWire-Schottmiller, Natasha Pillay-Smiley
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Immune-modulatory strategies, including checkpoint inhibition and tumor vaccines, have been tested in efforts to mitigate the pro-tumor microenvironment in pediatric high-grade glioma (pHGG). HSV1716 is a first-generation oncolytic virus that was previously reported safe with evidence of response in pediatric patients with relapsed or refractory extracranial tumors and in adults with high-grade glioma. METHODS PBTC-037 was a multicenter, phase I trial developed and performed by the Pediatric Brain Tumor Consortium (PBTC) to estimate the maximum tolerated dose or recommended phase II dose of HSV1716 administered during surgical resection. Patients aged 12 to 21 years with recurrent or refractory pHGG for whom surgical resection was clinically indicated were eligible. After maximal tumor resection, patients received one intraoperative dose of HSV1716. RESULTS Two patients were enrolled; one was later deemed ineligible (due to out-of-window screening evaluations) yet was continued in follow up for safety. Shortly after enrollment of the 2 patients, the study was closed to accrual due to a change in the sponsor’s investment focus. One patient completed the 8-week reporting period without toxicities. The only grade 3 or higher adverse event noted was grade 3 hyperglycemia at 2- and 3-months post injection. The second patient that was later deemed ineligible received the injection of HSV1716 and had no evidence of dose-limiting toxicity. The two patients had progressive disease 1.9 and 2.9 months after enrollment; both eventually died due to progressive disease at 7.5 months. CONCLUSIONS We describe the administration of HSV1716 to two pediatric patients with recurrent high-grade glioma, without evidence of dose-limiting toxicity. Oncolytic viruses are currently being tested in pediatric patients in larger trials and in combinatorial trials in other tumor types. Despite the limited numbers, the data presented here will hopefully provide incremental steps toward improved immunovirotherapy of pediatric brain tumors.
OTHR-17. FACILITATING THE POSTMORTEM DONATION OF WHOLE BRAIN AND SPINAL CORD IN PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM CANCERS
Authors: Caroline A Kopsidas, Denise Morinigo, Niku Nourmohammadi, Augustine Eze, Roy Debasish, Miriam Bornhorst, Sridevi Yadavilli, Roger Packer, Javad Nazarian
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Postmortem tissue donation is often presented to families during end-of-life discussions. The sensitive nature requires every step to be handled with care, leading with empathy and delicately balancing scientific research and humanity. The Children’s National Hospital Postmortem Tissue Donation Workflow (The Workflow) provides a step-by-step guide for coordinating a successful donation. It outlines the order in which clinical research teams communicate with patient care teams, families and collaborators to make the donation possible. This program, established in 2010, aims to acquire more pediatric brain and spinal cord tumor specimens to further understand the disease biology. OBJECTIVE This paper aims to provide a template for coordinating a successful postmortem tissue donation. Ultimately, to broaden the network of tissue donation across all hospitals and institutions, thus furthering scientific research. METHOD In order to create The Workflow, Clinical Research Coordinators from Children’s National Hospital conducted numerous postmortem donations and noted the failures and successes of each case. This information was compiled into a stepwise workflow including email templates and checklists. It begins with contacting the care team, and the following hours to days are spent obtaining a pathologist for tissue procurement, and facilitating the shipment of samples. While these steps must be completed in a timely manner for sample integrity, we also prioritize the wishes of the family and act with compassion at the forefront. RESULTS/DISCUSSION Children’s National Hospital was designated as a Center of Excellence for postmortem coordination by the Swifty Foundation in 2018. Our team has since established and standardized a workflow for the donation process. The Children’s National Hospital Postmortem Workflow allows our research team to study brain tumors including DMGs, High and Low Grade Gliomas, and Medulloblastomas. The generosity of the families and hard work of each collaborator allows us to expand our knowledge of tumor biology.
LGG-16. BRAFV600K LOW-GRADE GLIOMA EMERGENCE DURING THERAPY FOR BRAFV600E HIGH-GRADE GLIOMA
Authors: Luke Proctor, Amy Smith, Ana Aguilar-Bonilla
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND BRAFV600E mutations are prevalent in pediatric brain tumors, constituting 20% of low-grade and 5% of high-grade gliomas. Other single-nucleotide substitutions in BRAF are described in adult cancers but rarely in pediatric brain tumors. Our case sheds light on a unique scenario—a patient with a BRAF-mutated high-grade spinal glioma who later developed slowly progressive intracranial low-grade glioma, subsequently undergoing rapid high-grade transformation. METHODS Case Report RESULTS Our patient initially presented as a thirteen-year-old male with a two-month history of progressive bilateral hand weakness/paresthesias. Spine MRI revealed a fusiform expansile intramedullary neoplasm from C3-T2, brain MRI was negative. Biopsy showed an anaplastic astrocytoma with BRAFV600E mutation and MYC-N amplification. Initial treatment included proton radiation and a 2-year course of Dabrafenib/Trametinib, maintaining disease stability. After four months off therapy, he developed local progression, and re-staging brain MRI showed new cerebellar/supratentorial lesions. Dabrafenib/Trametinib was re-started until progression two years later. He developed hydrocephalus and underwent ETV and brain tumor biopsy, which revealed a low-grade glioma with BRAFV600K mutation. At this point, Dabrafenib/Trametinib continued for another 1.5 years; he exhibited slow progression of the brain tumors before a cerebellar lesion developed rapid progression. He had GTR of the rapid-growing lesion, and pathology reported a Grade 4 invasive astrocytoma harboring BRAFV600E, two VUS MTOR mutations, and MGMT promoter methylation. Current treatment involves radiation therapy concurrent with temozolomide. CONCLUSIONS While combinatorial Dabrafenib/Trametinib is effective in glioma therapy, resistance and progression challenges persist. Our case presents a unique manifestation—a patient with a spinal high-grade glioma with BRAFV600E who developed a secondary low-grade glioma with BRAFV600K in the brain, which, after several years, transformed into a high-grade glioma. Future research is crucial for comprehending the intricate role of BRAF mutations in pediatric gliomas, paving the way for improved patient outcomes.
HGG-04. MALIGNANT GLIOMA IN L-2-HYDROXY GLUTARIC ACIDURIA; THOROUGH MOLECULAR CHARACTERIZATION OF A CASE AND LITERATURE REVIEW
Authors: Fleur Cordier, Pieter Wesseling, Bastiaan B J Tops, Lennart Kester, Pim J French, Martin van den Bent, Felix Hinz, Eleonora Aronica, K Mariam Slot, Floor Abbink, Marjo van der Knaap, Mariëtte E G kranendonk
Journal: Neuro-Oncology (2024)

Abstract L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare neurometabolic disorder characterized by accumulation of L2-hydroxyglutarate (L-2-HG) due to mutations in the L2HGDH gene. L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. Here, we present a 16-year-old girl with L-2-HGA who developed a tumor in the right cerebral hemisphere, which was discovered after left-sided neurological deficits of the patient. Histologically, the tumor had a high-grade diffuse glioma phenotype. DNA sequencing revealed the germline L2HGDH mutation as well as inactivating mutations in TP53, BCOR and NF1. Genome-wide DNA-methylation analysis was unable to classify the tumor with high confidence. More detailed analysis revealed that this tumor clustered amongst IDH-wildtype gliomas by methylation profiling and did not show the glioma CpG island methylator phenotype (G-CIMP) (in contrast to IDH-mutant diffuse gliomas with accumulated levels of D-2-HG). These findings were against all our expectations given the inhibitory potential of 2-HG on DNA-demethylation enzymes. Our final integrated histomolecular diagnosis was diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. Due to rapid tumor progression the patient died nine months after initial diagnosis. In this manuscript we provide extensive molecular characterization of the tumor as well as a literature review focusing on oncogenetic considerations of L-2-HGA-associated CNS tumors.