tbuckley/cabot-search huggingface dataset:
DIPG-65. NOVEL PATIENT-BASED PHARMACOKINETIC DRUG SCREENING REVEALS GEMCITABINE POTENTIAL IN PEDIATRIC H3K27-ALTERED DIFFUSE MIDLINE GLIOMAS
Authors: Liska M Scheffers, John Bianco, Yan Su, Femke C A Ringnalda, Elizabeth C M de Lange, Alwin D R Huitema, Dannis G van Vuurden
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric H3K27-altered diffuse midline glioma (DMG) remains incurable, with median overall survival of less than one year. Ineffectiveness of chemotherapy is largely attributed to the blood–brain barrier, hindering drug exposure to the tumor. Current drug sensitivity testing use concentrations vastly different from those attainable in the human brain, with optimal combination, timing, and sequence of drugs remaining underexplored. This study aims to systematically select and validate EMA/FDA approved drugs for effective treatment of DMG, based on human pharmacokinetics. METHODS In silico anticancer drug pharmacokinetic (PK) properties were correlated with published DMG cell sensitivities and ranked based on therapeutic index potential. Predictions of brain extracellular fluid time-concentration profiles (AUChumanECF) using plasma PK values of drug candidates, corresponding to human values, were made via physiologically based pharmacokinetic (PBPK) modeling with LeiCNS-PK3.0. In vitro cellular treatment protocols were established that mimic clinically achievable AUChumanECF, to be validated in vivo. RESULTS This PBPK drug screening approach revealed gemcitabine as a highly potent drug for DMG therapy for most cell lines tested (AUCplasma/AUCin_vitro = 337.6±233.0). Replicating a phase I clinical study in pediatric leukemia patients (3 weekly courses of 3600 mg/m2), 3 weekly 6-hour exposures to 12.5 µM.h gemcitabine demonstrated up to 99% cell kill as compared to viability at start of treatment. Notably, the cytotoxic effects of gemcitabine became apparent 3-5 days following drug exposure for most cell lines, and would have been missed using conventional drug screening with direct readouts. CONCLUSIONS This human PBPK-based drug screening approach underscores the significance of precise timing and dosing in elucidating clinically relevant therapeutic effects, highlighting high-dose gemcitabine as a potential therapy for DMG. Cytotoxic effects of gemcitabine on DMG cell viability are cumulative, and undetected when using conventional drug screening. This underlines the importance of investigating real-life human exposure patterns in the context of DMG.
LGG-26. A ROLE FOR BRAF FUSION PARTNERS IN ONCOGENIC SIGNALING
Authors: Sean Misek, Anna Borgenvik, Ruth Fekade, Alexander Zhang, Timothy Ragnoni, Aaron Fultineer, Kevin Zhou, Daniel Bondeson, Dana Novikov, Sher Bahadur, Seung Hyun Choi, Amy Goodale, Alexandra-Larisa Condurat, Carolina Cordero, Nicole Persky, Laura Kiessling, David Root, Michael Eck, Jesse Boehm, David Jones, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2024)

Abstract t was originally hypothesized that loss of BRAF N-terminal negative regulatory domains, which are deleted in the KIAA1549:BRAF rearrangement, results in constitutive activation of the BRAF kinase. This model suggests that BRAF fusion partners are dispensable for BRAF oncogenic signaling. Paradoxically, our data suggest expression of truncated BRAF is insufficient for transformation and identify specific domains in KIAA1549 that are necessary for transformation. These domains are critical for regulating subcellular localization of the fusion protein and highlight an aberrant pattern of cellular localization that is not observed with wildtype BRAF. Altered subcellular localization results in proteolytic cleavage of KIAA1549:BRAF, and we identify the protease responsible for this cleavage event. This protease is therapeutically tractable and clinically relevant inhibitors have been developed, presenting a MAPK-independent mechanism to target the fusion. We also highlight an unexpected role for rare fusion partners, including FAM131B, in BRAF activation. In total, these data suggest that BRAF fusion partners are not indispensable for transformation as was previously thought, presenting unexplored opportunities to therapeutically target pLGG tumors with BRAF rearrangements. We are currently working on the IP measures required to disclose the specific enzyme(s) at ISPNO.
TRLS-01. INTRAVENTRICULAR B7-H3 CAR T CELLS FOR DIFFUSE INTRINSIC PONTINE GLIOMA: SAFETY AND EFFICACY REPORT FROM THE COMPLETED PHASE 1 TRIAL BRAINCHILD-03
Authors: Nicholas A Vitanza, Rebecca Ronsley, Wenjuan Huang, Kristy Seidel, Alison Thomsen, Juliane Gust, Jason Hauptman, Michlle Choe, Erin Crotty, Sarah Leary, Joshua A Gustafson, Rebecca A Gardner, Sowmya Pattabhi, Jason Wendler, On Ho, Colleen Annesley, Julie R Park, Michael C Jensen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND BrainChild-03 is a first-in-human clinical trial that completed the phase 1 component of repeatedly dosed intraventricular B7-H3 CAR T cells to children with diffuse intrinsic pontine glioma (DIPG) without lymphodepleting chemotherapy. METHODS We report on BrainChild-03 Arm C, patients with DIPG receiving up to 10x10^7 B7-H3CAR T cells/dose. Primary endpoints were feasibility and safety. Secondary endpoints were disease response and correlatives of CAR T activity. RESULTS 23 patients enrolled. All had successful CAR T manufacturing. 21 patients were treated; 17 received sufficient doses for safety evaluation (4 doses/8 weeks) without a dose limiting toxicity (DLT). 4 other treated patients include: 1 patient DLT (pontine hemorrhage 8 days post-initial dose) and 3 unevaluable patients (2 discontinued protocol therapy for rapid progression; 1 did not meet eligibility to begin treatment). Overall, patients received 224 doses (median: 7, range: 1-60). Common adverse events included headache, nausea/vomiting, and fever. Of 21 treated patients, 11 enrolled after progression and survived 9.7 months (range: 6-16.9) after initial CAR T cell infusion. Of the 10 patients enrolled prior to progression, the overall survival is 16.9 months (range: 7.6-40.5) with 5/10 patients still alive. Three patients are alive 3 years from diagnosis, including 2 patients still on protocol therapy. Patients were not allowed to receive other anti-tumor agents, radiation, or surgical debulking while on protocol therapy. Circulating CSF CAR T cells were identified in 18/21 (85.7%) of patients and elevations in chemokine/cytokines associated with T cell activation and migration, including CXCL10 and IFNy. CONCLUSIONS Repeated intraventricular B7-H3 CAR T cell dosing is feasible and tolerable for children with DIPG, even after progression, with evidence of local immune activation. Early signals of survival extension underscore the potential for clinical benefit and the consideration to advance to phase 2 multi-site clinical trials.
HGG-30. TARGETED THERAPY OF PEDIATRIC HIGH GRADE GLIOMAS
Authors: Ludmila Papusha, Alexander Druy, Ekaterina Salnikova, Margarita Zaytseva, Agnesa Panferova, Irina Vilesova, Andrey Flegontov, Igor Kasich, Artur Merishavyan, Andrey Sysoev, Vitaly Degtyarev, Marina Koldasheva, Agunda Sanakoeva, Anton Artemov, Anastasia Procvetkina, Alexander Karachunskiy, Eugene Hwang, Roger Packer, Galina Novichkova
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Recent advances in understanding tumor biology facilitate utilization of targeted therapies (TT) in pediatric neuro-oncology. METHODS We analyzed the efficacy of targeted therapy in patients with progressive pHGG treated with TT according to molecularly-identified actionable events. Molecular characterization of the tumor included DNA panel and transcriptomic RNA sequencing. RESULTS Eighteen patients were included (median age 3.7 years, range 0.1-17.7) with anaplastic pleomorphic xanthoastrocytoma (n=10), infant-type hemispheric glioma (n=4), and diffuse high-grade glioma (n=4). Metastatic disease was present in 3/18 patients. Molecular genetic alterations included BRAF V600E mutations (n=8), NTRK1/2/3 fusions (n=4), ROS1 fusions (n=4), MET fusion (n=1), KIT P627L mutation (n=1). Eight patients received an NTRK/ALK/ROS1 inhibitor (entrectinib), seven patients received combination therapy with BRAF and MEK inhibitors (dabrafenib and trametinib), and one patient anti-BRAF monotherapy (dabrafenib). Two patients were treated with a multi-tyrosine kinase inhibitor (cabozantinib). The median duration of targeted therapy was 10.6 months (1-42). Most patients tolerated treatment well with no grade 4-5 toxicities. The overall response rate was 66% (12/18), including 4 complete (22%) and 8 partial responses (44%). At 12 months, PFS was 86% with dabrafenib/trametinib and 42% with entrectinib; at 18 months PFS was 44 % with dabrafenib plus trametinib and 42% with entrectinib. Three out of four patients with ROS1 rearranged glioma experienced disease progression on entrectinib after an initial good response in all cases; two of them subsequently received lorlatinib with clinical benefit. All four patients with NTRK1/2/3 rearranged gliomas remain on entrectinib therapy without signs of progression. Cabozantinib therapy resulted in prolonged complete and partial responses in both cases. CONCLUSIONS TT for patients with progressive pHGG is feasible and provides unexpectedly good clinical efficacy.
METB-01. EFFECTS OF H3.3G34V MUTATION ON GENOMIC H3K36 AND H3K27 METHYLATION PATTERNS IN ISOGENIC PEDIATRIC GLIOMA CELLS
Authors: Tina Huang, Andrea Piunti, Jin Qi, Elizabeth Bartom, Amanda Saratsis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Histone H3.3 mutation (H3F3A) occurs in 50% of cortical pediatric high-grade gliomas (pHGGs). This mutation replaces glycine 34 with arginine or valine (G34R/V), impairing SETD2 activity (H3K36-specific trimethyltransferase). Consequently, reduced H3K36me3 is observed on H3.3G34V nucleosomes relative to wild-type, contributing to genomic instability and driving a distinct gene expression signature associated with tumorigenesis. However, it is not known if this differential H3K36me3 enrichment is due to H3.3G34V mutant protein alone. Therefore, we set to elucidate the effect of H3.3G34V mutant protein in pediatric glioma on H3K36me3, H3K27me3 and H3.3 enrichment in vitro. METHODS Experiments were conducted using an established H3.3G34V mutant patient-derived pediatric high-grade glioma cell line (KNS42), and Histone H3.3 wild-type human astrocytes (NHAs). Lentiviral delivery of a doxycycline-inducible RNAi vector targeted against H3F3A was transduced to KNS42 cells to knock down H3.3G34V protein expression. Cell lines were then compared via ChIP-Seq, Western Blot, proliferation and viability studies. RESULTS We found that the doxycycline-inducible shRNA knockdown of mutant H3F3A encoding the H3.3G34V protein resulted in loss of H3.3G34V enrichment and increased H3K36me3 enrichment throughout the genome. After knockdown, H3.3G34V enrichment was preserved at loci observed to have the greatest H3.3G34V and H3K36me3 enrichment prior to knockdown. Induced expression of mutant H3.3G34V protein in vitro was insufficient to induce genomic H3K36me3 enrichment patterns observed in H3.3G34V mutant glioma cells. We also observed strong co-enrichment of H3.3G34V and wild-type H3.3 protein, as well as greater H3K27me3 enrichment, in cells expressing H3.3G34V. CONCLUSIONS Our study demonstrates the effects of H3.3G34V mutant protein on genomic H3K36me3, H3K27me3 and H3.3 enrichment patterns in isogenic cell lines. Further studies examining the impact of theses findings are therefore underway.
CP-03. EXTRACELLULAR MATRIX REMODELING REVEALS NON-CELL AUTONOMOUS TUMOR FORMATION MECHANISM IN ADAMANTINOMATOUS CRANIOPHARYNGIOMAS
Authors: John A Jeang, Danny Jomaa, Dana Novikov, Jessica W Tsai, John R Apps, Saba Manshaei, Eric Prince, Todd C Hankinson, Juan-Pedro Martinez-Barbera, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2024)

Abstract Adamantinomatous Craniopharyngioma (ACP) is a rare pituitary tumor of the sellar region, with a bimodal presentation pattern in children and middle-aged adults. ACPs are primarily driven by a mutation in CTNNB1 that prevents beta-catenin from degrading properly, resulting in accumulation in the nuclei of epithelial whorl-like structures sometimes referred to as cluster cells. Clinical management is challenging due to the location of the tumor, such that complete surgical resection is often not possible so radiation therapy, which can lead to high morbidity, is also used. Greater insight into these tumors can help develop less damaging treatment strategies. In this analysis we have employed single-cell RNA sequencing technology to examine seven pediatric human ACPs (28594 cells). Using consensus non-negative matrix factorization, and traditional marker genes, we have partitioned our dataset into several cell types including cluster cells, palisading epithelial cells, microglia, T-cells, B-cells, plasma cells, and fibroblasts. Though cluster cells themselves do not actively proliferate, we believe the complex inter-cellular signaling is responsible for tumor formation. We propose a model in which malignant fibroblasts form from the existing epithelium and remodel the extracellular matrix (ECM) creating a stiffened tumor microenvironment. To support this claim we show activation markers suggesting myofibroblast differentiation, the expression of EMT signatures indicating a transformation from epithelial to fibroblast, and RNA velocity analysis that demonstrates lineage tracing. We believe that the remodeling of the ECM is a wound healing response influenced by TGF-beta, SPP1, and other signaling pathways. Our analysis of ACPs reveals the role of the tumor microenvironment in the formation of these tumors.
DIPG-71. XPEDITE: A STUDY TO EXPEDITE DIPG AND DMG RESEARCH
Authors: Timothy J Stuhlmiller, Lisa Ward, Sarah Lewis, Zachariah D Cole, Donald Chuyka, Sarah Ginn, Bryan Federowicz, Mark A Shapiro
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG), particularly the subtype known as diffuse intrinsic pontine glioma (DIPG), poses a significant challenge due to its aggressive nature and low survival rates, especially in children. Despite ongoing research and clinical trials, the survival rate remains alarmingly low. The scarcity of cases and siloed nature of current registry efforts have hindered the establishment of a reliable natural disease history for benchmarking studies and led to the need for randomization in clinical trials. METHODS xPedite (NCT06140719) is a fully virtual, patient-driven, nationwide, real-time observational study to collect, annotate, standardize, and report the critical data elements of DMG and DIPG in a regulatory-compliant framework. Patients of any age can join via electronic consent, with recruitment supported by provider referrals and patient advocacy organizations DDRFA and My DIPG Navigator. Medical records are accessed from institutions, sequencing vendors, and health information networks. Notably, data elements are annotated comprehensively and longitudinally in a 21 CFR Part 11-compliant clinical database by xCures remote study staff, eliminating the need for data entry by treating site staff or physicians. Data collected include anti-cancer interventions, non-cancer medications, biomarker results, radiological endpoints, steroid use, vitals, demographics, raw DICOM images, and genomics. In addition to clinical data, patient- and caregiver-reported outcome questionnaires (PROs) and video assessments of mobility and neurological status are collected for clinician review. The objective of the study is to collect these clinical, imaging, biomarker, and assessment data in a manner suitable to provide to health authorities to reduce randomization in future trials. In a commitment to scientific understanding and collaborative research, the data collected through the xPedite study is openly available to academic, government, and non-profit researchers. As of January 2024, 182 patients were enrolled in xPedite. Real-time enrollment and data statistics are available at https://xcures.com/dmgdashboard/.
BIOM-07. DEVELOPING A CEREBROSPINAL FLUID-BASED BIOMARKER FOR MINIMAL RESIDUAL DISEASE AND RELAPSE IN PAEDIATRIC BRAIN TUMOURS USING METABOLOMIC METHODS
Authors: Alison Whitby, Bhoomi Shastri, Dong-Hyun Kim, Madhumita Dandapani
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Many paediatric brain tumours have poor outcomes due to relapse (50% in ependymoma and 30% in medulloblastoma) following treatment. Most of these occur within two years, suggesting persistent minimal residual disease (MRD) below the imaging detection threshold. Diagnosing MRD at the end-of-treatment or early relapse using a sensitive, minimally-invasive liquid biopsy could improve outcomes. Extracting metabolites arising from aberrant cancer metabolism, from cerebrospinal fluid (CSF) is promising because of the proximity of tumour to CSF. METHODS Liquid chromatography coupled with tandem high-resolution mass spectrometry (LC-MS/MS) using 25µl CSF extracted with 75µl methanol was shown to differentiate malignant paediatric brain tumours (n=47;day 14 samples) from controls (n=49). RESULTS Ependymomas (n=33) differed from medulloblastomas (n=14). Eighteen metabolites were identified as differentially abundant between tumours and controls with 14 metabolites being increased in abundance in tumours. These included amino acids and derivatives (n=8), metabolites in one carbon metabolism (n=1), carnitine cycle (n=2), aerobic glycolysis (n=2), purine catabolism (n=2), ascorbate degradation (n=1) and creatinine synthesis (n=2). From those, betaine/creatinine ratio gave an area under the curve (AUC) of 0.96 (excellent) in receiver operating curve analysis. Using a cut-off ratio of 0.1775 for discriminating brain tumours from controls, had sensitivity and specificity of 92% and 89%. Medulloblastomas were largely similar to ependymomas; nevertheless, three metabolites could discriminate between them, and met the criteria of corrected p&amp;lt;0.05. A ratio of glutarate semialdehyde/malic acid had AUC of 0.85 (good). With a cut-off ratio of 0.0422, the sensitivity and specificity were 79% and 82%. CONCLUSION This is the first CSF-based metabolomics study in ependymoma and third in medulloblastoma. Ratios of CSF metabolites can be used as biomarkers to detect brain tumours sensitively and specifically. This work will further be developed into a liquid biopsy test for the detection of MRD and early tumour recurrence.
MDB-95. MEDULLOBLASTOMA IN INDONESIA: CLINICAL PROFILES AND OUTCOMES
Authors: Ludi Dhyani Rahmartani, Michael Nathaniel Budiarso, Eka Susanto, Mohamad Yanuar Amal, Endang Nuryadi, Kevin Gunawan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most frequent malignant brain tumor in children and adolescents, accounting for 20–25% of all brain tumors. Epidemiological data is fundamental to optimising pediatric brain tumor (PBT) health services and reducing overall morbidity and mortality. To bridge this gap, we aimed to present comprehensive pediatric medulloblastoma data, focusing on clinical profiles and outcomes within one of the national general hospitals in the country. METHODS A retrospective observational longitudinal study was conducted at Cipto Mangunkusumo National General Hospital, focusing on children registered under the PBT service from January 2021 to December 2023. The study analyzed patients’ profiles, medulloblastoma characteristics, factors related to diagnosis delay, and vital status follow-up. RESULTS All 16 patients underwent tumor removal surgery with a mean age of 7.13 ± 5.39 years, with an equal distribution of both sexes (50%). Histological confirmation of medulloblastoma was observed in all patients, with 2/16 (12.5%) classified as WNT, 9/16 (56.3%) as Non-WNT, and 5/16 (31.3%) lacking additional information. Regarding risk stratification, 13/16 (81.3%) of patients were classified as high-risk by age &amp;lt;3, residual tumor &amp;gt;1.5 cm2, and presence of metastasis. Vomiting 6/16 (37.5%), disequilibrium 5/16 (31.3%), and headache 3/16 (18.8%) were the predominant symptoms, with mean duration delay from symptom onset to first medical consultation of 2.5, 1.8, and 6.7 weeks, respectively. In the last follow-up, 5/16 (31.3%) of patients were deceased (4/11 in high-risk and 1/2 in low-risk groups), and 3/16 (18.8%) were lost to follow-up. CONCLUSION This study underscores the importance of early diagnosis and intervention for pediatric medulloblastoma, particularly in high-risk cases, which need heightened awareness among the community and healthcare providers. Additionally, addressing the issue of patients lost to follow-up is crucial for optimizing outcomes. Further research is warranted to enhance diagnostic methods and healthcare services for pediatric brain tumor patients nationwide.
EPID-01. ESTIMATING THE BURDEN DUE TO BRAIN AND OTHER CNS TUMORS IN ADOLESCENTS IN THE UNITED STATES
Authors: Mackenzie Price, Corey Neff, Carol Kruchko, Kristin A Waite, Gino Cioffi, Brittany Cordeiro, Marta Penas-Prado, Mark R Gilbert, Terri S Armstrong, Jill S Barnholtz-Sloan, Quinn T Ostrom
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain and other central nervous system (CNS) tumors in adolescents have unique biological and behavioral distinctions from both children and adults. As a result, they pose challenges to treatment and reporting. Here, we describe the epidemiology of brain and other CNS tumors in adolescents (ages 15-19 years) in the United States, including mortality, survival, and prevalence. METHODS The Central Brain Tumor Registry of the United States (CBTRUS) data (containing data from the CDC’s National Program of Cancer Registries (NPCR) and NCI’s Surveillance, Epidemiology and End Results (SEER) data) were used to calculate average annual age-specific incidence rates (AASIR) per 100,000 population overall and by sex and race/ethnicity. Average annual age-specific mortality rates (AASMR) per 100,000 population for deaths resulting from all primary malignant brain and other CNS tumors were calculated using mortality data from NCHS. NPCR survival data were used to calculate relative survival (RS). Estimated prevalence counts as of December 31, 2024 were estimated using incidence from CBTRUS and SEER, and survival from SEER. RESULTS AASIR for all brain and other CNS tumors among adolescents was 7.51/100,000. Tumors of the sellar region had the highest incidence (AASIR=2.74/100,000). Overall, incidence was higher for females and non-Hispanic White persons. Overall AASMR was 0.56/100,000. Total five-year RS was 92.0%. Tumors of the pituitary had the highest RS (five-years=99.9%) and glioblastoma had the lowest (five-years=16.4%). As expected, prevalence was highest for tumors of the sellar region (3,720 cases). CONCLUSION Incidence, prevalence, and survival patterns for brain and other CNS tumors vary between adolescents, adults, and children. An accurate statistical assessment of these tumors in adolescents is required to understand risk and impact on this unique population, and to serve as a reference for afflicted individuals, for researchers investigating new therapies, and for the clinicians who treat them.