tbuckley/cabot-search huggingface dataset:
MODL-09. IMAGE-BASED SCREENING IN MEDULLOBLASTOMA REVEALS TUMOR-SUPPRESSIVE EFFECTS OF THE NEUROPROTECTIVE AGENT URMC-12K
Authors: Shen Yan, Bernard Ciraulo, Dejana Jovanovic, Dina Hochuli, Veronica Akle Alvarez, Özgün Özalp, Stephan C F Neuhauss, Amin Allalou, Martin Baumgartner
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Enhanced motility and the invasive behavior of medulloblastoma (MB) influence microenvironment interactions and may promote distant spread. Current drug screening focuses on cytotoxic agents, leaving subtle but potentially therapeutically relevant drug phenotypes associated with motility and invasiveness unrecognized. The serine/threonine kinase MAP4K4 is upregulated in MB and promotes invasiveness1,2. Toxicities associated with existing MAP4K4 inhibitors in the CNS prevented further pre-clinical evaluation. URMC-12k is a novel MAP4K inhibitor identified as a motor-neuron-protective agent in ALS. Using advanced imaging approaches, we investigated URMC-12k as a tumor-suppressive drug in MB and characterized its effects at the molecular, cellular, and tissue levels. METHODS We use cell-based 3D invasion assays and quantitative microscopy to assess tumor-restraining activities of URMC-12k, and machine learning to detect URMC-12k phenotypes associated with repressed motility. We use tissue and zebrafish larval models to explore URMC-12k effects on cell and tissue viability and anti-invasion efficacy. We determined URMC-12k targets in MB cells using phosphoproteomics. RESULTS URMC-12k outcompetes existing MAP4K4 inhibitors in repressing basal and growth-factor-induced matrix invasion with no detectable effects on vertebrate developmental processes. A computational model trained to detect morphological alterations in the actin cytoskeleton associated with cell dynamics established a firm correlation between the URMC-12k-repressed motile behavior and alterations in the tumor cell actin cytoskeleton. Quantitative imaging further revealed that URMC-12k promoted increased cell clustering and reduced deposition of extracellular vesicles. Phosphoproteomics identified proteins involved in cell adhesion organization and vesicle trafficking as potential molecular effectors targeted by URMC-12k. CONCLUSIONS URMC-12k effectively inhibits MB cell migration and displays no toxicities at effective concentrations. The regulation of cell-cell adhesion molecules and the deposition of extracellular vesicles revealed by URMC-12k are tumor-promoting, druggable mechanisms of MAP4Ks in MB. 1. 1Migliavacca, J., et al. Commun Biol5, (2022). 2. 2Tripolitsioti, D. et al. Oncotarget9, 23220–23236 (2018).
HGG-34. EFFICACY AND SAFETY OF DOXORUBICIN PLUS STANDARD THERAPY IN PEDIATRIC HIGH GRADE GLIOMAS: AN OPEN-LABEL MONOCENTRIC NOT-RANDOMIZED PHASE II STUDY
Authors: Barbara Castelli, Marco Tellini, Carla Fonte, Maria Luigia Censullo, Milena Guidi, Marco Di Nicola, Laura Giunti, Anna Maria Buccoliero, Chiara Caporalini, Flavio Giordano, Isacco Desideri, Daniela Greto, Ludovico D’Incerti, Federico Balducci, Alessandra Pugi, Katia Tortora, Mirko Scagnet, Lorenzo Genitori, Iacopo Sardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs) comprise a very poor prognosis. Current treatment consists of maximal surgical resection followed by radiotherapy plus concomitant and adjuvant temozolomide (Stupp’s regimen). Despite innovative approaches, outcome remains dismal. Based on the results of previous in vitro and in vivo assays, also considering the wide experience in other pediatric tumors, we aimed to introduce doxorubicin (DOX) as add-on therapy to the standard of care. METHODS For testing safety and efficacy of add-on doxorubicin treatment in newly-diagnosed pHGGs, two open-label monocentric not-randomized phase II studies were consequently opened at our institution: GBM TMZ/DOX 2015 (EudraCT 2015-002307-28) and pGBM-WBRT/DOX2020 (EudraCT 2020-005131-74). GBM TMZ/DOX 2015 consisted of DOX 100 mg/mq in 96 hours infusion for 1-3 cycles at 8 week after radiotherapy. pGBM-WBRT/DOX2020 study introduced pan-encephalic radiotherapy followed by DOX 75 mg/mq in 48 hours for 4 cycles starting at week 12 after irradiation, to reduce metastatic relapse rate and to facilitate radiotherapy-induced blood brain barrier opening. Concomitant and adjuvant temozolomide were preserved. RESULTS Twenty-one heterogeneous malignant glioma patients (12 hystological diagnosis, 12 males and 8 females, mean age 9.1 ± 4.2 years, age range 2-22 years) were enrolled in the first study. However, for study exiting or for no clinical permissiveness at the time of DOX treatment, only 12 patients were treated with DOX: 2 received three DOX courses and 10 a single course, reducing hematological toxicities. DOX-group showed a longer progression free survival (PFS) compared to standard of care group (median PFS 9 versus 6 months respectively), although this trend was not statistically significative. The second study is on course. CONCLUSIONS The adjuvant DOX use in addition to the standard treatment in pHHGs is a practicable option, although to be consolidated, in terms of effectiveness on outcome.
DIPG-14. METABOLIC REPROGRAMMING AS A RESISTANCE MECHANISM IN DIFFUSE MIDLINE GLIOMA
Authors: Sina Neyazi, Pruthvi Gowda, Stephen C Frederico, Cuong M Nguyen, Maria C Trissal, Erika P Portero, John-Paul Haley-Read, Emily P Anderson, Craig J Thomas, Nika N Danial, Mariella G Filbin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline gliomas (DMG) are uniformly fatal pediatric brain cancers, refractory to current standards of care. Based on genomic and transcriptomic profiling data, we previously proposed that platelet-derived growth factor receptor alpha (PDGFRA) is crucial to the tumorigenic potential and maintenance of stem-like DMG cells and that targeting PDGFRA is an important therapeutic avenue in DMG. In comprehensive pre-clinical studies, we identified avapritinib, an FDA-approved PDGFRA inhibitor, to be highly effective in patient-derived xenograft (PDX) DMG models. We further reported the first clinical experience using avapritinib in recurrent DMG and demonstrated preliminary safety, tolerability, and efficacy of the drug in this population. While a subset of patients experienced a strong clinical response from avapritinib, tumor progression was eventually observed in all patients. METHODS Here, we investigated the molecular mechanisms that DMG cells upregulate following avapritinib treatment, with the aim to exploit them therapeutically. To uncover these mechanisms, we performed transcriptomic, metabolic and functional assays along with a combinatorial drug screening. RESULTS Transcriptional analysis of patient-derived DMG cell lines revealed an upregulation of genes associated with fatty acid metabolism and oxidative phosphorylation (OXPHOS) following treatment with avapritinib. Functional assays confirmed elevated OXPHOS in avapritinib-treated cells with significant (i) increase in mitochondrial energy transduction, (ii) increase in palmitate- (a product of fatty acid metabolism) driven oxygen consumption rate and (iii) greater incorporation of palmitate-derived carbons into the tricarboxylic acid cycle. To determine which therapies could target this dependency on OXPHOS and fatty acid metabolism, we performed a metabolic drug screening in patient-derived DMG cell lines and identified two metabolic drugs to have synergistic cytotoxic effects with avapritinib. CONCLUSION We revealed distinct metabolic reprogramming in avapritinib-treated DMG cells and showed that targeting these metabolic vulnerabilities might further increase the clinical benefit of PDGFRA inhibitor avapritinib.
LMIC-17. DIAGNOSTIC DELAY IN CHILDREN WITH CNS TUMORS IN A TERTIARY HOSPITAL IN MEXICO
Authors: Beth Sainz de la Peña-Hernández, Farina Arreguín-González, Ricardo Valdéz-Orduño, Blanca Almazán-García, San Juanita Sandoval-de Jesús, Eduardo Baños-Rodríguez, Alejandra López-Azcárraga, Jeannie García-Ramos, Ruben Sebastian-Barajas, Georgina Ochoa-Madrigal, Daniel Moreira, Alma Benito-Reséndiz
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Delays in diagnosis of central nervous system (CNS) tumors have been associated with increased morbidity and mortality. We aimed to describe the time intervals for diagnosis and explore factors related to diagnostic delays in a tertiary public hospital in a middle-income country. METHODS A retrospective study was carried out, collecting data from patients diagnosed with brain tumors between 2000 and 2021 at the National Medical Center “20 de Noviembre” in Mexico City. The data were analyzed using descriptive statistics. RESULTS Data were collected from 163 patients with a median age of 8 years (range 0-18 years). 81 (49.7%) patients were diagnosed with gliomas, 47 (28.8%) with embryonal tumors, 20 (12.3%) with ependymomas, 10 (6.1%) with germ cell tumors of the central nervous system, 3 (1.8%) with choroid plexus carcinoma, and 2 (1.2%) with other diagnoses. The median time of symptom start and first visit with a physician was 20 days (rage 1 to 180 days). The median time in which the patients arrived at the tertiary hospital after the first visit to a physician was 184 days (range 1 to 2520). The population served by the institution, included the 32 states, with 153 patients (93.9%) coming from an urban location, with easy access to medical services. 145 (89%) of the 163 patients had parents with a medium socio-economic level (urban housing, all basic services, at least one of the parents with higher education.) Of the patients studied, 75 (46%) died, 18 (11%) abandoned treatment, 65 (39.9%) survived and 5 (3.1%) were lost to follow-up. CONCLUSION An important delay was found in the start of treatment from the moment patients begin symptoms. The identified delays warrant local and national strategies that allow prompt referrals.
DIPG-33. COMBINING CLONAL TRACKING WITH SINGLE CELL RNA SEQUENCING REVEALS TEMPORAL SHIFTS IN CELL STATES ASSOCIATED WITH TRAMETINIB RESISTANCE IN MAPK ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Molina Das, Yura Grabovska, Jared Collins, Rebecca Rogers, Anna Burford, Alan Mackay, Rameen Beroukhim, Pratiti Bandopadhayay, Chris Jones
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND H3K27-altered diffuse midline glioma (DMG) is an aggressive and incurable paediatric high-grade glioma with median overall survival of 9-12 months. A distinct subset of DMG harbour alterations in the MAPK pathway, and we have previously shown that DMG-MAPK may exhibit sensitivity to MEK inhibitors but develop resistance under long-term exposure to drug. Elucidating these resistance mechanisms could spearhead better treatment strategies for these patients. METHODS To study clonal evolution under trametinib, we used CloneSifter lineage tracking technology to uniquely barcode 300,000 DMG-MAPK cells which were then treated with a GI80 dose of trametinib for 11 weeks. We extracted DNA to quantify barcode enrichment at endpoint across six technical replicate experiments and leveraged CloneSifter’s compatibility with single cell RNA sequencing (scRNA-seq) to couple clonal identity with transcriptional states in ~90,000 trametinib treated cells at varying timepoints. RESULTS DNA sequencing revealed 0.5% (1500/300,000) of the initial barcodes were enriched across trametinib replicates and were also detectable by scRNA-seq. Conducting cNMF analysis on the single cell dataset showed populations of trametinib treated cells associated with each other in a temporal manner, whereby early and late-stage resistant populations were defined by neuronal and stem cell like markers, respectively. A time-dependent enrichment of CloneSifter barcodes was also observed, suggesting dynamic expansion of clones over the treatment window. Notably, week 11 trametinib treated cells showed higher expression of resistance driver genes related to EMT, stemness and p38/MAPK upregulation. CONCLUSIONS Utilizing the sequence-specific reporter construct built in to the CloneSifter system allows for retrieval of resistant clones marked by enriched barcodes under treatment prior to drug exposure, enabling further characterization of monoclonal populations of trametinib-resistant cells. In summary, we have employed novel tools to study resistance development in DMG-MAPK that could be exploited to devise rational treatment strategies for these patients in an evolutionary-guided manner.
HGG-32. PNOC008: A PILOT TRIAL TESTING THE CLINICAL BENEFIT OF USING MOLECULAR PROFILING TO DETERMINE AN INDIVIDUALIZED TREATMENT PLAN IN CHILDREN AND YOUNG ADULTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA (EXCLUDING DIFFUSE INTRINSIC PONTINE GLIOMA)
Authors: Andrea T Franson, Lindsay B Kilburn, Tab M Cooney, Schuyler Stoller, Alyssa T Reddy, Anu Banerjee, Roger J Packer, Anne E Bendel, Mary M Skrypek, Jane E Minturn, Mohamed S Abdelbaki, Nicholas S Whipple, Priya Chan, John R Crawford, Erin E Crotty, Angela J Waanders, Jennifer D Elster, Eric H Raabe, Elizabeth George, Soniya N Pinto, Arastoo Vossough, Adam A Kraya, Michael Prados, Cassie Kline, Javad Nazarian, David A Solomon, Janel R Long-Boyle, Annette M Molinaro, Sebastian M Waszak, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children and young adults diagnosed with high-grade glioma (HGG) face extremely poor prognoses. Despite multiple clinical trials testing new treatments in this population, a survival advantage has yet to be achieved. Herein we assessed, in a single-arm, multi-center pilot trial, the feasibility of molecular profiling of primary HGG tumor tissue to create an individualized treatment plan with up to four FDA approved medications. METHODS Patients aged &amp;lt;21 years with newly diagnosed, localized, hemispheric HGG (Stratum A) or midline HGG (non-DIPG; Stratum B) were eligible. Tumor tissue underwent comprehensive molecular profiling (targeted gene panel, whole exome, and whole transcriptome sequencing). Based on detailed review of the molecular data by a dedicated tumor board, an individualized treatment plan that combined up to four FDA approved drugs was recommended. Circulating tumor DNA (ctDNA), imaging, and quality of life (QOL) measures were collected at multiple timepoints. RESULTS Fifty-five patients enrolled between 2018 and 2023 (median age 11 years [range 2-20], n=31 female, n=29 Stratum A). The most common integrated diagnoses included H3K27-altered diffuse midline glioma (n=17), H3/IDH-wildtype diffuse pediatric-type HGG (n=16), and H3G34-mutant diffuse hemispheric glioma (n=12). Median overall survival (OS) from the time of study enrollment was 26.5 months in Stratum A (lower 95% CI: 18.7) and 21.7 months in Stratum B (lower 95% CI: 16.8), with a median follow-up of 35.4 months for all patients (lower 95% CI: 32.5). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophils (n=28), decreased platelets (n=22), and decreased white blood cells (n=16). As of December 2023, seven patients remain on therapy. Central imaging, ctDNA, and QOL analyses are underway. CONCLUSIONS A personalized treatment recommendation for children and young adults with HGG based on comprehensive transcriptomic and genomic analysis is feasible. Current survival data are encouraging, and molecular subgroup analyses are ongoing.
ATRT-02. RECAPITULATING THE POST-SURGICAL BRAIN MICROENVIRONMENT OF ATYPICAL TERATOID RHABDOID TUMOURS TO IDENTIFY MEMBRANE PROTEIN CANDIDATES FOR TARGETED THERAPY
Authors: Shaylen M Mistry, Harry Porter, Phoebe McCorie, Anya Snary, Hannah Bailey, Robert Layfield, Ruman Rahman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical Teratoid Rhabdoid Tumours – (AT/RT) are rare and aggressive tumours primarily arising in the hind brain of children under three, conferring median survival of &amp;lt;12 months. Surgery remains the only standard treatment; however tumours recur from post-surgical residual disease. The utilisation of PolyEthylene Glycol Diacrylate – (PEGDA) hydrogel and decellularised human brain cerebellum extracellular matrix aim to recapitulate AT/RT post-surgery brain microenvironments, where we hypothesise AT/RT plasma membrane proteins represent viable molecular therapy targets. METHODS AT/RT and astrocyte membrane protein cellular fractions were extracted and analysed using liquid chromatography-mass spectrometry. Proteomic analyses was integrated to identify differentially expressed AT/RT and astrocyte membrane proteins. RESULTS PEGDA and decellularised brain tissue were biocompatible for AT/RT-astrocyte co-cultured spheroid growth. AT/RT and astrocyte KEGG Pathway analysis revealed more specific oncology-based pathway expression in membrane protein than total protein, thus reinforcing membrane proteins as suitable therapeutic targets. Between the top 20 expressed membrane proteins, only ATP1A1 was shared exclusively between all AT/RT cells and astrocytes, suggesting a potential functional role. Membrane proteins showing shared expression when normalised against each AT/RT cell line included ATP1A1, HSPD1, GNA13 and SLC3A2, indicating biological similarities between AT/RT subtypes. Membrane proteins expressed similarly in AT/RT-MYC subtypes include ATP1A1, SLC7A5 and EEF1A1. ATP1A1 network analyses of AT/RT and astrocyte membrane protein pathways displayed strong interactions with ATP1B1, SLC7A5 and SLC3A2, therefore likely to map common expressed shared pathways. CONCLUSIONS AT/RT membrane protein pathways offer novel therapeutic targets directly amenable for drug repurposing. Future work prioritises proteomic analysis utilising 3D AT/RT spheroids and cerebellum brain tissue to maximise accurately recapitulating AT/RT post-surgical microenvironments.
IMG-04. ASSOCIATION BETWEEN MICROSTRUCTURAL INTEGRITY OF BRAIN SUBSTRUCTURES AND NEUROCOGNITIVE OUTCOMES: A MULTI-TRAJECTORY ANALYSIS IN CHILDHOOD BRAIN TUMOR SURVIVORS
Authors: Ryan Oglesby, Chathurangi Pathiravasan, Rachel Peterson, Sahaja Acharya
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The relationship between the brain’s microstructural integrity and neurocognitive outcomes is not well characterized in childhood brain tumor survivors. In healthy children, mean diffusivity (MD) generally decreases and fractional anisotropy (FA) increases with age as the brain progressively myelinates and develops. Increasing MD and decreasing FA is suggestive of microstructural injury. We investigate the association between longitudinal neurocognitive outcomes and change in MD and FA in childhood brain tumor survivors. METHODS Patients diagnosed with a brain tumor at &amp;lt; 20 years of age with ≥ 2 neurocognitive assessments and paired DTI at each neurocognitive timepoint were retrospectively identified and eligible for inclusion. Multi-trajectory modeling was applied to cluster patients into distinct neurocognitive trajectories based on intelligent quotient, processing speed and working memory. Linear mixed models were used to determine whether the clusters were associated with change in MD and FA over time. RESULTS A total of 61 patients were eligible with 151 neurocognitive assessments paired with DTI. Mean follow-up was 4.8 years. Multi-trajectory modeling identified two clusters of patients with distinct neurocognitive trajectories. Compared to the low-performance group, the high-performance group (45.5%) had higher baseline neurocognitive scores with less decline in all neurocognitive outcomes. The high-performance group was also associated with a greater decrease in MD and greater increase in FA of the hippocampus and several white matter tracts such as the corpus callosum, pontine crossing tract, anterior limb of the internal capsule and inferior cerebellar peduncle, after adjusting for age and sex (all p&amp;lt;0.05). Additionally, the high-performance group was associated with a greater increase in FA in the superior, middle and inferior frontal gyri (all p&amp;lt;0.05). CONCLUSIONS The high-performance neurocognitive group was associated with greater microstructural integrity over time in multiple brain substructures compared to the low-performance group, as measured by change in fractional anisotropy and mean diffusivity.
ETMR-04. OPTIC NERVE SHEATH MENINGIOMAS IN CHILDREN-DIAGNOSTIC AND THERAPEUTIC CHALLENGES BASED ON A CASE SERIES
Authors: Deysha Ratnasingham, George Lawson, Harpreet Hyare, Carmen Soto, Sam Gurney, John Apps, Ian Reekie, Mette Jorgensen, Sarita Depani, Darren Hargrave, Elwira Szychot
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Optic nerve sheath meningiomas (ONSM) are rare, comprising 1-2% of paediatric CNS meningiomas. Despite slow growth, ONSM often lead to vision loss in the affected eye. Diagnosis is challenging due to the tumour’s proximity to the optic nerve, complicating biopsy or complete removal. METHODS We searched our Neuro-Oncology MDT database for patients treated for ONSM between Jan 2018 and Dec 2023. We retrospectively reviewed clinical presentation and diagnostic workup that led to the diagnosis of ONSM. RESULTS 6 children aged 3-15years (mean 9 years) were identified over 5 years. 3 children were treated at GOSH, 2 at UCLH and 1 at BCH. 3/6 patients were male. 2/6 underwent a biopsy. Presenting symptoms included headache, acute visual loss and eye pain. 2/6 patients presented with bilateral vision deterioration. The average time between onset of symptoms and presentation was 8 months (range 3–15 months). Identified causes of delayed diagnosis included delayed presentation related to COVID-19 pandemic (2 patients) and impaired quality of imaging due to dental braces (1 patient). Whilst awaiting diagnosis, 2 patients lost vision completely in their affected eye. Diagnostic workup included: optic disc examination (6 patients), lumbar puncture (2 patients), angiotensin-converting enzyme (sACE) (2 patients), MRI brain and spine (6 patients), CT scan (6 patients), PET-DOTATE scan (3 patients), NF2 genetic testing (4 patients). Two patients completed PBT therapy while 1 is undergoing radiotherapy. One patient underwent an enucleation, while the rest are under surveillance. CONCLUSIONS Paediatric ONSM diagnosis remains challenging despite advanced imaging. Our review highlights the added value of CT and PET-DOTATATE when a biopsy is high-risk. CT reveals calcification in 20-50% ONSM while the role of PET-DOTATATE is related to the expression of somatostatin receptor 2 in meningiomas. Despite optimal treatment, vision loss maybe unavoidable. Early multidisciplinary consultations are advised for enhanced outcomes.