tbuckley/cabot-search huggingface dataset:
IMG-29. IMPLICATIONS OF IMAGE HARMONIZATION FOR BRAIN TUMOR CLINICAL TRIALS
Authors: Abhijeet Parida, Zhifan Jiang, Syed Muhammad Anwar, Nicholas Stence, Nicholas Foreman, Roger J Packer, Michael J Fisher, Robert A Avery, Marius George Linguraru
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Clinical trials for rare pediatric conditions like optic pathway gliomas associated with NF1 (NF1-OPGs) require numerous sites that utilize different MRI scanners and protocols. These MRIs must be harmonized for reliable comparison using machine learning tools. We propose a deep-learning based MRI harmonization that enables reproducible data analysis across multiple sites and MRI platforms. METHODS One-hundred eighty clinical T1-weighted-MRIs of pediatric NF1-OPG subjects were acquired from three sites [Children’s National Hospital (site A, N=60), Children’s Hospital Colorado (site B, N=60), and Children’s Hospital of Philadelphia (site C, N=60)] using different MR scanners (GE, Phillips, and Siemens, respectively). MRIs from A and B were used to train a branched neural network and C were used for testing. Using unsupervised learning, the neural network identified differences in imaging protocols and harmonized data to a chosen protocol, e.g., that of site A, while preserving the patient anatomy. The harmonization was evaluated using Wasserstein distance (nWD), which measured similarity between two gray scale appearances of MRI intensity histograms. Anatomy preservation metric (AP) measured relative volume changes in gray matter (GM) segmented using Freesurfer, before and after harmonization. For both metrics, 100% means the best possible harmonization was achieved. RESULTS Before harmonization, nWD between grayscale appearance of MRIs from sites A and B was 27.3±3.1%. After harmonization, the similarity became 94.2±2.0% with a GM volume error of 3.11±0.56ml which corresponded to AP of 93.1±4.7%. For the test data, nWD similarity post harmonization improved from 38.2±3.9% to 93.4±2.2% with GM volume error of 4.12±0.47ml which corresponded to AP of 90.3±3.5%. CONCLUSIONS Our approach enables MRI harmonization while preserving anatomy for precise analysis using machine learning tools. It scales to new sites to support multisite clinical trials that utilize imaging outcomes for brain tumors and other rare diseases.
LGG-54. PEDIATRIC LOW-GRADE GLIOMAS TREATED WITH MEK INHIBITORS
Authors: Milena Fraustro, Breyonna Maddox, Lilibet Fernandez Valdes, Elizabeth Lopez, Toba Niazi, Ossama Maher, Ziad Khatib
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Low-grade gliomas (LGG) represent the most common brain tumor in children. It is well known that these tumors present mutations involving the BRAF gene, causing activation of the MAPK/ERK pathway. MEK inhibitors have now become an important treatment option over the recent years, slowing the growth of cancer cells. METHODS Retrospective analysis of 23 patients with LGG that were treated with MEK inhibitors at Nicklaus Children’s Hospital between 2015-2022. RESULTS Of the 23 patients; 6 were males and 17 were females, with a median age at diagnosis of 9.5 years of age. BRAF V600E mutation was present in 52% of patients (9/17). Other mutations found were: BRAF, BRAF KIAA1549, p.Q61K, and FGFR. Six patients had known associations with NF1. 7 of 23 patients had not received any prior treatment before MEK therapy, 8 underwent partial or total resection only prior, 4 had previous chemotherapy treatment, 3 underwent resection with chemotherapy, and 1 patient had both chemotherapy and proton radiation prior to MEK therapy. Targeted therapies included Trametinib (17/23), Dabrafenib (9/23), Selumetinib (5/23), and Binimetinib (1/23). Of the 9 patients with BRAF V600E mutation, 7/9 were given dual targeted therapies whereas only two were treated with only one inhibitor. The average length of therapy was one year. Most reported side effects were dermatologic manifestations such as dry skin or acne (9/23). Five patients showed objective improvement, 16 patients had stable residual disease, one had local recurrence, and one patient expired. Currently 12 patients are off therapy and 10 remain on treatment. Of the patients with BRAF V600E mutation, 4 had clinical and/or radiologic response, 1 patient expired due to disease progression and 1 has stable disease. CONCLUSION MEK inhibitors as a treatment of pediatric low-grade gliomas demonstrated promise as a therapeutic approach, so far proving to slow progression of disease in some cases. However, long-term side effects and toxicity remain unknown. Further large-scale prospective analysis would be helpful in future studies.
LGG-55. DIFFERENTIAL TOXICITY PROFILE OF INDIVIDUAL MEK INHIBITORS: A MULTI-INSTITUTION RETROSPECTIVE REVIEW
Authors: Jimin Shin, Anthony Zhang, Ashley Meyer, Andrea Ogle, Margaret Shatara, Andrew Cluster, Mohamed S Abdelbaki, Pournima Navalkele, Erica Faigenbaum, Stephanie Brosius, Chelsea Kotch, Evan Cantor, Nicole Brossier
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Most pediatric low-grade gliomas (pLGGs) are driven by molecular aberrations in the mitogen-activated protein kinase pathway (MAPK), which can be targeted by novel agents such as MEK inhibitors (MEKi.) However, MEKi use is accompanied by a varied side effect profile, with the most severe dose-limiting effects involving dermatologic, cardiac, and ophthalmic toxicities. METHODS Multi-institutional retrospective chart review of patients less than 25 years of age who underwent MEKi monotherapy between 2015-2022 was conducted. Data was collected from 4 sites, including Connecticut Children’s, St. Louis Children’s Hospital, Cardinal Glennon Children’s Hospital, and Children’s Hospital of Philadelphia. RESULTS Ninety-six patients were included in the analysis; 54 (56.4%) with brain tumors and 56 (58.3%) with germline mutation in NF-1. Forty-nine (51%) received trametinib, 42 (43.8%) selumetinib, 5 (5%) binimetinib. Of 42 patients with skin toxicity data available, 35 (83%) had cutaneous toxicity, with the most prevalent being acneiform rash (40.0%), followed by maculopapular rash (28.6%) and eczematous dermatitis (11.4%). The mean number of cutaneous skin toxicities was 2.4 (trametinib group = 2.2, selumetinib group = 2.6). Eighteen of 96 (18.8%) patients experienced cardiac toxicity, of which 11 (61.1%), experienced reduction in left ventricular ejection fraction (6 trametinib, 5 selumetinib), 4 (22.2%) developed pericardial effusions. 10 of 96 (10.4%) patients experienced ophthalmic toxicities, most commonly blurred vision (30.0%). Other toxicities included elevated CK (36, 37.5%), anemia (32, 33.3%), and eosinophilia (17, 17.7%). CONCLUSION There was not an observable clinically relevant difference in toxicities between MEKi, with skin toxicity the most prevalent. The prevalence of cardiac toxicity in the patient cohort reinforces the need for appropriate monitoring via echocardiography. MEKi remain an excellent option for therapy for LGG but with the need for continued supportive care and monitoring.
EPEN-02. CAR T-CELLS TARGETED TO B7-H3 OR HER2 FUNCTION INDEPENDENTLY OF ANTIGEN DENSITY IN XENOGRAFT MODELS OF EPENDYMOMA
Authors: Sanya Mehta, Jorge Ibanez, Haley Houke, Erik Emanus, Siri Ippagunta, Stephen C Mack, Giedre Krenciute
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Targeted treatment options are desperately needed for ependymomas (EPN). Chimeric antigen receptor (CAR) T-cells have immense potential to positively transform treatment outcomes; however, little is known regarding antitumor efficacy of CAR T-cells against EPNs. Specifically, antigen density has emerged as a major influencer of CAR T-cell potency. However, the specific high and low antigen density thresholds governing CAR T-cell efficacy for EPN are unknown. We hypothesize that antigen density heterogeneity governs CAR T-cell potency against EPN. METHODS Using quantitative flow cytometry, we determined antigen density of B7-H3 and HER2 (the two CAR targets currently in pediatric EPN clinical trials) on EPN patient derived cell lines (1425, ST1, CPITT, ST2, EPI, L46SJ). We generated second generation B7-H3 and HER2-CAR T-cells with CD28z signaling domain and compared long-term cytolytic activity, expansion, and cytokine production against EPNs. RESULTS We found that all EPN cell lines express remarkably high yet variable density of B7-H3 (6.3e4 – 3.4e5 molecules/ cell). In contrast, surface density of HER2 was consistently and significantly lower (860 – 2.5e4 molecules/ cell). In repeated-stimulation assays, B7-H3-CAR T-cells killed 7-10 times and expanded up to 325,360-fold when cultured against EPN. However, we observed no significant difference in total expansion or correlation with antigen density against EPNs. Surprisingly, expansion of HER2-CAR T-cells against EPNs was drastically higher (up to over 100-billion-fold) and greatly exceeded that of B7-H3-CAR-T cells against the same EPN cells despite much lower antigen density. CONCLUSIONS Our studies reveal significant antigen density heterogeneity of B7-H3 and HER2 in EPN, which may lead to target-specific impacts on CAR T-cell persistence. Indeed, results suggest that lower antigen density of HER2 may be superior for sustained CAR T-cell activity. Future work will validate whether HER-CAR T-cells have superior antitumor efficacy in vivo to further delineate role of antigen density thresholds in CAR T-cell potency.
HGG-09. CONTRASTING CLINICAL COURSES OF THREE PEDIATRIC PATIENTS WITH PDGFRA AMPLIFIED RADIATION-INDUCED HIGH-GRADE GLIOMA
Authors: Alyssa M Greenwell, Kanta Bhambhani, Stephanie Toll, William Kupsky, Deniz Altinok, Hamza S Gorsi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Radiation-induced gliomas (RIG) can occur in 3% of patients receiving cranial radiation. Often, these gliomas are high-grade, treatment refractory, and share common molecular profiles like PDGFRA amplification, regardless of their previous malignant origin. Despite similar genetic alterations, the clinical course of these tumors is varied and not well-studied. Herein, we describe three patients with a PDGRFA-amplified RIG with a particular focus on their contrasting disease course. CASE DESCRIPTION: Our first patient is a now-deceased male diagnosed with medulloblastoma at 5 years of age, treated with surgical resection and craniospinal radiation followed by chemotherapy per COG ACNS0332. Ten years later, he was diagnosed with diffuse pediatric type high-grade-glioma (HGG) in the pons with PDGFA, KIT, MTAP amplification, and CDKN2A/B loss. His condition deteriorated quickly, and he succumbed to his disease in 8 weeks after family decided against further therapies. Our second patient is a now 20-year-old female, initially diagnosed with a craniopharyngioma at 6 years of age and treated with surgical resection and adjuvant radiation therapy. Eleven years later, she developed a diffuse pediatric type HGG in the pons with PDGFRA, MDM2, and MYCN amplification. She was treated with radiation therapy and has had stable disease on serial imaging for 3 years. Our third patient is a now-deceased male diagnosed with a right temporal melanotic neuroectodermal tumor at 5 years of age, treated with surgical resection and craniospinal radiation followed by chemotherapy per POG99701. Fifteen years later, he developed a diffuse pediatric-type HGG in the cerebellum/pons with PDGRFA amplification. He was treated with proton radiation and concurrent oral Temozolomide per COG ACNS0423. His disease progressed on treatment, and he died prior to initiation of a PDGFRA kinase inhibitor (avapritinib). CONCLUSIONS Further investigation into the underlying factors that drive the differing disease course in patients with RIG is needed.
IMG-31. DEUTERIUM METABOLIC IMAGING OF RESPONSE TO PRECISION THERAPY IN BRAF-V600E MUTANT GLIOMAS
Authors: Georgios Batsios, Suresh Udutha, Anne Marie Gillespie, Claudia Petritsch, Sabine Mueller, Pavithra Viswanath
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Oncogenic BRAF-V600E mutations are frequently observed in low- and high-grade gliomas in children. BRAF transduces signals from receptor tyrosine kinases to downstream effectors such as MEK1/2 and ERK, which regulate metabolism and proliferation. The combination of the BRAF-V600E inhibitor dabrafenib and the MEK1/2 inhibitor trametinib (Dab/Tra) improves patient survival. However, there is considerable variation in response durability, underscoring the need for early biomarkers of treatment response. Magnetic resonance imaging (MRI), which is the gold standard for patient management, does not reliably assess response to therapy. Since the BRAF/MEK pathway regulates metabolism, the goal of this study was to determine whether Dab/Tra induces alterations in glucose metabolism that can be leveraged for non-invasive imaging of response to therapy. METHODS We performed gene expression profiling, in vivo metabolomics, stable isotope tracing, and deuterium metabolic imaging in patient-derived and syngeneic BRAF-V600E mutant models (AM38, 2341). RESULTS Our studies indicate that Dab/Tra downregulates glucose metabolism to lactate in AM38 and 2341 cells. In vivo infusion with [U-13C]-glucose in mice bearing intracranial AM38 tumors confirmed that Dab/Tra downregulates 13C-lactate production in the tumor. Mechanistically, Dab/Tra destabilizes hypoxia inducible factor-1a and downregulates glycolytic genes, including SLC2A1, HK2, PFKFB3, and LDHA. Importantly, deuterium metabolic imaging using [6,6’-2H]-glucose, which is a clinical stage method of imaging glycolysis, shows a reduction in lactate production within 48h of treatment with Dab/Tra in AM38 tumor-bearing mice. CONCLUSIONS Our studies mechanistically link BRAF/MEK inhibition with reduced glycolysis and identify [6,6’-2H]-glucose as a novel, non-invasive agent for imaging early response to therapy. Since [6,6’-2H]-glucose is a safe, orally administered agent, our studies can be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether patients are responding to therapy at an early timepoint that predicts extended survival.
STEM-03. A NOVEL MOUSE MODEL OF CHOROID PLEXUS CARCINOMA UNRAVELS SEQUENTIAL DEDIFFERENTIATION OF HINDBRAIN CHOROID PLEXUS TISSUE AND REVEALS NEW THERAPEUTIC PROSPECTS
Authors: Levke-Sophie Peter, Lea Altendorf, Karoline Hack, Vanessa Thaden, Carolin Göbel, Christian F Krebs, Saskia-Larissa Jauch-Speer, Uwe R Kordes, Denise Obrecht-Sturm, Christian Thomas, Ulrich Schüller, Melanie Schoof
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Choroid Plexus tumors constitute 10-20% of brain tumors in the first year of life. Among those, Choroid Plexus Carcinomas (CPC) pose a significant challenge due to their aggressiveness, resulting in poor survival rates and long-term adverse effects stemming from intense therapeutic approaches. Although loss of p53 and Sonic hedgehog signaling have been implicated in CPC development, a deeper biological understanding is needed to expand mechanistic insights and advance targeted therapies. METHODS We generated a novel mouse model with a simultaneous loss of TP53 and overexpression of MYCN and Gli2 in central nervous system precursors (hGFAP-cre::P53Fl/Fl::lsl-MYCN::lsl-Gli2). Resulting tumors were histologically characterized and compared to human CPC. Moreover, spatial transcriptomic data were generated for molecular characterization. Finally, mouse tumor-derived cell lines were employed for differentiation analysis and therapeutic testing. RESULTS Examinations at different developmental stages revealed brain tumors in the choroid plexus as well as smaller lesions in the subcallosal cortex with a penetrance of 80% within 18 days. We observed a gradual dedifferentiation of hindbrain CP tissue from day 5 onwards, indicating a continuous developmental sequence corresponding with expanding tumor growth. The mouse model recapitulates early tumor development, aggressive and metastatic growth along with histological features of human tumors. Spatial transcriptomic analysis highlighted chromosomal aberrations as well as other features known from human CPCs and emphasized the disturbance of ciliary pathways in tumor development. In vitro studies revealed rapidly growing tumor cells with stem cell-like differentiation potential and high sensitivity to targeted therapies. CONCLUSION Through in-depth analysis, including multiple data types, we show that our novel CPC mouse model closely resembles human tumors. Our tumors reveal a strict pattern of dedifferentiation implying similar mechanisms in humans. Additionally, primary mouse tumor cells in culture facilitate further in vitro analysis, and newly generated spatial transcriptomic data enables further insights into tumor biology.
HGG-07. INVESTIGATING THE ROLE OF SENESCENCE IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Timothy H Chang, Alexander Nassar, Claudia Kleinman, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2024)

Abstract Cellular senescence has expanded well past the original definition of just proliferative exhaustion and tumor suppression. Today, senescence is considered a “Hallmark of Cancer” and the senescence-associated secretory phenotype (SASP) secretes molecules that can promote oncogenesis, angiogenesis, and an immunosuppressive tumor microenvironment (TME). Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors with dismal outcomes and limited therapeutic options. Accumulating evidence suggests potential therapeutic vulnerabilities in targeting senescence in adult solid and brain tumors. Furthermore, senescent immune cells in the TME appear to play an important role in the initiation and progression in adult solid tumors. The role of senescence in pHGGs, however, has not been well described. Here, we show evidence of senescent glial and immune cells in pHGG tumors. Using patient-derived cell lines, we also investigate triggers of senescence and further characterize SASP in pHGGs. By understanding the role of senescence in gliomagenesis, we hope to open new approaches in treating pHGGs.
HGG-12. A PHASE IB/II STUDY ON ASIDNA™ IN ASSOCIATION WITH RE-IRRADIATION IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS WITH RELAPSING HIGH-GRADE GLIOMA
Authors: François DOZ, Pierre LEBLOND, Liesbeth CARDOEN, Jacques GRILL, Wael JDEY, Marie DUTREIX, Fouzia AZZOUZ, Mamadou DIALLO, Line CLAUDE, Pascale VARLET, Claire ALAPETITE
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND AsiDNA is a synthetic cholesterol-oligodeoxyribonucleotide conjugate, inducing false DNA damage signaling, which prevents DNA repair in tumor cells. AsiDNA therefore increases the vulnerability of tumor cells to irradiation without increasing toxicity in healthy tissues. Preclinical data showed encouraging results of AsiDNA combined to irradiation in glioma and medulloblastoma models. We aimed to determine the safety and efficacy of AsiDNA, a DNA-repair inhibitor, in children, adolescents and young adults with recurrent High-grade Glioma (HGG) eligible for re-irradiation. METHODS AsiDNA was administered intravenously using a 3 consecutive days loading dose, followed by a weekly dose (350 mg/m2/dose or 600 mg for patients ≥ 50kg) for 11 weeks. Focal radiotherapy, using 1.8 Gy daily fraction, 5 days a week, was administered in combination during the first weeks: 18 Gy for brainstem diffuse midline glioma (DMG) and 36 Gy for supra-tentorial HGG (DMG or non-DMG). The first part of the study aimed to assess the safety and to confirm the recommended phase-II dose based on dose limiting toxicities (DLT) during the first 8 weeks. A second part was planned to assess activity/efficacy of the combination based on the progression-free survival (PFS) rate at 3 months. AsiDNA pharmacodynamics (PD) was studied in peripheral blood mononuclear cells (PMBC). RESULTS Eight (8) patients were enrolled: median age 14 y (6.2-24.5), 5 DMG. No DLT was observed. Median FU was 9.1 months, disease progression was observed in 8 patients; 6 died because of disease progression. Median PFS was 3.9 months. The PD results showed no significant target engagement in PBMCs. CONCLUSIONS Considering the low PFS as well as lack of efficacy on PD markers, the DSMB recommended stopping the study.
TRLS-11. PNOC005: ONCOLYTIC MEASLES VIRUS FOR THE TREATMENT OF CHILDREN AND YOUNG ADULTS WITH RECURRENT MEDULLOBLASTOMA OR ATYPICAL TERATOID RHABDOID TUMOR
Authors: Cassie Kline, Bohyeon Yu, Truman Knowles, Aeesha Ranavaya, Jane Minturn, Anuradha Banerjee, Sarah Leary, Mohamed Abdelbaki, Nicholas Whipple, Stewart Goldman, Ashley Margol, Nour Dabobo, Andreas Rauschecker, Elizabeth George, Ali Nabavizadeh, Owen Hoare, Jangham Jung, Joanna Phillips, Michael Prados, Annette Molinaro, Nalin Gupta, Corey Raffel, Kristina Cole, Aaron Diaz, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND PNOC005 is a phase 1 clinical trial investigating the safety and tolerability of intratumoral or intrathecal administration of oncolytic measles virus (MV-NIS) in children and young adults with recurrent medulloblastoma (MB) or atypical teratoid/rhabdoid tumor (ATRT). METHODS Patients with recurrence of MB or ATRT were stratified into Stratum A (local recurrence) or B (disseminated recurrence). Stratum A patients received MV-NIS directly into the tumor bed at time of surgical resection. Stratum B patients received a single dose of MV-NIS via lumbar puncture. After safety was demonstrated in Stratum A and B, Stratum C was added with repeat dosing on Day 0 and 7 for patients with recurrent disseminated MB. Specimens for viral shedding were collected. Blood was collected on days 0, 4, 7, 14, and 28. RNA-sequencing deconvolution and time-series analysis were performed to estimate the composition and phenotypes of peripheral blood mononuclear cells (PBMCs). RESULTS Thirty-four patients (median age 8.5, range 2-31) enrolled between February 2017 and April 2021, with 23 evaluable patients with MB and 4 with ATRT. One patient experienced a dose-limiting toxicity (grade 3 alanine aminotransferase increase). There were four MV-NIS-related adverse events grade 3 or greater across all strata. Viral shedding was detected in 5 patients, all of which cleared by end-of-treatment. We found a similar gene-expression program in PMBCs that correlated across patients (n=18), which was upregulated at days 4-7 post treatment and consistent with an antiviral response. Concomitant changes in B, T, and natural-killer cell composition and activation were consistent with this interpretation. CONCLUSION This is the first trial investigating intratumoral as well as repeated intrathecal delivery of MV-NIS in children with MB and ATRT. We show that therapy is safe and well-tolerated with minimal adverse effects. Immune markers and biologic correlates preliminarily indicate anti-viral effects in tumors.