tbuckley/cabot-search huggingface dataset:
LGG-07. MULTI-OMICS ANALYSIS IDENTIFIES MOLECULAR DRIVERS AND THERAPEUTIC TARGETS IN DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR WITH 1Q GAIN
Authors: Margit Mikkelsen, Xiaoyu Li, Kaiwen Yu, Anthony High, Haiyan Tran, Larissa V Furtado, Nalin Leelatian, Julia D Berry, Bret C Mobley, Michael C Dewan, Adriana May, Julia Kofler, Jessica Foster, Margot Lazow, Daniel R Boué, Ibrahim Qaddoumi, Giles W Robinson, Junmin Peng, Daniel C Moreira, Jason Chiang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse leptomeningeal glioneuronal tumors (DLGNT) with 1q gain (1q+) display aggressive clinical behavior. We sought to better describe the clinical characteristics of patients with DLGNT and identify molecular drivers and therapeutic vulnerabilities of DLGNT with 1q+. METHODS DLGNTs were collected from multiple institutions, sent for methylome array and if quantity-sufficient, were subjected to RNA-seq, proteome, and phosphoproteome profiling. Wherever available, clinical data was collected. RESULTS Twenty DLGNTs (13 with 1q+, 7 without 1q+) were collected. Clinical data was obtained on 15 patients (8 with 1q+, 7 without 1q+). The median progression-free survival (PFS) was 17.5 months for those with 1q+ tumors, compared to 51 months for those without (p=0.058). All with 1q+ tumors (n=4) that received CSI radiotherapy progressed (median 12 months), compared to none without (n=3) (p=0.12). There were no responses (complete or partial) in 1q+ tumors that received chemotherapy (n=8), with 2 progressions on therapy. In tumors without 1q+ that received chemotherapy (n=6), 2 responded (1 complete, 1 partial) and 1 progressed on therapy. For 1q+ tumors that received targeted therapy (n=6), there were no responses and 2 progressions on therapy, compared to 1 response and 1 progression for tumors without (n=3). Gene Set Enrichment Analysis of all differentially methylated regions demonstrated enrichment of genes acting in mRNA processing, transcriptional regulation, p53 signaling, TGF-β receptor signaling, and T cell receptor signaling in 1q+ tumors. It identified genes with transcription factor (TF) binding sites for TFs involved in MAPK, PI3K/AKT/mTOR, WNT, and p53 pathways. Consistent with these results, hypomethylated genes at chromosome 1q in 1q+ tumors are positive regulators of MAPK, PI3K/AKT/mTOR, WNT, and p53 signaling. CONCLUSIONS DLGNT with 1q+ were more refractory to current treatment options. We identified putative molecular drivers in 1q+ tumors. Our findings suggest therapy targeting the multiple affected pathways should be considered.
MDB-68. DISCOVERING DRUG SENSITIVITIES IN MEDULLOBLASTOMA USING PATIENT- AND PDX-DERIVED TUMOROIDS
Authors: Chris Meulenbroeks, Phylicia Stathi, Marc van de Wetering, Chio Carranza Villarejo, Norman Mack, Benjamin Schwalm, Neal Geisemeyer, Julia Schueler, Anna S Kolodziejczak, Till Milde, Sabine LA Plasschaert, Mariëtte E G Kranendonk, Eelco W Hoving, Paul A Northcott, Martine F Roussel, Stefan M Pfister, Jens Bunt, Marcel Kool
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor types and is subdivided into four major types: WNT, SHH, Group 3 and Group 4. Treatment, including resection, cranio-spinal radiotherapy, and chemotherapy, often leads to undesirable long-term side effects. MB prognosis depends on type, subtype, and genetic alterations, reflecting the high level of heterogeneity observed in these tumors and indicating that specific patient populations with particularly poor prognosis require alternative treatment approaches. Therefore, preclinical models are essential for recapitulating MB heterogeneity and developing subtype-specific treatments. METHODS Long-term in vitro MB tumoroid models were developed from patient and PDX tumors and molecularly characterized using DNA methylation and transcriptomic analyses. High-throughput single drug screening (225 compounds) and combination screening were performed to identify (subtype-specific) drug sensitivities. RESULTS Fifteen tumoroid lines were established from TP53-mutated SHH (n=6), Group 3 (G3) MYC-amplified (n=4) and non-amplified (n=5) patient (n=6) and PDX (n=9) tumors. DNA methylation analyses confirmed the maintenance of molecular identity in these tumoroids after long-term culture (&amp;gt;5 passages). Transcriptome analyses reveal a more proliferative, progenitor-like phenotype in these tumoroids compared to patient/PDX tumors. Hight-throughput drug screens identified both common and type-specific drug sensitivities within MB. Notably, drugs targeting CDK7, CDK12, CHECK1, BCL2L, and HDAC demonstrated efficacy in both G3 and TP53-mutated SHH-MB, while TOP1/2 and MDM2 inhibitors were specific for G3-MB. Currently, these drugs are being further investigated to select the most effective synergistic drug combinations for in vivo validation in PDX models. CONCLUSIONS Thus far, we have established already fifteen MB tumoroid models representing SHH-MB and G3-MB and identified several drug targets, including cell cycle kinases and HDACs. Tumoroids closely resemble patient tumors, based on methylome and transcriptome, enhancing their relevance for drug discovery applications in a high-throughput fashion and for prioritizing new treatment strategies for MB patients in clinical trials.
QOL-21. FUNCTION-BASED OUTCOME MEASURES AND HOW THEY CAN BE APPLIED IN PATIENTS WITH PEDIATRIC BRAIN TUMOR FOR TRACKING RECOVERY AND RESEARCH
Authors: Elaine Tsao, Vera Tsetlina, Jared Levin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Currently an estimated 15,000 children are diagnosed with cancer annually in the United States. Among pediatric patients, central nerve system tumors make up the highest percentage of solid tumor malignancies. Tumors of the peripheral nervous system also occur, most commonly in syndromes such as neurofibromatosis. Tumor growth and tumor treatments can result in developmental and functional impacts on patients. As survival rates continue to improve through the years with advancement of pediatric cancer treatment, an increasing focus is being placed on improving function and quality of life both during and after treatment. This presentation aims to introduce a variety of validated outcome measures that assess a patient’s strength and function, to discuss how they can be applied to patient monitoring, and to propose future studies in the pediatric neuro-oncology population. METHODS This presentation will review the currently validated and commonly used outcome measures used by physicians and therapists for assessing a patient’s strength, endurance, and function. Emphasis will be placed on how these tools can be used in assessing and monitoring patients with conditions such as chemotherapy induced peripheral neuropathy, posterior fossa syndrome, and cachexia. RESULTS AND CONCLUSIONS This presentation aims to educate attendees on the current tools and outcome measures available to track a patient’s function and progress during and after treatment of neuro-oncologic conditions. It aims to highlight how these tools can be used in clinic for patient monitoring, and for future possible prospective research.
MDB-66. HIGH-THROUGHPUT SMALL MOLECULE DRUG SCREENING, TRANSCRIPTOMICS AND INTEGRATIVE AI IDENTIFY TARGETABLE MYC-DEPENDENT THERAPEUTIC VULNERABILITIES IN HIGH-RISK MEDULLOBLASTOMA
Authors: Gemma Llargués-Sistac, Louisa Taylor, Janet Lindsey, Marie Claire Buttigieg, Alaide Morcavallo, Chantelle Bowers, Harvey Che, Colin Kwok, Daniel Williamson, John Anderson, Laura K Donovan, Rebecca M Hill, Bissan Al-Lazikani, Louis Chesler, Steven C Clifford
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION MYC-amplified Group 3 medulloblastomas (MBGroup3-MYC) do not respond to conventional up-front therapies and are almost universally fatal (&amp;lt;5% survival). MYC is not directly targetable. Thus, the systematic development of therapies which target complementary MYC-dependencies offers clear potential to rationally re-design effective therapeutic strategies. METHODS Isogenic cell-based models with regulable shRNA MYC-knockdown were developed in three independent MYC-amplified backgrounds (D283Med; D425Med; HD-MB03). These were utilised to i) define the MYC-dependent transcriptome/proteome in MBGroup3, through analysis in conjunction with our primary tumour cohort, and ii) as the basis of an automated MYC-dependent high-throughput drug screen (HTS; &amp;gt;500 clinically-actionable compounds). Bespoke integrative AI tools and bioinformatic analysis, and subsequent siRNA/pharmacodynamic validation, identified and validated candidate MYC-dependent therapeutic vulnerabilities. Prioritised drugs were advanced to pre-clinical trials across two in vivo MBGroup3 models (GTML/Trp53KI/KI (GEMM; MYCN-driven) and GMYC (GEMM-derived allografts; MYC-driven)) to evaluate candidate efficacy and toxicity. RESULTS shRNA-mediated MYC knockdown could be maintained for 28 days without escape in all models and, as anticipated, was associated with cell cycle abrogation and elevated caspase-3/-7 activity. HTS across all models revealed that MYC expression confers differential dependencies to small molecule inhibitors, with 82 compounds spanning 11 major drug classes demonstrating MYC-dependent activity. AI-based integration of HTS data with model and primary patient MYC-dependent transcriptome data shortlisted multiple druggable molecular targets which, in turn, were independently validated. To date, we have progressed alisertib (AURKAi), volasertib (PLK1i) and prexasertib (CHK1i) to in vivo pre-clinical trials. Promisingly, both alisertib and prexasertib demonstrated efficacy within MBGroup3-MYC models. CONCLUSIONS Integrated human tumour and model-based screening approaches have enabled identification and validation of critical MYC co-dependencies, targetable using established small-molecules, to inhibit MBGroup3 tumour growth. Their further evaluation, including integration into established and/or rationally-designed combinations, will be essential next steps in their (pre-)clinical development.
MDB-67. MEDULLOBLASTOMA MOLECULAR SUBGROUPING AND OUTCOMES DATA OF A SINGLE CENTER FROM A LOW-MIDDLE-INCOME COUNTRY
Authors: Naureen Mushtaq, Farrah Bashir, Quratulain Riaz, Soha Zahid, Gohar Javed, Maria Tariq, Bilal Mazhar Qureshi, Kiran Hilal, Vijay Ramaswamy, Cynthia Hawkins, Eric Bouffet, Khurram Minhas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most common malignant childhood brain tumor. The molecular subgrouping of medulloblastoma is a major determinant of management in high-income countries. Subgrouping is still very limited in low- and middle-income countries, and its relevance to management has yet to be evaluated in this setting. We describe molecular findings and their implications in the outcome of a single tertiary care center. METHODS Children between 3 and 18 years diagnosed with medulloblastoma between April 2014 and December 2020 at Aga Khan University Hospital were included. Subgrouping was performed by nanostring through a collaboration with the Hospital for Sick Children, Toronto. RESULTS Thirty-five children were identified (85.17% male); the median age was 8. Nineteen patients were high-risk, including 9 with metastatic disease. In 28 children, there was a clear molecular subgroup: 4 WNT (11.4%), 7 Sonic Hedgehog (20%), 3 Group 3 (8.6%), and 14 Group 4 (40%) medulloblastomas. Molecular subgrouping was inconclusive for two patients (5.7%) and not done in 5 patients (14.3%). All patients underwent surgery; 91.4% received radiation therapy and chemotherapy. Of 35 children, overall Survival at 5 years was 100%, 57.1%, 66.7%, and 85.7% for WNT, Sonic Hedgehog, Group 3, and Group 4, respectively. WNT and Group 3 had 100% Progression-free survival, whereas Sonic Hedgehog and Group 4 had decreased progression-free survival of 42.9% and 85.7%, respectively. Average-risk patients had an overall survival of 93.8%, whereas high-risk patients exhibited a statistically significant lower overall survival of 63.2% (P=0.014). CONCLUSION Our cohort demonstrates excellent outcomes for WNT and Group 4, despite one WNT being metastatic and four Group 4 patients being high-risk. Modern risk stratification is an excellent predictor of survival, suggesting that treatment can be tailored according to subgrouping in the LMIC setting.
MDB-69. RADIOLOGICAL PATTERNS OF RECURRENCE IN MEDULLOBLASTOMA SUBGROUPS AND CORRELATION WITH SURVIVAL
Authors: Arpita Sahu, Swetha M Nair, Archya Dasgupta, Soujanya Mynalli, Ayushi Jain, Epari Sridhar, Abhishek Chatterji, Amitkumar Choudhari, Kajari Bhattacharya, Maya Prasad, Girish Chinnaswamy, Nandini Menon, Vikas Singh, Prakash Shetty, Ali Asgar Moiyadi, Tejpal Gupta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastomas can recur in up to one-third of the patients despite optimal therapy. The knowledge of the molecular group can provide clues to the possible pattern of relapse and the course of disease, with therapeutic implications. In the present study, we have identified anatomical locations and radiological patterns of relapse. METHODS AND MATERIALS Patients with a histopathological diagnosis and available subgroups of medulloblastoma with first relapse, treated in a single tertiary care center during 2005-2021 with available magnetic resonance imaging of brain and spine were included in the retrospective study. Statistical analysis was done using Pearson chi-square test and Fisher’s exact test. RESULTS 127 patients were included in the final analysis. Median age at diagnosis was 12 years and time to first recurrence was 21 months. Tumor bed relapse was seen in 49% cases, maximum in SHH subgroup, p&amp;lt;0.01. Involvement of the ventricular system (including cisterns and ventricles) was seen in 37% of cases, and was significantly associated (p:&amp;lt;0.01) with non-WNT, non-SHH tumours. Leptomeningeal metastasis was seen in 36% of cases, with significant association (p&amp;lt;0.01) in group 3 (75% of all group 3 cases) and group 4 tumors (50% of all group 4 cases). Disease in spine was most common in group 3 (65%) and group 4 tumours (71%), p&amp;lt;0.01. Hippocampus was involved in 19 cases (15%), mostly in non-WNT, non-SHH (14 cases). Significant difference in survival after recurrence was seen with ventricular, extraventricular metastases with one year survival 83% and 73% respectively, p=0.02. Hippocampal involvement showed significantly decreased survival, one year survival of 37%, p&amp;lt;0.01. CONCLUSIONS Leptomeningeal dissemination and diffuse disease were mostly seen in group 3 tumours, indicating their aggressive nature. The lower rates of ventricular relapse and around hippocampus in SHH medulloblastoma provide the opportunity to explore hippocampal avoidance-craniospinal irradiation.
MDB-78. ISOCITRATE DEHYDROGENASE 1 INHIBITION PRIMES GROUP-3 MEDULLOBLASTOMAS FOR CUPROPTOSIS
Authors: Derek Dang, John McKolay, Kyle Smith, Pooja Panwalkar, Stefan Sweha, Siva Kumar Natarajan, Matthew J Pun, Sunjong Ji, Diya Patel, Olamide Animasahun, Abhinav Achreja, Martin P Ogrodzinski, Jennifer Cotter, Debra Hawes, Fusheng Yang, Robert Doherty, Andrea T Franson, Allison R Hanaford, Charles G Eberhart, Eric H Raabe, Brandon Chen, Costas A Lyssiotis, Yatrik Shah, Sophia Y Lunt, Alexander R Judkins, John Prensner, Carl J Koschmann, Sebastian Waszak, Deepak Nagrath, Paul Northcott, Sriram Venneti
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND MYC-driven Group-3 medulloblastomas (MB) are deadly and malignant pediatric brain cancers and we sought to define actionable metabolic dependencies in these tumors. METHODS To identify uniquely upregulated genes in Group-3 MB, we performed transcriptomic analysis on two previously published medulloblastoma RNA-seq datasets. To elucidate the relationship between c-MYC/IDH1/DLAT and assess impact on tumor metabolism, we performed metabolic and transcriptional profiling of Group-3 MB cell lines that were either untreated or were subjected to shRNA-mediated knockdown of DLAT or treatment with IDH1 inhibitor. We also treated Group-3 MB cell lines containing varying levels of DLAT expression with copper ionophore elesclomol and assessed its ability to induce toxicity. Finally, we established in vivo models of Group-3 MB via orthotopic implantation to assess the effect of DLAT knockdown, IDH1 inhibition, and cuproptosis induction on tumor growth and survival outcomes. RESULTS We identified upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of Group-3 MB. DLAT was induced by c-MYC and targeting DLAT lowered TCA-cycle metabolism and glutathione synthesis in Group-3 MB cells. We also noted upregulation of isocitrate dehydrogenase 1 (IDH1) in Group-3 MB. Remarkably, genetic and pharmacologic suppression of IDH1 epigenetically reduced c-MYC and downstream DLAT levels. DLAT is a central regulator of cuproptosis, a copper-dependent cell death mechanism induced by the copper ionophore elesclomol. DLAT expression in Group-3 MB cells correlated with increased sensitivity to cuproptosis. Elesclomol was CNS-penetrant and suppressed tumor growth in vivo in Group-3 MB animal models. CONCLUSIONS Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill Group-3 MB by cuproptosis.
MDB-75. MOLECULAR PATHOLOGY, TREATMENT AND PROGNOSIS OF INFANT SONIC HEDGEHOG MEDULLOBLASTOMA: A GLOBAL MULTI-COHORT STUDY
Authors: Stacey Richardson, Debbie Hicks, Melissa Gough, Jemma Castle, Stephen Crosier, Miguel Garcia-Ariza, Idoia Martín-Guerrero, Sabine LA Plasschaert, Franck Bourdeaut, Christelle Dufour, Julien Masliah-Planchon, Francesca R Buttarelli, Maria-Luisa Garre, Veronica Biassoni, Maura Massimino, Yonehiro Kanemura, Vijay Ramaswamy, Amar Gajjar, Paul Northcott, Giles Robinson, Andrey Korshunov, Stefan M Pfister, Martin Mynarek, Stefan Rutkowski, Edward C Schwalbe, Simon Bailey, Steven C Clifford
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Clinical studies in infant medulloblastoma (iMB; &amp;lt;5 years) have, to date, focussed on modestly-sized or national trials cohorts and have not directly compared therapeutic approaches or placed these in the context of dedicated biomarker studies, to inform future treatment strategies. METHODS We assembled a multi-national cohort of molecularly and clinically-annotated iMBs (&amp;lt;5 years at diagnosis; n=646), the largest to date. We investigated molecular pathology, treatments received, and relationships to outcome within this population. RESULTS The SHH group (iMBSHH; n=267, 40%) predominated, encompassing SHH-1 (37.7%, median age 2.0 years), SHH-2 (47.0%, 1.4 years) and SHH-3 (14.4%, 3.0 years) WHO subgroups. MBEN histology was significantly enriched in SHH-2, and SUFU mutation and MYCN amplification in SHH-1 and SHH-3, respectively. Notably, TP53 mutations were identified in all subgroups; in SHH-1 and SHH-2 (each n=3) tumours lacked features typically associated with TP53-mutated SHH-3 (LCA histology and MYCN amplification) and did not have a worse survival. Upfront radiation-sparing treatments were used in 132/267 children and comprised regimens founded on intraventricular methotrexate (IVT-MTX; 54.5%), high-dose (HDCTx; 22.0%) or standard-dose (23.5%) chemotherapy. Across all radio-naive iMBSHH, non-DN/MBEN histology (HR 2.76, CI 1.26-6.01, p=0.011) and SHH-1 (vs SHH-2, HR 2.51, CI 1.25-5.01, p=0.009) conferred worse PFS in univariable analysis; subgroup was the only independently prognostic risk-factor (multivariable analysis; SHH-1 HR 2.65, CI 1.27-5.51, p=0.009). 5-year OS for HDCTx recipients was very favourable in SHH-1 (100%) and SHH-2 (93.3%), and subgroup-dependent for IVT-MTX (SHH-1; 76.4%, SHH-2; 100%, p=0.009). In CSI-treated iMBSHH (n=49), non-DN/MBEN histology (HR 10.23, CI 2.22-47.04, p=0.003) and MYCN amplification (HR 7.35, CI 2.01-26.87, p=0.003) conferred worse PFS. CONCLUSION iMBSHH outcomes in this cohort are dependent upon WHO subgroup, histology and therapy received. These findings provide an evidence-based foundation for selection of cohorts and therapies for prospective assessment in forthcoming iMBSHH clinical trials (e.g. SIOP-CONNECT-YC-MB-LR).
MDB-79. THE DEUBIQUITINATING ENZYME USP7 COOPERATES WITH SONIC HEDGEHOG SIGNALING TO PROMOTE MEDULLOBLASTOMA
Authors: Sara Maria Cigna, Irene Basili, Flavia Bernardi, Ludovica Lospinoso Severini, Antoine Forget, Chia-Hsiang Chang, Hua Yu, Gabriele Cancila, Veronique Marsaud, Julie Talbot, Audrey Mercier, Charlene Lasgi, Stéphanie Puget, Kevin Beccaria, Thomas Blauwblomme, Daisuke Kawauchi, Suresh Kumar, Jin-Wu Tsai, Lucia Di Marcotullio, Olivier Ayrault
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Constitutive activation of the Sonic Hedgehog (SHH) signaling pathway during cerebellar development may lead to medulloblastoma (MB), one of the most common malignant pediatric brain tumor. Clinically, SHH-MB with mutations downstream of SMO or TP53-mutated are a real challenge and alternative targeted therapies are sorely needed for this group of patients. In SHH-MB, the transcription factor Atoh1 is constitutively overexpressed and essential for tumor initiation and progression. Previous work demonstrated that proteasomal-mediated degradation of Atoh1 induces tumor regression in vitro and in vivo, therefore deciphering mechanisms controlling Atoh1 stabilization should provide new avenues for drug development in SHH-MB. METHODS Using a proteomic approach, we identified the deubiquitinating enzyme Usp7 as a positive regulator of Atoh1 in MB cells. We then applied a SILAC-based quantitative ubiquitinomics to investigate the Usp7 target landscape in SHH-MB. We also employed several biochemical approaches to demonstrate the functional interaction between Atoh1 and Usp7 in SHH-MB. In parallel, we validated the impact of Usp7 depletion in vitro and in vivo using relevant SHH-MB models. Last, we investigated large transcriptomic and proteomic datasets to unveil the prognostic value of Usp7 in SHH-MB human tumors. RESULTS We demonstrate that Usp7 binds and accumulates Atoh1 protein by counteracting its ubiquitylation. Post-natal electroporation in vivo directly into the developing cerebella also indicates that overexpression of Usp7 promotes proliferation, whereas in the absence of Atoh1 Usp7 was no longer able to spread cell growth, demonstrating a functional link between the Usp7-Atoh1 axis. In vivo, disruption of Usp7 expression in SHH-MB blocks tumor proliferation. Pharmacological inhibition of Usp7 triggers tumor growth in a syngeneic SHH MB mouse model. Lastly, SHH-MB cells with either TP53 or SMO downstream mutations are sensitive to Usp7 inhibition. CONCLUSIONS Overall, our data pinpoint Usp7 as a promising target against Atoh1, a master regulator of SHH-MB.