tbuckley/cabot-search huggingface dataset:
MDB-06. ALTERNATIVE SPLICING MEDIATED BY OTX2 DRIVES THE DEVELOPMENT OF GROUP 3 MEDULLOBLASTOMA
Authors: Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D Hendrikse, Paul Layug, Victor Gordon, Kimberly A Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Gareth Palidwor, Christopher J Porter, Stephane Richard, Tanveer Sharif, Brad W Doble, Kathleen J Millen, Michael D Taylor, Tamra E Werbowetski-Ogilvie
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND OTX2 is a transcription factor and known molecular hallmark of Group 3 medulloblastoma (MB). While previous studies have focused on its association with active enhancer elements to modulate the chromatin landscape, here, we demonstrate an unexpected role for OTX2 in regulating Group 3 MB alternative splicing (AS). METHODS We used TurboID to broadly interrogate the Group 3 MB OTX2 protein interactome and identify associations with splicing regulators. RNA-sequencing was performed to identify OTX2-driven AS events, a subset of which were validated in Group 3 and Group 4 MB patient tumors and the developing human cerebellar rhombic lip (RL). Splice blocking morpholinos were used to mimic OTX2-regulated splicing events and to determine their role in MB cell fate decisions both in vitro and in vivo. RESULTS OTX2 associates with the Large Assembly of Splicing Regulators (LASR) complex through protein-protein interactions and modulates the localization of a LASR protein to help stabilize the complex and sustain a Group 3 MB splicing program. Motif enrichment analysis demonstrates that members of the LASR complex are also significantly enriched near OTX2-regulated alternatively spliced exons. OTX2 is found on nascent mRNA, and its role in AS is independent of DNA-regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in the human cerebellar RL origins. Among the OTX2-regulated spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumor growth, while enhancing differentiation and survival in vivo. CONCLUSIONS While splicing defects are commonly observed in adult cancers, the functional role of AS in the most aggressive MBs has never been explored. These findings identify OTX2-mediated AS as a major determinant of cell fate decisions and highlight AS events as novel therapeutic targets to drive Group 3 MB differentiation.
MDB-02. RECURRNET SPINAL DESMOID FIBROMATOSIS IN A CHILD WITH APC GERMLINE MUTATION-RELATED MEDULLOBLASTOMA
Authors: Nahla Aly Mobarak, Ali Abdullah O Balbaid, Fahad Alotabi, Salman A AlMalki, Basma Alyamna, Musa Alharbi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Familial adenomatous polyposis (FAP) is an autosomal-dominant dominant Familial Cancer Syndrome FCs Caused by Germline inactivation of adenomatous polyposis coli (APC) tumor suppressor gene, results in up-regulation of the WNT signaling pathway which increases the risk of colorectal cancer CRC, colon polyposis and extracolonic tumors like gastric and duodenal carcinomas WNT-activated Medulloblastoma MBL and Desmoid fibromatosis (DF) DF are locally aggressive soft tissue tumors with high local recurrence rates after Surgical excision role of adjuvant chemotherapy or Radiotherapy is still unclear. METHODS A 6-year-old boy product of non-consanguineous marriage with positive family HX brain tumor Diagnosed with Non-Metastatic Average Risk MBL WHO grade IV classic histology, he had craniotomy and Gross tumor resection followed by craniospinal irradiation at 23.4 Gy, plus a boost to posterior fossa/tumor bed up to 54 Gy, followed by 8 maintenance chemotherapy cycles as HIT-MED protocol Cisplatin/VCR/CCNU total. 3 years post end of therapy the pateint was in complete remission from MBL when routing MRI surveillance showed a new left paravertebral muscle lesion within the irradiation field from T1 to T4 levels which progressed gradually over a short follow-up time he had surgical resection of the tumor with Pathological diagnosis of Desmoid fibromatosis. after six months he had a second recurrence of the spinal tumor that needed a second surgical resection. Result: positive Genetic testing for Germline pathogenic mutation of APC gene exons 7 to 16 confirmed the diagnosis of autosomal familial adenomatous polyposis type 1(FAP1). Up to date, he is stable on endoscopic and MRI surveillance with radiological evidence of slow progression of the paraspinal tumor CONCLUSION Medulloblastomas associated with APC germline mutation have favorable outcomes that may need de-escalating therapeutic protocol with reduced intensity craniospinal irradiation aiming to reduce the incidence of secondary tumors after adjuvant treatment for MBL
DEI-02. DIRECT PATIENT OUTREACH IN PEDIATRIC NEURO-ONCOLOGY TO IMPROVE ACCESS TO GENOMIC PROFILING – THE MAKE-AN-IMPACT PROGRAM
Authors: Sameer Farouk Sait, Tara O’Donohue, Katherine Hill, Emily Stockfish, Alexandra Giantini-Larsen, Tina Alano, Tejus Bale, Marc Rosenblum, Jamal Benhamida, Ira Dunkel, Michael Berger, Maria E Arcila, Marc Ladanyi, Alexandra Miller, Debyani Chakravarty, David Solit, Neerav Shukla, Matthias Karajannis
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Genomic profiling and precision medicine have revolutionized cancer care but are not accessible to all due to high costs, insurance issues, limited access to testing facilities or qualified personnel. We established a program providing free clinical genomic testing worldwide (Make-An-IMPACT) and report findings from the pediatric CNS tumor cohort. METHODS Following a referral from: (1) a physician, (2) a disease-specific advocacy group, or (3) submission of contact information through program website, patients were enrolled on an IRB-approved protocol (NCT01775072). CSF cell free DNA (cfDNA) and matched normal samples were analyzed using MSK-IMPACTTM, a New York State Department of Health authorized hybridization capture-based next-generation panel DNA sequencing clinical assay. If a driver mutation wasn’t reported, raw genomic data was reviewed. OncoKBTM was used to determine the level of evidence supporting the clinical actionability of genomic aberrations. RESULTS 24 patients (median age 7.5; range 0.1-20 years) were enrolled; 9 (38%) from 5 non-US countries and 6 (25%) from non-NYC US sites. African American and Hispanics constituted 8% and 13% of the cohort. Potentially actionable alterations were identified in 4/24 (17%) cases; 2/24 (8%) subsequently received matched therapy. In unbiopsied or non-diagnostic cases, a disease defining alteration was identified in 8/15 (53.3%). BRAF-KIAA1549 fusions were identified in 2/3 DLGNT patients and 1p loss in all 3. Both patients with BRAF fused DLGNT started targeted therapy with Trametinib, one of whom achieved a durable treatment response for 2.5 years. 3/8 patients with unbiopsied brainstem lesions had a H3.3K27M mutation, while 2 had non-H3.3K27M mutations detected (1 SMARCB1 deletion, 1 IDHR172G mutation) leading to treatment regimen changes. CONCLUSIONS This study captured a broad range of pediatric CNS malignancies with a diverse patient representation across geographic regions. CSF cfDNA profiling provided important diagnostic and therapeutic information reported in real time to patients and local physicians.
DEI-01. CLINICAL AND SOCIOECONOMIC FACTORS ASSOCIATED WITH PARTICIPATION IN POST-MORTEM TISSUE DONATION IN PEDIATRIC BRAIN TUMORS: A RETROSPECTIVE CHART REVIEW
Authors: Lauren K Boland, Judith M Kabat, Melissa Williams, Alicia Lenzen, Ashley S Plant-Fox, Nitin Wadhwani, Angela J Waanders
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The gift of post-mortem tissue donation is a critical resource in the discovery and interrogation of pathobiological mechanisms of pediatric brain tumors. Broad generalizability of research findings requires a representative population to participate in pre-clinical studies. As a “Center of Excellence” within the Gift from a Child initiative, our institution has a well-established post-mortem tissue donation program funded by the Swifty Foundation. Our primary objective was to determine if clinical and socioeconomic differences exist between patients that participated in and those that declined research-based autopsy. METHODS We performed a single-institution retrospective chart review of pediatric patients with central nervous system (CNS) malignancies who died from their disease between 1/1/2021 and 12/31/2022. Individual clinical, demographic, and socioeconomic data were assessed. Population-level data were estimated using Zip Code Tabulation Areas. Descriptive statistics were used to compare categorical data. RESULTS Among 26 patients who died secondary to disease in the study timeframe, 23 (88%) were approached and 8/23 (35%) consented to participation. In the consented group (C) vs. declined group (D), there was a higher percentage of White, Non-Hispanic/Latino patients by self-reported race (C: 88% vs. D: 55%) and no patients who identified as Asian or Hispanic/Latino (C: 0% &amp; 0% vs. D: 13% &amp; 27%). Of all patients approached, 2 required interpreters (9%) and both families declined participation. The rate of private insurance was higher in the consented group (C: 75% vs D: 47%) compared to Medicaid as primary insurance in the declined group (C: 13% vs D: 53%). CONCLUSIONS Patients from racial and ethnic minorities are underrepresented in tissue donation programs. Future research should aim to understand and improve identified disparities to ensure advancements benefit all children with CNS malignancies. One area we plan to address is improved communication with non-English speaking families by educating interpreter services prior to discussion.
DIPG-12. ASSESSING THE EFFICACY OF BAY2402234 IN COMBINATION WITH ONC201 IN IMMUNE-COMPETENT MURINE MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Sean Mizoguchi, Bettina Kritzer, Steven J Cerna, Roger Packer, Sridevi Yadavilli, Tim Phoenix, Javad Nazarian
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Radiation therapy remains the sole standard-of-care treatment for Diffuse Midline Glioma (DMG), an aggressive and lethal brain tumor. Despite numerous clinical trials, median overall survival has not improved. Therefore, precise preclinical modeling is essential to guide clinical trials toward positive patient outcomes. ONC201, a ClpP antagonist, has demonstrated efficacy in treating DMG (NCT05580562, NCT05476939). However, efficacy is short-term and acquired resistance necessitates combination therapies. Therefore, we assessed the efficacy of BAY2402234, a potent and selective Dihydroorotate Dehydrogenase (DHODH) inhibitor, in combination with ONC201 in a murine model of DMG. METHODS Forty 6-week-old C57/B6 mice underwent pontine orthotopic injection with isogenic DMG cells via stereotactic surgery. The cell line used, 24B-7, has a mutational profile (PDGFRA+p53+H3.3K27M) and growth morphology representative of pontine DMGs. In our previous work, untreated mice injected with these cells had a median survival of 58 days. Upon confirmation of tumor growth using IVIS, mice were assigned to treatment groups based on BLI signal, and treatment was initiated. When mice showed signs of tumor burden or &amp;gt;20% weight loss they were euthanized. At euthanasia, the brain was collected, sectioned sagittally, and divided between fixation and freezing. These samples will evaluate tumor growth, morphology, and characterization compared between treatment groups by both immunohistochemistry and western blot. RESULTS As expected, ONC201 treated mice demonstrated an increase in median survival compared to the untreated group. While well-tolerated, neither BAY2402234 nor the combination of BAY2402234 and ONC201 exhibited a statistically significant increase in median survival after statistical correction. (Vehicle: 55 days, ONC201: 62 days, p=0.0026; BAY2402234: 58.5 days, p=0.0403; Combination: 57 days, p=0.1491). Ongoing efforts include target validation and tumor analysis through western blot and immunohistochemistry. ONC201 treatment will be evaluated by investigating ATF4, DR5, and CHOP. BAY2402234 treatment will be evaluated by investigating phosphor-gH2AX and gH2AX. CONCLUSIONS Pending tumor analysis.
LGG-57. BH3 MIMETICS IMPROVE RESPONSE TO AUTOPHAGY INHIBITION IN BRAFV600E GLIOMAS
Authors: Michele Crespo, Shadi Zahedi, Andrew Morin, Darya Wodetzski, Madeline Groat, Emil Bratbak, Kendra Jones, Andrea Griesinger, Cecilia Caino, Jean Mulcahy Levy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Autophagy inhibition improves the effectiveness of RAF pathway inhibition (RAFi) and overcomes resistance mechanisms. Mechanistic links between autophagy and apoptotic cell death may explain this ability. BH3 mimetics with autophagy and RAFi further improves this response. METHODS RAFi sensitive (MAF 794, AM38) and resistant (MAF 794R, MAF 905-3, AM38R, B76) BRAFV600E tumor cell lines were analyzed at baseline, following RAFi (vemurafenib), autophagy inhibition (chloroquine or shRNAs), BH3 protein inhibition (navitoclax or shRNAs), and combination therapy. Growth assays and caspase activation were monitored by Incucyte Zoom. qRT-PCR evaluated key pro-apoptotic BH3-only members of the BCL-2 family. BH3 profiling was completed using the Letai JC-1 plate-based protocol. Western blot analysis assessed protein levels. Cell Titer Glo determined cell viability. RESULTS Combination therapy increased key pro-apoptotic BH3-only proteins including PUMA. shRNAs targeting ATG5 and ATG7 (proteins required for autophagosome formation) also increased PUMA protein and mRNA levels following RAFi. This suggests autophagy-mediated regulation of BH3 proteins helps determine cellular apoptotic thresholds. Combined autophagy and RAFi increased caspase activation and cell death compared to single drug treatment. BH3 profiling demonstrated BCL-2 dependence to inhibit apoptosis. Inhibition of pro-survival BCL-2 family members BCL-2 and BCL-XL (pharmacologically and genetically) with RAFi, MEKi, and autophagy inhibition further increased caspase activation and reduced cell viability. CONCLUSIONS BH3 mimetics competitively bind pro-survival BCL-2 family members, increasing apoptosis. Autophagy inhibition improves treatment response by overcoming the apoptotic threshold in RAFi resistant cells and magnifying the apoptotic response in sensitive cells. BH3 profiling reveals CNS BRAFV600E are BCL-2 and BCL-XL dependent, making them good candidates for additional treatment with BH3 mimetics. The addition of navitoclax increased caspase activation and reduced cell viability. Autophagy inhibition can magnify this response even more. This presents an attractive treatment for MAPK activated CNS tumors by enhancing apoptotic cell death by targeting the MAPK pathway, autophagy and BH3.
IMG-23. AN MRI-BASED RADIOMIC SIGNATURE TO PREDICT LONG-TERM SURVIVAL IN PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Frédérique Frouin, Fahad Khalid, Vincent Frouin, Volodia Dangouloff-Ros, Nathalie Boddaert, Jacques Grill
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine gliomas are characterized by a short life expectancy after diagnosis, with a mean overall survival of less than 12 months. To stratify patients and possibly better adapt therapy, we are proposing a radiomic signature that predicts, at the time of diagnosis, which patients might survive beyond 2 years. METHODS A retrospective database comprising 80 patients who had undergone 3D multimodal MRI at the time of diagnosis was compiled. All images were acquired at a single center, and the protocol included T1-weighted images acquired before and after contrast injection, T2-weighted and FLAIR images. Depending on the patient, some modalities were missing (around 10% per modality). After manual tumor delineation, a dedicated radiomic pipeline extracted 79 features (first-order statistics and texture parameters) per imaging modality. In addition, gender, age and 14 tumor shape features were collected without missing data. After feature selection (maximum of 4 features per model), five logistic regression models were defined, one per modality and another for clinical and shape variables. Each patient was eligible for 2 to 5 models, with an average score calculated over these models. RESULTS Based on a leave-one-out approach, the multi-model was able to define patients who survive more than 2 years correctly, (sensitivity=100%, specificity =79%). A prediction could be made for each patient despite missing MR modalities. Defining a radiomic signature based on the multi-model score (cut-off=0.5), Kaplan-Meier analysis shows a good separation of the two groups (p-value&amp;lt;0.001). This result is superior to that obtained with the TP53 mutation (available for 61 patients, with p-value&amp;lt;0.01). CONCLUSIONS We have demonstrated the value of multimodal 3D MRI in predicting which DIPG patients might survive beyond 2 years. The robustness of this radiomic signature has yet to be tested using multicentric images.
TRLS-17. INTERIM CLINICAL, PHARMACOKINETIC, AND TECHNICAL REPORT OF A PHASE 2 STUDY OF SONODYNAMIC THERAPY (SDT) USING SONALA-001 TOGETHER WITH MR-GUIDED LOW-INTENSITY FOCUSED ULTRASOUND (MRGFUS) IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Hasan R Syed, Roger J Packer, Adriana Fonseca, Robert F Keating, Sabine Mueller, Kazim Narsinh, Winson Ho, Toba Niazi, Peter Fenn, Ryan Clanton, Lenora Henry, Wyatt Potter, Corina Andresen, Stuart Marcus, Ely Benaim, Lindsay Kilburn
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children with DIPG have limited treatment options and poor prognosis with median survival of 9-12 months. Preclinical studies reveal that sonodynamic therapy (SDT) via MR-guided focused ultrasound (MRgFUS) activates SONALA-001 (ALA) metabolite, protoporphyrin IX (PpIX), inducing tumor cell death and extending survival in glioma models. METHODS We present preliminary data from an ongoing first-in-child drug-device trial (NCT05123534) of SONALA-001 SDT in children with DIPG aged ≥ 5 years post-radiation therapy. The trial evaluates the safety of ALA-SDT, preliminary efficacy and pharmacokinetics (PK) of SONALA-001 at 5mg/kg administered 6-12 hours before SDT and establishes the RP2D. Each cohort involves three subjects: the first receiving half-pons treatment 30-days apart; the others receiving entire pons treatment. Single-treatment approach was amended to allow up to 12 monthly-treatments. RESULTS Six patients (4M:2F, 5-12 years) in 2 cohorts received 22 SDT-treatments between August 2022 and February 2023. Sonication duration averaged 147 minutes. Five of 6 patients received repeated treatments. All were discharged post-procedure day 1 with no DLTs or related AE grade ≥ 3. For SONALA-001, the Cmax occurred at end of infusion, followed by rapid clearance (15.7 mL/min/kg); plasma half-life of &amp;lt; 1 hour, indicating rapid distribution. The PpIX-Cmax occurred 4-6 hours post-dose, declining with a longer mean half-life than SONALA-001 of 6 hours. Both Cmax and AUCall demonstrate circulating-PpIX and systemic exposure were significantly lower than for SONALA-001. Two of 6 patients achieved a partial response per RAPNO central-review, and 2 continue in the study treatment for 11 and 15 months, respectively. CONCLUSION SDT is an innovative and to-date well-tolerated strategy for children with DIPG post-initial radiotherapy. Sonications did not result in any adverse procedural effects. SONALA-001 exhibits rapid distribution and clearance, while PpIX PK align with metabolite formation. After dose escalation completion, dose-expansion at R2PD will offer insights into safety, PK, and efficacy.
DIPG-63. RE-IRRADIATION FOR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): THE SPANISH EXPERIENCE
Authors: Elena Panizo, Felisa Vazquez-Gomez, Marta Perez-Somarriba, Ofelia Cruz, Blanca Lopez-Ibor, Palma Solano, Blanca Martinez- De las Heras, Marta Cortés-Hernandez, Miguel Garcia-Ariza, Roberto Carlos Raynero-Mellado, Marta Martinez-Merino, Ana De Lucio, María Tallón, Carmen Garrido-Colino, Irene Ortiz-Gonzalez, Raquel Portugal, Maria Baro, Carmen Gonzalez-Sansegundo, Felipe Calvo, Alvaro Lassaletta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite advances in its biological understanding, current treatments for diffuse intrinsic pontine glioma (DIPG) have shown minimal impact on overall survival in this fatal disease. Radiotherapy (RT) is the only therapeutic intervention that has demonstrated efficacy in improving symptoms and prolonging progression-free survival. In addition, re-irradiation (rRT) is emerging as an alternative treatment for advanced disease, albeit palliative. This study presents the Spanish experience with re-irradiation in DIPG. METHODS We retrospectively reviewed demographic, clinical and RT data of patients with DIPG treated with rRT in Spain. RESULTS Between April 2015 and December 2023, 44 Pediatric patients with progressive DIPG underwent rRT in 16 Spanish institutions. Median time from diagnosis to progression was 10 months (range, 4.2-24.3). Median dose of rRT was 20 Gy (range, 18-40) in a median of 2 Gy fractions (range, 1.3-4). Twenty-one patients (47.7%) underwent additional treatments in addition to RT. Clinical and radiological improvements were observed in 77.3% and 60% of cases, respectively. Treatment was well tolerated with only 3 patients experiencing severe toxicity (one requiring a VP-shunt, and two finalizing rRT due to bronchoaspirations). Median overall survival was 15.1 months (range, 8.2-61.2), with a median time from rRT to death of 4.2 months (range, 0.6-10.3). Compared to patients who experienced earlier relapses, those who relapsed after 10 months exhibited superior overall survival (21.8 vs. 12.9 months; p &amp;lt; 0.001%), and a longer interval from rRT to death (6.2 vs. 3.8 months; p = 0.058). There was no survival benefit in patients receiving additional treatments. CONCLUSIONS rRT effectively improves symptoms and prolongs survival in many progressive DIPG patients. However, the ideal candidates for rRT remain undefined. The retrospective nature of the study makes it difficult to assess the true impact of additional treatments. We encourage prospective research into the combination of rRT with other therapies.