tbuckley/cabot-search huggingface dataset:
MDB-14. TREATMENT AND OUTCOMES OF MEDULLOBLASTOMA: FIRST REPORT FROM ARMENIA
Authors: Julieta Hoveyan, Samvel Bardakhchyan, Eduard Asatryan, Ruzanna Papyan, Saten Hovhannisyan, Henrik Grigoryan, Shushan Hovsepyan, Nara Lalazaryan, Paylak Sujyan, Armine Lazaryan, Armen Mkhitharyan, Lusine Hakobyan, Lilit Sargsyan, Samvel Sargsyan, Zeena Salman, Ibrahim Qaddoumi, Gevorg Tamamyan, Nisreen Amayiri, Simon Bailey
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma accounts for approximately 20% of all primary CNS tumors. Although advanced diagnostic tools and risk-adjusted treatment regimens produce a more than 70% five-year overall survival in HICs the data from LMICs is scarce. This study analyzed the outcome of children with medulloblastoma treated in Armenia. METHODS Demographic and treatment data was collected from medical records of pediatric and young adult patients (≤ 25 years) treated in four major centers in Armenia from 1995-2023. Event-free survival and overall survival were estimated using Kaplan-Meier method. RESULTS During the study period 41 patients with medulloblastoma were registered (20.7% of primary CNS tumors), male-to-female ratio 1.73:1. The median age at diagnosis was 8 years (range: 0.83-25 years). Most common presenting symptoms were nausea and vomiting (82.5%), headache (75%) and ataxia (50%). Metastatic status was evaluated (spinal MRI and CSF cytology) in 48.8% of patients (25% M+ disease). Risk assessment was available for 30 patients (12 standard-risk and 18 high-risk). All patients underwent surgery, gross-total or near-total resection was achieved in 53.7% of cases. Radiation therapy and chemotherapy given to 63.4% and 58.5% of cases, respectively. Of 8 infants included in this study 4 were treated with chemotherapy only, 3 died without further treatment. Median time from surgery to RT/chemotherapy was 6 weeks. Five-year EFS and OS were estimated 58.3% (95% CI 37.5-71%) and 62.5% (95% CI 43.75-77.1%), respectively. Patients with GTR/NTR had a higher OS than patients with STR (83.3% vs 33.3%, p=0.005). No statistically significant difference in EFS/OS was detected based on risk group, metastatic status, or completion of the protocol. CONCLUSIONS OS was lower than expected in this study. Accurate risk assessment and risk-stratified treatment were often lacking during the study period. Compliance to the standardized treatment protocols and multidisciplinary care are needed for improving outcomes of medulloblastoma.
MODL-11. LOW-GRADE GLIOMA 3D PATIENT-DERIVED ORGANOID PLATFORM AS TRANSFORMATIVE TOOL FOR TUMOR BIOLOGY AND TRANSLATIONAL RESEARCH
Authors: David R Beale, Alana Martinez Alonso, Valerie P Baubet, Mariarita Santi-Vicini, Angela Viaene, Peter Madsen, Mateusz P Koptyra, Phillip B Storm, Adam C Resnick
Journal: Neuro-Oncology (2024)

Abstract Unlike many high-grade tumors, low-grade glioma (LGG) has faced challenges in advancing scientific and clinical breakthroughs, affected by the limited capacity to develop representative preclinical tumor models. Major barriers to establishing traditional LGG cell culture systems have been cellular senescence and the need to introduce additional genetic modifications to obtain cultured growth. Such LGG models, while extremely valuable, require extensive periods for development and result in clonally selected lines which may not present the complexity of LGG tumor biology. To mitigate such challenges in LGG model development and address the need for three-dimensional tissue cultures, we have successfully generated organoids from fresh tissue specimens obtained from surgical resection. We have demonstrated success of this method on various pediatric brain tumor histologies and have expanded these approaches successfully to LGG. Through such efforts, we have developed 14 LGG tumors’ organoid models as well as other low-grade tumor’s models such as craniopharyngioma, schwannoma, meningioma, optic glioma, and oligodendroglioma. The tissue was processed immediately post-extraction and cultured in media solution on rotating platform. Organoid growth was observed within 1-3 weeks of initiation and tested for growth for up to 3 months. Phenotypic analysis revealed organoid cell composition representing clinical histology. The immune component was preserved in organoids for up to 40 days. MAPK pathway activity, a hallmark marker for KIAA-BRAF fusion positive pilocytic astrocytoma was preserved for up to 4 weeks. Our successful deployment of three-dimensional patient-tissue derived organoids provides for an efficient, simple workflow for the generation of unique and transformative preclinical models for the LGG field. Supported by the Children’s Brain Tumor network’s open science model, 3D organoids will provide investigations with broader resources for LGG tumor biology preclinical testing and support translational studies on behalf of the development of novel clinical trials.
MDB-18. SYNERGISTIC TARGETING OF CDK8 AND MTOR FOR MYC-DRIVEN MEDULLOBLASTOMA
Authors: Dong Wang, Caitlin Ritz, Yuhuan Luo, Bethany Veo, Angela Pierce, Rajeev Vibhakar
Journal: Neuro-Oncology (2024)

Abstract MYC-driven medulloblastoma represents a highly aggressive subgroup with poor prognosis and limited treatment options. CRISPR-Cas9 screening across MB cell lines revealed cyclin-dependent kinase 8 (CDK8) as a top dependency for MB growth. Loss of CDK8 significantly decreased both MYC expression and MB growth. Mechanistically, our RNA-Seq analysis demonstrated that CDK8 depletion suppressed ribosome biogenesis and mRNA translation. We found dual role of CDK8 in regulating protein synthesis. Firstly, CDK8-mediated phosphorylation of 4EBP1 was essential for initiating eIF4E-dependent translation and maintaining the typical function of medulloblastoma cells. Secondly, the inhibition of CDK8 led to a reduction in Pol II phosphorylation, resulting in the suppression of gene expression, particularly genes associated with ribosomal function. Targeting CDK8 effectively suppressed cancer stem and progenitor cells characterized by increased ribosome biogenesis activity. We revealed the synergistic effects of the combination inhibition of CDK8 and mTOR in MYC-driven MB cell lines and in xenograft models. Our findings suggest a promising therapeutic approach for MYC-driven MB by targeting CDK8 and mTOR to improve patient outcomes.
QOL-05. MEMANTINE FOR PREVENTION OF COGNITIVE LATE EFFECTS IN CHILDREN RECEIVING CRANIAL RADIATION THERAPY FOR FOCAL BRAIN TUMORS: A PILOT STUDY
Authors: Heather M Conklin, Raja B Khan, Jason M Ashford, Christina Owens, Andrea Simmons, Christina Bosley, Chia-Wei Hsu, Haitao Pan, Amar Gajjar, Thomas E Merchant
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Childhood brain tumor survivors treated with cranial irradiation are at significant risk for cognitive late effects that negatively impact quality of life. Memantine (an NMDA receptor antagonist), taken during radiotherapy for brain metastases in adults, resulted in reduced cognitive declines. This is the first investigation of feasibility, acceptability, and preliminary efficacy of memantine for reducing cognitive late effects in children undergoing radiation therapy. METHODS In a randomized, double-blind, controlled trial (MEMCRT; NCT03194906) children took memantine (20 mg/d) or placebo for 12 weeks. During the medication phase, participants received weekly phone calls to assess adherence using pill counts and monitor side effects using the SAFTEE structured interview. At baseline, 6 weeks (end of radiation therapy), and 12 weeks (end of medication), participants completed a brief battery of cognitive measures. RESULTS 30 patients (age at irradiation=11.93±2.87; 47% male) were included; memantine (n=16) and placebo (n=14) groups did not differ in age, sex, race, socioeconomic status or baseline IQ (ps&amp;gt;.26). Study participation (71% of those approached) and medication adherence (88% completed 12 weeks, with 97% of medication taken) were high. Side effects were minimal (only one CTCAE≥ 3; headache in the placebo group) with no difference between groups in change in side effect severity from baseline to any medication week, across any symptom inquiry (ps&amp;gt;.23). At 12 weeks, Cohen’s d effect sizes (ES) indicate the memantine group had better performance on measures of processing speed (Cogstate Identification ES=.61), academic fluency (Woodcock Johnson-IV Reading Fluency ES=.45; Math Fluency ES=.81), and fatigue (PedsQL Multidimensional Fatigue Scale ES=.72). CONCLUSIONS Study findings indicate memantine used as a neuroprotectant during radiation therapy for children with focal brain tumors is feasible and acceptable, with preliminary evidence for better cognitive outcomes that require validation in a larger, definitive trial.
LGG-50. POOR RESPONSE TO MEKI RE-INITIATION IN PEDIATRIC LOW-GRADE GLIOMA AFTER TREATMENT DISCONTINUATION. A PLGG TASKFORCE STUDY
Authors: Inci Yaman Bajin, Robert Siddaway, Adrian Levine, Tara McKeown, Liana Nobre, Anirban Das, Julie Bennett, Vijay Ramaswamy, Annie Huang, Eric Bouffet, Lucie Lafay-Cousin, Dong Anh Khuong Quang, Jordan Hansford, Revathi Rajagopal, Nicholas G Gottardo, Rachel Rowe, Jordann Dutton, Amanda Li, Sheila McThenia, Jason Fangusaro, Sébastien Perreault, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGG) exhibit dramatic objective response to treatment with MEKi (Mitogen-Activated Protein Kinase inhibitors). Although the initial response to MEKi is promising, it is unknown whether it is safe to stop MEKi therapy and if the response to re-initiating MEKi would have the same impact. The study objective was to compare the first and second response to MEKi in patients with pLGG who stopped therapy and had further tumor progression. METHODS PLGG identified at neurooncology centers in Canada, Australia, and US, which were treated twice with MEKi were included. Second therapy was defined as MEKi upon progression for tumors where treatment was stopped. Response to MEKi between 2 treatments (MEKi1, MEKi2) were analyzed by using RANO criteria. RESULTS Mature data on 19 patients reveals a median patient age of 13 years (range 7–24), and the most common tumor location is hypothalamic/chiasmatic (89%). PLGG alterations include KIAA1549:BRAF fusion in 69%, NF1 in 21%, and other alterations in 10%. The overall response (minor and partial) to MEKi1 was 63% compared to 26% in MEKi2 (p=0.04). Furthermore, upon restarting MEKi2, 11% had further growth on therapy in contrast to none at MEKi1. MEKi1 resulted in average of 37% size decrease (range, 3%-98%), including 6 PLGG with over 50% response. In contrast, the average decrease to MEKi2 was 10% (range, 6%-40%, p=0.005), and none had &amp;gt;50% size reduction. Comparing each patient MEKi1 to MEKi2 revealed that initial response was superior to the second one in all PLGG. CONCLUSION These data suggest that the second response to MEKi is inferior when compared to initial therapy. Expansion of this cohort and biomarker correlates are ongoing. Biological insights are required for this observation, and careful consideration should be made for stopping MEKi, especially in strategic locations such as the optic pathway.
ETMR-30. CLINICAL AND MOLECULAR CHARACTERIZATION OF<i>DICER</i>-MUTANT CENTRAL NERVOUS SYSTEM SARCOMA
Authors: Alexis Dowiak*, Lane Williamson*, Julija Povilaikaite*, Edgar Cabrera, Nelson Aponte, Johnny Garcia, Lina Quiroz, Martha Piña, Cindy Martinez, Diana Valencia, Liliana Barragan, Alma Benito Reséndiz, Henriette Magelssen, Ángela Trujillo, Diana Osorio, Oscar Figueredo, Roger Packer, Isabel Sarmiento, Amaranto Suarez, Naureen Mushtaq, Zied Abdullaev, Dipak Poria, Ute Bartels, Eric Bouffett, Barbara Rivera Polo, Kenneth Aldape, Vijay Ramaswamy, Adriana Fonseca
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Central nervous system (CNS) sarcomas are rare mesenchymal non-meningothelial tumors accounting for 0.2% of brain tumors. Due to their rarity, there is a lack of substantive clinical, histological and molecular data. METHODS Patients diagnosed with primary CNS sarcomas were identified through several international collaborations. DNA methylation profiles were generated using 850K microarray assays, followed by unsupervised hierarchical clustering and t-SNE analyses. Additionally, targeted DNA sequencing was employed to characterize the somatic landscape. Clinical data was collected and summarized using descriptive statistics, and survival estimates were calculated using the Kaplan-Meier method. RESULTS We analyzed DNA methylation data of 65 tumor samples. Clustering analyses demonstrated DICER-1 CNS sarcomas segregate into two distinct epigenetic subgroups. Copy number analysis demonstrated frequent CNV alterations and chromothripsis in 35% of the samples. DICER-1 mutations were present in 85% of cases and associated with frequent additional alterations in TP53 (65%) and KRAS (51%). The median age at diagnosis was 10.4 years (r: 0.4 - 71 y) and 52% (n=34) of subjects were male. Tumors were frequently (91%) located in the supratentorial compartment, frontal lobe involvement was noted in 62% of cases. Patients were treated with multimodal approaches including surgery, ICE chemotherapy, and focal radiation. At median follow-up time of 27.5 months, the 2-year progression-free and overall survival was 50.8% (r: 0.31-0.67) and 53.5% (r: 0.34-0.69) respectively. CONCLUSIONS DICER-1 CNS Sarcoma is an aggressive entity that segregates into two epigenetic subgroups, clinical and genotype correlations remain to be elucidated. Current multimodal approaches are only effective in a subset of patients. The identification of MAPK pathway alterations in most cases should be explored as a therapeutic avenue.
MODL-10. COMPUTATIONAL DRUG SENSITIVITY PREDICTS TAILORED THERAPY FOR MEDULLOBLASTOMA SUBGROUPS
Authors: Anna M Jermakowicz, Luz Ruiz, Robert Suter, Nagi Ayad
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most common malignant pediatric brain tumor. Tumors are typically characterized as SHH α- δ, WNT α-β, Group 3α- γ, or Group 4 α- γ. Current standard-of-care includes surgery, radiation, and chemotherapy; however, treatment response and prognosis vary widely between subgroups. Despite extensive characterization of medulloblastoma tumors into four molecular subgroups, few subgroup specific therapies have advanced to the clinic and a universal approach is unlikely to be effective due to the considerable intertumor heterogeneity of medulloblastoma. Hence, there is an urgent demand for innovative therapeutic strategies. METHODS To address heterogeneity between patients, we have developed a novel platform called DrugSeq, which predicts drug sensitivities in patients and is able to stratify drug response based on subgroup. We first calculated disease signatures for each patient by normalizing patient gene expression to median gene expression across the Cavalli dataset. Using previously developed transcriptional consensus signatures (TCSs), which contain genes that are consistently dysregulated following drug treatment, we then calculated the discordance between each patient disease signature and drug TCS. In doing so, we were able to identify drugs to target specific molecular subtypes based on Cavalli molecular classifications. RESULTS As a proof of concept we identified vismodegib and curcumin as selective for SHH-MB. Furthermore, we correlated predicted drug response with target protein expression. For example, we found that predicted sensitivity to vismodegib correlates closely with GLI1 protein expression. CONCLUSIONS Collectively, we show that DrugSeq may identify novel therapies and facilitate patient stratification in clinical trials, leading to more successful targeted medulloblastoma therapies.
IMG-24. MAPK-ALTERED PEDIATRIC LOW-GRADE GLIOMA: MRI HINTS TO EXPLAIN THE INTERPLAY BETWEEN GLIOMA AND IMMUNE CELLS
Authors: Antonia Ramaglia, Gianluca Piccolo, Marta Molteni, Claudia Mercuri, Gabriele Gaggero, Patrizia De Marco, Marco Pavanello, Andrea Rossi, Maria Luisa Garrè, Claudia Milanaccio, Antonio Verrico
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In MAPK-altered pediatric low-grade glioma (pLGG), immune infiltration may be involved in treatment response. It is debated whether tumor immune cell infiltration is due to expansion of endogenous resident microglia or to the active recruitment of bone marrow-derived microglial progenitors from the bloodstream. This study aimed to investigate the relation between neuroradiological features of MAPK-altered pLGG and treatment response to MAPK-inhibitors (MAPKi). METHODS We conducted a retrospective analysis of all patients with unresectable BRAF-V600E mutated brain pLGG, radiotherapy naïve, treated with MAPKi at our institution since 2015. MRI studies were reviewed by two experienced neuroradiologist and tumor response assessed according to RAPNO criteria. RESULTS 12 patients were enrolled (9 female). Median age at treatment start was 6.2 years (range 2.7–14.3 years). Four were pilocytic astrocytomas, 6 gangliogliomas, and 2 desmoplastic infantile gangliogliomas. Five patients received MAPKi as first line, 7 following other chemotherapy lines. Median follow-up was 4.1 years (range 2.5–8.7 years). Tumor response was associated with contrast enhancement (CE): 9 out of 10 patients with CE at treatment onset had at least partial response and subsequent CE resolution, while both 2 out of 2 patients without CE showed stable disease. A 4-year old contrast enhancing-ganglioglioma who reached partial response and CE resolution with MAPKi, presented disease progression four days after treatment withdrawal; treatment re-start determined tumor and CE reduction after only 7 days. CONCLUSIONS We hypothesize that brain-blood barrier breakage is induced by tumor infiltration of bloodstream immune cells, and that this trafficking is stimulated by tumor cell secreted products and determined by microglial progenitors shift from the bloodstream to the tumor site. MAPKi treatment may incite blood-brain barrier reconstitution as it reduces the trafficking between tumor site and bloodstream. ACKNOWLEDGEMENT This work was supported by grant number NET-2018-12366666 NeuroArtP3 from the Italian Ministry of Health.
ETMR-24. SOX2 INFLUENCES IDENTITY OF GLIA-LIKE PROGENITORS AND TUMORIGENESIS IN CHOROID PLEXUS THROUGH LIM HOMEODOMAIN TRANSCRIPTION FACTORS
Authors: Lukas Faltings, Mariam Zahran, Heena Jalili, Kristen Green, James Virga, Siddhi Modi, Navjot Guru, Ping Cao, Haotian Zhao
Journal: Neuro-Oncology (2024)

Abstract Choroid plexus (CP) tumors encompass a spectrum of rare brain neoplasms ranging from benign papilloma (CPP) to aggressive carcinoma (CPC) that collectively affect the pediatric population. Poor outcomes for high-grade lesions and side effects of current treatment paradigms underscore a critical need to develop safer and more efficacious therapies guided by biological understanding of these tumors. We developed mouse models from common molecular defects found in human disease. These models exploit sustained NOTCH signaling activation in the hindbrain upper rhombic lip to generate CPP and CPC. To delineate cellular composition of CP tumors, we conducted snRNA-seq in murine CP tumors. Similar to adult CP, cells in NOTCH-driven CPP partitioned into clusters identified as epithelial, mesenchymal, endothelial, immune, neuronal, and glial cells. Though tumor cells are confined to epithelial compartment based on inferCNV analysis of snRNA-seq data, they are derived from glia-like progenitors. Tumor cells are in a distinct differentiation state characterized by a lack of epithelial maturation, and aberrant expression of markers of neural progenitor/stem-like cells including SRY-Box Transcription Factor 2 (SOX2). Consistently, SOX2 inactivation decreased tumor cell proliferation and blocked NOTCH-driven CP tumor formation. ChIP-seq studies revealed SOX2 binding to promoters of LIM homeodomain transcription factors Lmx1a and Lmx1b. Enforced SOX2 expression activated the expression Lmx1a and Lmx1b, whereas Sox2 loss reduced their expressions in tumor cells. Importantly, knockdown of Lmx1a or Lmx1b decreased tumor cell proliferation, whereas overexpression of Lmx1a/b rescued proliferation of tumor cells subjected to SOX2 suppression. Contextualizing these results in CP development, SOX2 critically maintains progenitor cell identity through regulating Lmx1a/b expression in the rhombic lip. Finally, analysis of human CP tumor samples revealed abnormal expressions of SOX2 and LMX1A. Together, these results indicate that oncogenic signaling subverts SOX2 transcriptional programs that specify normal progenitor identity and lock tumor cells in unique differentiation state to facilitate CP tumor growth.
DIPG-81. PHASE IB CLINICAL TRIAL ASSESSING SAFETY, TOLERABILITY, AND PRELIMINARY EFFICACY OF ALOCELYVIR (ALLOGENEIC MESENCHYMAL CELLS + ONCOLYTIC ADENOVIRUS) COMBINED WITH RADIOTHERAPY IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Alvaro Lassaletta, Felisa Vazquez-Gomez, Alba Rubio, Jose Luis Moreno-Carrasco, Carmen Gonzalez Sansegundo, Africa Gonzalez-Murillo, Beatriz Horcajo-Morera, Francisco Bautista, Gonzalo Garcia-Aguilera, Ana Castillo, Ines Solís, Pedro Borrego, Anna Llort, Serafin Castellano, Marta Perez-Somarriba, Miguel Garcia-Ariza, Ana Galera, Kishore Melwani, Hyaissa Ippolito, Belen Rivero, Gustavo Melen, Javier Garcia-Castro, Manuel Ramirez
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite recent advances in our understanding of biology, pediatric patients diagnosed with diffuse intrinsic pontine glioma (DIPG) still face a bleak prognosis. In recent years, oncolytic adenovirus therapy has emerged as a promising approach in cancer treatment. METHODS We conducted a phase Ib clinical trial in patients newly diagnosed with DIPG, utilizing ALOCELYVIR, an advanced therapy medicine that combines allogeneic mesenchymal stem cells carrying an oncolytic adenovirus. ALOCELYVIR was administered as weekly intravenously infusions from the first week of radiation for 8 doses, at a dose of 0.5x106 cells/kg/dose. The primary objective was to assess the safety of combining ALOCELYVIR with radiotherapy in patients with newly diagnosed DIPG. PCR analysis of adenovirus in plasma, anti-adenovirus type 5 antibodies, and immune reconstitution were analyzed. RESULTS A total of 6 patients, aged 5 to 15 years, were recruited. Four patients underwent biopsy, confirming an H3K27-mutated DIPG. All patients except one completed the trial; this patient progressed during radiotherapy, and after the fifth dose of ALOCELYVIR. Adenovirus replication in plasma was observed in four patients. Median OS was 11.5 months (range, 3-25), and median PFS was 7.5 months (range, 2-13). One patient is still alive 25 months after diagnosis. Adverse events among patients were all mild, including fever, asthenia, vomiting, headache, and myalgias, all grade I. Clinical and radiological pseudoprogression were documented in four patients, necessitating the addition of steroids +/- bevacizumab as anti-inflammatory treatment. CONCLUSIONS Our phase Ib clinical trial demonstrates the feasibility and safety of combining ALOCELYVIR with radiotherapy in pediatric patients newly diagnosed with DIPG. Furthermore, the manageable adverse event profile observed underscores the potential of ALOCELYVIR as a therapeutic option for DIPG. These findings warrant further investigation through larger clinical trials to elucidate the full therapeutic potential of ALOCELYVIR in improving outcomes for pediatric patients with DIPG.