tbuckley/cabot-search huggingface dataset:
IMMU-14. MULTI-INSTITUTION ANALYSIS OF TREATMENT MATCHING STATUS AND OUTCOMES IN PEDIATRIC CNS TUMOR PATIENTS
Authors: Emma J Horowitz, Rose Parisi, Gavrielle Rood, Acacia Bowden, David Byrwa, Roshal Patel, George Turco, David Korones, Jeffrey Andolina, Melanie Comito, Matthew Barth, Lauren Weintraub
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND With the advent of immunotherapies and targeted therapies, research is needed to assess how pediatric brain tumor genomic biomarkers may impact treatment modality choice and outcomes. METHODS We conducted a retrospective analysis of 160 pediatric patients (78 male, 82 female) with a median age of 9 years (2 months-26 years) diagnosed with a primary CNS tumor at four academic institutions from 2008-2023. Tumor mutational burden (TMB), treatment type, outcomes, and matching status were analyzed. Matching status refers to the presence of tumor genomic markers that matched with the pharmacologic target. RESULTS Low-grade glioma (N=68, 42.5%) and high-grade glioma (N=36, 22.5%) were the most common tumors. Other tumors included medulloblastoma (N=17, 10.6%), atypical teratoid rhabdoid tumor (N=4, 2.5%), ependymoma (N=8, 5%), ganglioglioma (N=7, 4.4%), other embryonal tumors (N=5, 3.1%), and choroid plexus tumors (N=5, 3.1%). Of the patients who received targeted or immunotherapy (N=30), most patients had matched (N=19) versus unmatched therapy (N=11) and similar survival rates (p=0.44). Although not statistically significant (p=0.065), patients who received standard therapy had higher overall survival rates (N=103/130) compared to those receiving targeted or immunotherapy (N=19/30). When comparing only patients with high TMB tumors (≥3 mutations/megabase), patients were significantly more likely to survive when receiving standard therapy only (N=20/33) versus targeted or immunotherapy (N=1/7) (p=0.026). Notably, targeted and immunotherapy were not used upfront in these cases. Among patients who had progressed or recurrent disease specifically, there was a non-statistically significant trend towards better survival rates for those who received targeted or immunotherapy (p=0.46). CONCLUSIONS Patients with high TMB tumors who received targeted or immunotherapy have worse outcomes than patients with low TMB, or with high TMB receiving standard therapy. High TMB tumors often require therapy for relapsed/refractory disease. These findings are critical for identifying patient subsets in need of alternative treatment options.
DIPG-82. RADIOSENSITIZATION WITH RAD52 INHIBITION IN DIFFUSE MIDLINE GLIOMA
Authors: Eita Uchida, Yukitomo Ishi, Jun Watanabe, Hiam Abdala-Valencia, Benjamin Singer, Samantha Gadd, Rintaro Hashizume
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG) is one of the most devastating childhood cancers that limited response to radiation therapy (RT). There is a critical need for new therapeutics that enhance the radiation effect. We, therefore, tested the hypothesis that targeting RAD52 activity sensitizes the radiation response of DMG. METHODS Genome-wide CRISPR/Cas9 screening was performed to identify the potential therapeutic target. RAD52 inhibition was used by shRNA-mediated RAD52 depletion and treatment with RAD52 inhibitor, D-I03. The protein expression, cell proliferation, DNA damage marker expression, DNA repair pathway, and transcriptional alteration were analyzed by western blotting, MTS assay, colony formation assay, immunocytochemistry, DNA repair pathway assay, and RNA sequencing. Mice with DMG patient-derived xenograft (PDX) models were treated with RAD52 inhibitor alone or combination with RT. RESULTS Genome-wide CRISPR/Cas9 screening identified RAD52 as a potential therapeutic target in DMG cells. RAD52 inhibition suppressed DMG cell proliferation. Importantly, RAD52 inhibition in combination with RT further increased the radiosensitivity of DMG cells. Immunocytochemistry of DNA double-strand breaks (DSB) marker γH2AX and repair marker 53BP1 showed that RAD52 inhibition sustained DNA damage with high levels of γH2AX at 24 hours following radiation while the level of 53BPI was decreased, thereby inhibiting DNA DSB repair. Western blotting also revealed that RAD52 inhibition causes a sustained level of phosphorylated Rad50 and γH2AX in irradiated DIPG cells over 24 hours. DNA repair assay showed that RAD52 inhibition suppressed homologous recombination DNA repair pathway. RNA sequencing showed that RAD52 inhibition downregulated genes associated with the DNA repair pathway. Finally, the combination therapy of RAD52 inhibitor and RT further suppressed tumor growth and increased survival of mice bearing DMG PDXs, outperforming either monotherapy. CONCLUSIONS these results highlight RAD52 inhibition as a potential radiosensitization and provide a rationale for developing combination therapy with radiation in the treatment of DMG.
GCT-14. TREATMENT APPROACH FOR METASTATIC INTRACRANIAL GERMINOMA: A MULTI-INSTITUTIONAL EXPERIENCE
Authors: Phoebe C Power^, Kevin X Liu^, Susan N Chi, Karen D Wright, Karen J Marcus, Daphne A Haas-Kogan, David Ebb, Torunn I Yock, Shannon M MacDonald*, Kee Kiat Yeo*
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Germinoma is the most common CNS germ cell tumor in children. Treatment with 24Gy craniospinal irradiation (CSI) with boost to 40Gy alone results in excellent survival irrespective of disease stage. For localized germinoma, recent studies have demonstrated the efficacy of neoadjuvant chemotherapy in decreasing the field/dose of radiation therapy (RT) needed for cure. For metastatic germinoma however, the optimal RT approach when combined with chemotherapy is unclear. Herein, we present our experience in treating patients with metastatic germinoma. METHODS We performed a retrospective, IRB-approved study of patients with metastatic germinoma diagnosed between 2001-2023 at Boston Children’s Hospital, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Mass General Hospital. Clinical features, treatment plan, and outcomes were collected and analyzed using the Kaplan-Meier method and Fisher’s exact test. RESULTS Twenty-eight patients with metastatic germinoma were identified. Median age at diagnosis was 15.9 years (range:6.2-25.9). Metastasis was intracranial in 20, craniospinal in three and CSF-only in five patients. Six patients received CSI only. Twenty-two patients received neoadjuvant chemotherapy and CSI. Median number of chemotherapy cycles was 4 (range:3-6). Seventeen patients had complete response, four patients had partial response, and one patient had progressive disease with chemotherapy. All patients went on to receive CSI, with median dose of 21Gy (range:18-36Gy) with median IF boost to 36Gy (range:30-51.6Gy). Median duration of follow-up was 11 years (range:0.3-25.3). There were no recurrences or deaths within the cohort. Analysis of long-term outcomes data revealed no significant differences in frequency of endocrinopathies, CNS vasculopathies, or memory loss between the doses of RT. CONCLUSIONS Our data show that neoadjuvant chemotherapy followed by CSI is associated with excellent overall survival in patients with metastatic germinoma. Importantly, our experience suggests that in combination with neoadjuvant chemotherapy, 21Gy CSI may be sufficient as a curative dose in this patient population.
OTHR-28. SUCCESS AND IMPACT IN 5 YEARS OF POST-MORTEM BRAIN TUMOR TISSUE PROGRAM: GIFT FROM A CHILD
Authors: Nicole Lyons, Javad Nazarian, Augustine Eze, Niku Nourmohammadi, Mateusz Koptyra, Adam Resnick, Jane Minturn, Beth Frenkel, Sonora Reingruber, Angela Waanders, Miriam Bornhorst, Melissa Williams, Michelle Monje-Deisseroth, Jared Hysinger, Ann-Helen Liljensten, Mark Souweidane, Jeffrey Greenfield, Cindy Campbell, Christopher Padilla, Amy Smith, Sydney Peck, Nick Vitanza, Sarah Leary, Jeff Stevens
Journal: Neuro-Oncology (2024)

Abstract The Gift From A Child post-mortem brain tumor tissue donation program was developed with patient families, care teams, and researchers to ensure patients can choose to donate brain tumor tissue regardless of logistics and circumstances. In the past 5 years, the program has developed a network of 7 Research Centers of Excellence (RCOE) that work with over 75 referring institutions, non-profit foundations, patient communities, and consortiums. Since the institution of this program, there has been an increase in the total number of donations. External donations also continue to grow as awareness builds, independent of new RCOEs joining the network. Program success is demonstrated by the increasing percentage of external donations and the number of new referral institutions each year. There has also been an overall increase in both total and percentage of donations from external referral sources, with an increasing majority of donations being external. From 2019 to 2023, the total number of external donations has jumped from 45 to 89 per year, reflecting an increase from 42% to 65% of the total donations. The referrals for external donations come from the treating neuro-oncology and general care teams, self-referrals from patient families directly, and from the patient family community on behalf of current patients. Resources are accessible via a 1-800 number, the GFAC website, and calls directly to RCOE or the GFAC team. Overcoming institutional and other logistical barriers ensures that all patients have access to GFAC. Patients who would otherwise be unable to donate are now represented in research that informs future treatments, leading to pre-clinical research that better represents the actual patient population. All data from donations via GFAC is shared with CBTN to ensure open access. This has led to an increase in successful projects and cell lines developed from the donated tissue.
MDB-109. CHARACTERIZING DISTINCT SIGNATURES OF RNA TRANSLATIONAL REGULATION UPON MYC OVEREXPRESSION IN H9 NEURAL STEM CELLS
Authors: Anwesha Dasgupta, Ian Yanuzzi, Jorge Ruiz-Orera, John R Prensner
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB), a childhood brain tumor, emerges typically between 6-8 years, originating from cerebellar neuronal stem cells. Recurrent genetic alterations, notably MYC amplifications, are associated with poor therapy response. Subgrouped as WNT-MB, SHH-MB, Group 3 MB, and Group 4 MB, Group 3 MB is characterized by high-level MYC amplification in approximately 17% of cases. Patients with Group 3 MB and MYC activation present distinct transcriptional and proteomic signatures, including elevated levels of ribosomal proteins and ribosome assembly proteins. METHODS We conducted a comprehensive analysis of RNA-seq and Ribo-seq in human neural stem cells (H9 NSCs) with amplified MYC expression. H9-NSCs were cultured in tumor stem media and transduced with lentivirus for either GFP control or MYC cDNA. RNA and ribosome-protected fragments were isolated from cell lysates for RNA-seq and Ribo-seq in biological triplicates. Ribo-seq data was analyzed using ORFquant for coding sequence quantification and deltaTE for translational efficiency. RESULTS Overexpressing MYC in H9-NSCs led to significant differential expression of 4194 genes (p adj &amp;lt; 0.05) using RNA-seq and 2860 genes (p adj &amp;lt; 0.05) using Ribo-seq. While RNA-seq and Ribo-seq exhibited high correlation for most genes, we identified 364 differentially translated genes (p adj &amp;lt; 0.05) upon MYC overexpression. Genes regulated solely at the translational level were enriched for functions in cytoplasmic translation initiation, viral translation, and response to interleukin-4. Key genes highly regulated at the Ribo-seq level included CCND3, YBX1, and EEF2. Validating with proteomics data from the CPTAC medulloblastoma tissue set confirmed protein-specific upregulation of these targets in MYC-driven Group 3 medulloblastomas. CONCLUSIONS MYC overexpression revealed distinct behaviors in differentially expressed genes, either regulated at the level of translation alone, correlated with transcription, or independent of transcription. We anticipate that our findings will contribute to a refined understanding of the molecular landscape of MB, particularly in the context of Group 3 MB.
ETMR-26. MIR-34/449 FAMILY PLAYS A CRUCIAL ROLE IN CHOROID PLEXUS MULTICILIATION AND TUMORIGENESIS
Authors: Navjot Guru, Ahnaf Zaman, Maheen Umer, Mariam Zahran, Anjali Siluveru, Lukas Faltings, James Virga, Andrew Attia, Ping Cao, Haotian Zhao
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Choroid plexus (CP), an epithelial structure within the brain ventricles, produces cerebrospinal fluid and serves barrier functions in the brain. Primary CP neoplasms are rare intracranial tumors that predominantly occurs in childhood. Recent studies revealed multiciliated cells in the CP in humans and mice. In contrast, benign CP papilloma, and malignant CP carcinoma (CPC) in humans are characterized by solitary cilia, and disturbances to multiciliation program directed by transcription factor GMNC. Additionally, most CPC in humans carry mutations in TP53 tumor suppressor. Consistently, Trp53-deficient CPC in mice display singular cilia consequent to defects in GMNC multiciliation program. Thus, the impairment of multiciliation enables tumor cell proliferation. MicroRNAs (miRNAs) are non-coding small RNAs with gene regulatory functions. Specifically, the mir-34/449 family comprises of six miRNAs collaborate to influence multiciliation in diverse tissues but role of mir-34/449 family in the brain is poorly understood. Knowledge of multiciliation program regulation may provide crucial insights into tumor suppression mechanisms in CPC. METHODS To investigate the role of mir-34/449 family in the CP, human CP organoid and mir-34/449 mutant animals were used. RNAscope, In situ hybridization as well as immunofluorescence staining was utilized to identify gene expression in tissues. RESULTS Preliminary studies revealed GMNC program activity and multiciliated cells in CP organoid derived from human induced pluripotent stem cells. Disruption of the mir-34/449 family led to supernumerary cilia and ectopic multiciliation program activity in the CP. Importantly, Trp53-deficient CPC exhibited distinct expression of the mir-34/449 family. Further, sequencing studies revealed an overlap of differentially expressed miRNAs in CP tumors in humans and mice, with an enrichment of the mir-34/449 family. CONCLUSIONS Together, these findings indicate that the mir-34/449 family regulates multiciliation in the CP, whereas the study of its interactions with the multiciliation program holds the key to understanding multiciliation as a tumor suppression pathway in CPC.
IMMU-10. DEVELOPING NOVEL CHIMERIC ANTIGEN RECEPTOR THERAPIES FOR PAEDIATRIC HIGH GRADE GLIOMA
Authors: Alexander J Davenport, Leesa Lertsumitkul, Ryan S Cross, Misty R Jenkins
Journal: Neuro-Oncology (2024)

Abstract Paediatric high-grade gliomas (pHGG), particularly Diffuse Midline Glioma (DMG), present a formidable challenge in oncology. Due to the aggressive biology and location of pHGGs the implementation of adult treatment modalities (surgery, chemotherapy, and radiotherapy) is severely limited resulting in pHGG remaining a terminal disease. Thus, there is a pressing and urgent unmet clinical need for the development of innovative therapeutics. We will demonstrate the identification of cell surface targets using mass spectrometry proteomics. We have developed novel binders and engineered them into second-generation CAR T cells. We will present pre-clinical in vivo intracranial mouse models examining the efficacy of novel CAR T cell therapies. We have recently reported effective CART cell targeting of HER2 in DMG, and presently we will also demonstrate superior efficacy of additional CAR T cell targeting, both in vitro and in vivo in preclinical PDX models of DMG. We will present new data that CAR T cells targeting EphA3 show curative efficacy in pre-clinical models of DMG. Recognising that single targeting CAR T cells are unlikely to provide long-term clinical benefit, we will also present our combination approaches using CAR T cells targeting antigens such as GD2, EGFR, HER2, EphA3, CD276 and CD63. We are expanding our research to other CAR T combination strategies focusing on immune-modulating drugs such as checkpoint inhibitors or co-stimulatory agonists. We are committed to advancing CAR T cell therapies for pHGG patients and their families with an aim to aid in the development of much-needed new therapeutic options.
EPEN-14. MOLECULAR MARKERS AND PREDICTORS OF OUTCOME FOR PAEDIATRIC INTRACRANIAL EPENDYMOMA IN THE PROSPECTIVE, MULTICENTRE E-HIT2000 TRIAL AND SUBSEQUENT HIT-REGISTRIES: A POOLED ANALYSIS OF 244 PATIENTS
Authors: David R Ghasemi, Katja von Hoff, Denise Obrecht-Sturm, Janna Wenning, Martin Mynarek, Nicolas U Gerber, Martin Benesch, Björn O Juhnke, Brigitte Bison, Monika Warmuth-Metz, Beate Timmermann, Andreas Faldum, Gudrun Fleischhack, Michael Grotzer, Pablo Hernáiz Driever, Andreas Beilken, Martin Ebinger, Norbert Graf, Michael Frühwald, Irene Schmid, Arend Koch, Markus Bergmann, Christian Hagel, Roland Coras, Ingmar Blümcke, Guido Reifenberger, Jörg Felsberg, Kathy Keyvani, Patrick N Harter, Marco Prinz, Ori Staszewski, Till Acker, Wolfgang Brück, Christian Hartmann, Andreas von Deimling, Clemens Sommer, Martin Hasselblatt, Markus J Riemenschneider, Camelia-Maria Monoranu, Elisabeth Rushing, Marcel Kool, Stefan M Pfister, Ulrich Schüller, Torsten Pietsch, Rolf D Kortmann, Robert Kwiecien, Hendrik Witt, Kristian W Pajtler, Stefan Rutkowski
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Throughout the past decade, molecular tools have revolutionised ependymoma classification, yet their application has been limited in clinical trial cohorts. METHODS We present the molecular analysis of paediatric ependymoma patients from the E-HIT2000 trial (n = 165), or subsequent HIT2000-interim and I-HIT-MED registries (n = 79) based on DNA-methylation profiling with multi-level classification using the Heidelberg Brain Tumor Classifier v12.5 and the analysis of chromosome 1q, 6q, and CDKN2A copy number status. Prior to further analysis, cases without ependymoma group prediction were excluded (n = 16/244). RESULTS 5-year PFS and OS rates varied by group: EPN-PFA (n=146/228) 45±4% and 76±4%; EPN-PFB (n=19/228) 90±7% and 100%; EPN-ZFTA (n=59/228) 63±7% and 87±5%; and EPN-YAP1 (n=4/228) 50±25% and 100%. EPN-PFA was subclassified into nine subtypes. Poor median PFS was observed for PFA1c (n=22, 5-yr-PFS 32±10%/5-yr-OS 77±9%), PFA1d (n=13, 35±14%/72±14%), PFA1e (n=15, 47±13%/59±13%), and PFA2a (n=16, 27±12%/50±14%). Presence of 1q gain was associated with inferior survival (n = 39/146, 29±8%/65±8%). 6q loss impacted PFS, but not OS (n=8, 25±14%/100%). Among 59 EPN-ZFTA cases, 46 clustered with EPN ZFTA-RELA fused, and 12 clustered within recently described subgroups of EPN-ZFTA (EPN-ZFTA alt., Cluster 1: 1/12, Cluster 2: 11/12). Strikingly, 6/11 EPN ZFTA-alt. (Cluster 2) cases showed infratentorial (4/6) or supratentorial midline location (2/6). Homozygous deletion of CDKN2A (CDKN2A-/-; n=8) was only observed in EPN ZFTA-RELA. Presence of EPN ZFTA-alt. (cluster 2) (5-yr-PFS: 36±15%; p&amp;lt;0.001), and CDKN2A-/- (19±16%; p&amp;lt;0.0001) was associated with inferior PFS compared to EPN ZFTA-RELA CDKN2A-wt (81±6%). OS was only impacted for patients with EPN ZFTA-RELA CDKN2A-/- (5-yr-OS: 38±20%, p&amp;gt;0.0001). CONCLUSIONS We present strong evidence supporting the inclusion of molecular criteria into the next generation of clinical trials for children with ependymoma.
HGG-18. ONC201 COMBINED WITH THE ONCOLYTIC ADENOVIRUS DELTA-24-RGD AS A NEW THERAPEUTIC REGIME FOR PEDIATRIC HIGH-GRADE AND DIFFUSE MIDLINE GLIOMAS
Authors: Daniel de la Nava, Iker Ausejo-Mauleon, Javad Nazarian, Sabine Mueller, Joshua E Allen, Carl Koschmann, Sriram Venneti, Matthew D Dun, Candelaria Gomez-Manzano, Juan Fueyo, Ana Patiño-Garcia, Marta M Alonso
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric high-grade (pHGGs) and diffuse midline gliomas (DMGs) patients have the worst survival rates in childhood cancer. The oncolytic adenovirus Delta-24-RGD and the imipridone ONC201 are two of the most promising therapeutic agents in the field, having demonstrated safety and effectiveness in clinical trials. Therefore, we evaluated whether the Delta-24-RGD/ONC201 combination could increase the therapeutic benefit in pHGGs and DMGs. METHODS A battery of human pHGG, DMG, and murine DMG cell lines was used for the study. Viral replication was assessed by hexon titration. Characterization of combination response was assessed by MTS, RNAseq, Seahorse, and immunofluorescence. In vivo experiments were performed to assess the efficacy of the proposed combination. The tumor microenvironment infiltration was evaluated by flow cytometry. RESULTS ONC201 cotreatment with Delta-24-RGD did not affect the virus replication capability in vitro. Cytotoxicity studies showed that cotreatment was either synergistic or additive. Importantly, cells treated with the combination maintain the mitochondrial damage caused by ONC201, showed a significant reduction of IGF1/IGF1R and PDGF pathways, and increased nuclear DNA damage. Remarkably, Delta-24-RGD/ONC201 treatment in human pHGG and DMG xenograft-bearing mice showed a safe toxicity profile and a significant increase in the median overall survival compared to each agent alone. Combination treatment in murine DMG models revealed a reshaping of the tumor microenvironment towards a proinflammatory phenotype. We observed an increase in both lymphoid and myeloid lineage in the combined treatment versus either single treatment. Interestingly, Delta-24-RGD/ONC201 produces a higher activation in CD8+ T cells, higher activation and proliferation in CD4+ T cells, and less immunosuppressed regulatory T cells. CONCLUSIONS Our data supports that the Delta-24-RGD/ONC201 combination improved the efficacy compared to each agent alone by potentiating nuclear DNA damage and improving the antitumor (immune) response. Altogether, our results reveal the potential of this combination for future clinical trials.