bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-37. Exploring the role of the epigenetic factor H2A.Z acetylation in DIPG
Authors: Sanguino Yolanda Colino , de la Fuente Laura Rodriguez , Kisswani Dana , Kearney Padraic , Jackson Evangeline , Duchatel Ryan , Holliday Holly , Jabado Nada , Tsoli Maria , Ziegler David , Dun Matthew , Mora Fatima Valdes 
Published: June 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) is the most aggressive brain tumor found in children with a peak incidence of 5-7 years of age, with median survival after diagnosis less than one year. In more than 60% of DIPG cases, a recurring somatic mutation in the H3F3A gene, that causes a lysine 27 to methionine substitution is seen in the histone variant H3.3 (H3.3K27M). Wildtype histone variants H2A.Z and H3.3, are frequently found in the same nucleosome and cooperate to regulate transcription. We and others have identified that acetylation of H2A.Z (H2A.Zac) can be an oncogenic driver in adult cancer types through mislocalization of H2A.Z at promoters and enhancers of cancer-associated genes loci. However, the role of H2A.Z in H3.3K27M+ DIPG has never been studied. Thus, we hypothesized that H2A.Zac cooperates with H3.3K27M to drive DIPG oncogenesis. Here we aim to unravel the molecular relationship between H2A.Zac and H3.3K27M in DIPG and their link to oncogenesis. First, using a histone mass spectrometry dataset, we found that the level of H2A.Zac is significantly higher in samples with H3K27M compared to H3.3WT. In addition, the comparison between H2A.Zac with H3.3K27M ChIP-seq data in several DIPG cell lines showed that around 30% of H3.3K27M peaks overlapped with H2A.Zac marked regions, a similar proportion found between H3.3 and H2A.Z under physiological conditions. Interestingly, active enhancers are the most enriched regulatory regions for H3.3K27M/H2A.Zac overlapping regions and those enhancers are associated with genes involved in pathways commonly altered in H3.3K27M gliomas. These data suggest H2A.Zac levels are altered in DIPG and H2A.Zac may be involved in aberrant enhancer activation in DIPG and thus constitute a novel therapeutic target for H3.3K27M+ DIPG.
DIPG-43. Glucosylceramide synthase inhibitors induce ceramide accumulation and sensitise H3K27 Mutant Diffuse midline Glioma to irradiation
Authors: Paret Claudia , Sandhoff Roger , Zahnreich Sebastian , Wehling Pia Charlotte , El Malki Khalifa , Faber Jörg 
Published: June 2022

Abstract
BACKGROUND AND AIMS: Glycosphingolipids (GSL) are amphipathic lipids particularly abundant in the brain where their amount and expression patterns change drastically during the embryonic to postnatal stages and during tumorigenesis. The biosynthesis of GSL begins with the formation of glucosylceramide from ceramide, a step catalysed by the glucosylceramide synthase (UGCG). UGCG can be inhibited by eliglustat, which is used for treating children with Gaucher‘s disease. We have previously shown that the GSL composition is deregulated in H3K27M mutant diffuse midline glioma (H3K27M mut) and that eliglustat inhibits cell proliferation. Here we analysed the mechanism of action of eliglustat in H3K27M mut and its effect on irradiation. METHODS: The concentration of different components of the sphingolipid metabolism (ceramide, ceramide-1-Phosphate (CIP), sphingomyelin, Sphingosine and Sphingosine-1-Phosphate (S1P)) was assessed by mass spectrometry in the H3K27M mut cell line SF8628, before and after treatment with eliglustat. The combination of eliglustat with ionizing radiation was analysed by clonogenic assay. RESULTS: The treatment of H3K27M mut cells with eliglustat resulted in a significant increase in the concentration of ceramide, Sphingosine, C1P, but not S1P. The increase was concentration and time dependent and was not observed after longer incubation. Eliglustat treatment reduced the colony formation ability after irradiation. CONCLUSIONS: Ceramide is a known mediator of apoptosis involved in the molecular mechanisms underlying cellular response to irradiation. Increased endogenous ceramide levels, induced by blocking the synthesis of GSL, may sensitize H3K27M mut cells to irradiation. However, ceramide can be converted in C1P, a potent inhibitor of apoptosis and inducer of cell survival. Thus, the time and concentration dependent shift to ceramide and C1P requires further investigation in order to achieve an appropriate balance between the levels of these two metabolites and identify the optimal therapeutic window for combination with irradiation and potentially chemotherapy
DIPG-56. Development and application of a novel antibody against CD99 as a therapeutic strategy in Diffuse Midline Glioma
Authors: Venkataraman Sujatha , Balakrishnan Ilango , Madhavan krishna , Chetty Senthilnath Lakshmana , Pierce Angela , Fosmire Susan , Nuss Zachary , Coleman Philip , Green Adam , Vibhakar Rajeev 
Published: June 2022

Abstract
BACKGROUND: There is an unmet need to identify novel targeted therapies for Diffuse Midline glioma (DMG) which is currently a refractory disease. Recently, we identified high expression of a cell surface antigen, CD99 in H3K27M-mutant expressing DMGs compared to other normal brain counterparts. We developed a novel chimeric CD99 antibody and tested the anti-tumor efficacy of this antibody in vitro and in vivo. METHOD: Bio-legend cell-surface screening was performed in H3K27M-mutant and WT DMG cells. Functional role of CD99 was studied using CD99 proficient and depleted tumors. Designed and synthesized CD99 antibody with a new binding sequence on a human IgG scaffold and performed cell toxicity and growth-inhibitory studies using DMG tumor and normal cells. We also performed these studies in combination with radiation. Multiple patient-derived orthotopic DMG xenograft models was used to test the antibody efficacy. Different antibody delivery routes, that are clinically relevant were investigated. RESULTS: CD99 expression is transcriptionally regulated by H3K27M and is enriched on the cell surface of K27M tumors compared to WT DMG tumors. Our new CD99 antibody (10D1 clone) significantly reduced DIPG tumor cell proliferation in vitro. Intravenous infusion of this antibody in DIPG tumor bearing mice showed complete clearance of tumor that prolonged animal survival suggesting the enhanced anti-tumor efficacy of 10D1-CD99 and importantly, its ability in crossing the blood-brain-barrier and reaching the pons target site. Loco-regional administration of 10D1 showed similar anti-tumor effects even at much reduced antibody concentrations while toxicity to CD99-expressing T cells was minimum. Radiation increased CD99 expression and enhanced the cytotoxic effect of 10D1-CD99. CONCLUSION: We have developed a novel CNS penetrant CD99 antibody that is an attractive therapeutic strategy in treating DMG. 10D1 is currently in development as a therapeutic.
DIPG-62. Reducing the levels of genomic 5-hydroxymethylcytosine by inhibiting the TET pathway induces apoptosis and decreases proliferation in Diffuse Intrinsic Pontine Glioma (DIPG)
Authors: Parthasarathy Akhila , Arnold Antje , Eberhart Charles , Raabe Eric 
Published: June 2022

Abstract
The H3K27M mutation, observed in 70%-90% of DIPG, causes global hypomethylation. The Ten-Eleven-Translocation enzymes, TETs, which convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) regulate the methylation patterns in the genome. Previously, we observed an increase in the 5hmC levels and altered TET activity in DIPG. We hypothesize that targeting the TETs in DIPG could restore the epigenetic balance. In this study, we target the TET pathway with cell-permeable 2-hydroxyglutarate (2HG) and Bobcat339, a cytosine-based TET inhibitor. We see a dose-dependent decrease in 5hmC (46-96% reduction) and increase in 5mC (~5fold increase) in multiple DIPG cell lines treated with 2HG. We see a corresponding increase in apoptosis and reduction in proliferation (~8fold increase in cleaved-Caspase3 signal (P=0.0001) and ~55% reduction in BrdU-incorporation measured by IF (P=0.0036) in JHH DIPG16A with similar results in JHH DIPG1, HSJD007, and SUDIPG6). We see a 54-90% reduction in 5hmC and ~3fold increase in 5mC with Bobcat 339 treatment in DIPG cell lines JHH DIPG1, JHH DIPG16A, HSJD007, and SUDIPG6. We also see a corresponding increase in apoptosis as measured by cleaved PARP western blot and decrease in proliferation as measured by BrdU incorporation (approximately 32-53% decrease in proliferation). Combined treatment with 2HG and Bobcat339 lead to greater decreases in 5hmC and increases in 5mC compared to single treatment, with synergistic suppression of cell growth as measured by SynergyFinder in HSJD007, JHH DIPG1, and JHH DIPG16A. In vivo studies targeting DIPG orthotopic xenografts are currently underway. These results suggest that TETs contribute to the hypomethylated state observed in DIPG. Thus, inhibiting the TETs can be explored as a potential therapeutic approach to treat DIPG.
DIPG-63. Therapies for diffuse gliomas in pediatric patients: a systematic review and meta-analysis
Authors: Paracha Awais , Abdelbaki Mohamed S , Navalkele Pournima 
Published: June 2022

Abstract
Diffuse gliomas are one of the most challenging pediatric brain tumors of the current era. The new WHO classification has brought in a paradigm shift in the diagnosis and management of diffuse gliomas. Although these tumors are not surgically resectable, an integrated molecular analysis could make them more amenable to targeted agents. We conducted a thorough systematic review and meta-analysis of therapies for diffuse gliomas in pediatric patients. Methods: Using PRISMA guidelines, PubMed, (Medline), Cochrane, and Google Scholar database searches are being conducted using search terms “diffuse midline glioma”, “diffuse midline astrocytoma” and “diffuse glioma management”. PubMed search filters used to find relevant articles were “human” species, “English” language, and “age birth to 18 years”. Results: Interim analysis using the PubMed database has revealed 387 articles of which 32 articles describe details of therapies used in pediatric patients. We found 8 case reports, 17 case series, and 7 clinical trials elucidating therapies for diffuse gliomas. Comprehensive analysis of modalities of therapies including neurosurgery, chemotherapy, and radiation therapy, along with survival analysis for these patients stratified by H3.3K27M mutant status is ongoing.
DIPG-64. Feasibility and early results of radiotherapy, concomitant nimotuzumab and vinorelbine and re-irradiation at progression, for newly diagnosed childhood and adolescence diffuse midline glioma (DMG)
Authors: Schiavello Elisabetta , Biassoni Veronica , Barretta Francesco , Gattuso Giovanna , Pecori Emilia , Gandola Lorenza , Boschetti Luna , Mastronuzzi Angela , Cacchione Antonella , Quaglietta Lucia , Milanaccio Claudia , Simonetti Fabio , Buttarelli Francesca Romana , Antonelli Manila , Massimino Maura 
Published: June 2022

Abstract
BACKGROUND: The purposes of this trial were evaluating the feasibility, response and PFS/OS of patients receiving upfront radiotherapy and reirradiation at progression with concomitant nimotuzumab/vinorelbine chemotherapy as the standard arm of the ongoing protocol for DIPG. METHODS: Patients aged 2-21 years with not-pretreated DMG (evidence of H3.3K27M mutation at immunohistochemistry) received vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Focal photons irradiation was delivered within the 3rd week after first nimotuzumab+vinorelbine administration with a total dose of 54 Gy in 1.8 Gy daily fractions. For local progression re-irradiation was proposed at 19.8 Gy; in case of dissemination craniospinal-irradiation at 36 Gy was adopted. MRI were blindly centrally reviewed at diagnosis and every 12 weeks thereafter. RESULTS: Aggregated preliminary results are available for 20 patients from 4 Italian centers: 12 males, median age 11 years (range 3-17). Median time of observation was 12.5 months; 8 had thalamic/basal ganglia disease, in 5 pons was involved (2 pontobulbar, 3 pontomesencephalic), 6 spinal, 2 cerebellar. 13 patients had only biopsy, the others partial or near-total resection.14 relapsed: 5 locally, 4 with dissemination, 5 with both; 12 died, one was lost at follow-up. Two patients received reirradiation, one of them was irradiated three times without evidence of radionecrosis, still alive at 26 months from diagnosis. Median EFS/OS were 8.3/10.2 months, respectively; EFS/OS at 1 year were 25.8/36.7%. Survival curves between spinal and cerebral locations showed no difference. Patients after partial/near-total resection vs biopsied seemed to have earlier relapses (P 0.017) with EFS at 6 months of 34.3/75.0% respectively. CONCLUSIONS: This is one of the first series of DMG homogeneously and prospectively treated; treatment was feasible. A potential role of reirradiation emerge as in DIPGs.
DDEL-03. The use of programmable valves as a vehicle for intrathecal chemotherapy delivery in infants with CNS tumors and hydrocephalus.
Authors: Dvir Rina , Rosenberg Tom , Elhasid Ronit , Levin Dror , Constantini Shlomi , Roth Jonathan 
Published: June 2022

Abstract
INTRODUCTION: Current chemotherapy protocols for treatment of embryonal brain tumors in infants recommend administration of intrathecal chemotherapy either by a lumbar tap or via an Ommaya reservoir. Children with concurrent hydrocephalus and shunts may have sub-therapeutic levels of chemotherapy in the CSF due to constant CSF drainage to extra-CNS compartments. We present our experience in delivery of chemotherapy to young children via programmable valves. RESULTS: A retrospective analysis of infants with CNS malignancies and hydrocephalus treated with a shunt and a programmable valve (CERTAS™ Plus Programmable Valves - Integra Life Sciences) was conducted. Five infants 1.1-3 years of age (mean 2) were included. Pathologies included atypical teratoid rhabdoid tumor (ATRT N=2), medulloblastoma (N=2), and metastatic rhabdomyosarcoma(N=1). Intrathecal injections were conducted in an outpatient setting unless hospitalization was required for other reasons. Only one child required sedation due to noncompliance. A total of 61 chemotherapeutic administrations were performed directly through the valve while set on an extremely high opening pressure for several hours( 35 with hydrocortisone and cytarabine, 26 with topotecan). There were no infections, leaks or major complications. One child required a wound revision due to exposure of the proximal catheter related to extremely thin skin, one child developed somnolence and fever which were not related to a shunt malfunction or infection, and one child had clinical and radiological shunt over-drainage solved by increasing of valve settings. CONCLUSIONS: Programmable ventriculoperitoneal valves appear to a safe method for delivery of chemotherapy in infants with malignant CNS tumors .This technique may potentially have an added value for children with concurrent shunts, and may also obviate the need for an additional ventricular access device .
EPCT-09. ROVER: A phase 1/2 study of avapritinib in pediatric patients with solid tumors dependent on KIT or PDGFRA signaling
Authors: Chi Susan , Hsieh Antony , Foley Megan , Shi Hongliang , Swamy Preethi , Rodstrom Jill , Rudoltz Marc 
Published: June 2022

Abstract
Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor. KIT alterations are common in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. H3K27M-mutant gliomas are dependent on PDGFRA signaling. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, or H3K27M-mutant gliomas. Selective KIT and PDGFRA inhibitor avapritinib demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50&lt;2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM); cellular IC50 of PDGFRA wild-type was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios ranging from 0.74–1.00) has demonstrated potential for CNS antitumor activity. Avapritinib is approved in the USA to treat adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V), and adults with advanced systemic mastocytosis. In the EU, avapritinib is approved for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. Objectives of ROVER 2-part phase 1/2, multicenter, open-label study (NCT04773782) are avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients aged 2 to &lt;18 years with solid R/R tumors dependent on KIT or PDGFRA signaling, including H3K27M-mutant gliomas, and no alternative treatment options. Part 1 will enroll ≥12 patients; primary endpoint is confirmed age and body surface area physiologically based pharmacokinetic modeling predicted dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥25 patients at the recommended avapritinib dose from Part 1; the primary endpoint is objective response rate. Avapritinib once-daily will be administered in continuous 28-day cycles. Enrollment in this study is planned at 26 sites in 10 countries, including centers in North America, Europe, and Asia/Pacific.
EPEN-13. Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology
Authors: Gödicke Swenja , Ehlert Max , Obrecht Denise , Rutkowski Stefan , Schüller Ulrich 
Published: June 2022

Abstract
PFA ependymomas are aggressive posterior fossa tumors that mainly effect children and have a poor prognosis despite intensive therapy. Histopathology reveals glial neoplasms that usually show perivascular pseudorosettes throughout the tumor. Tumor cell density may vary within a tumor and sometimes shows well demarcated nodules of extremely densely packed tumor cells within surrounding loose glial tissue harboring diffusely distributed tumor cells. To determine potential molecular differences in such areas and to understand the clinical meaning, we analysed 70 clinically well-annotated PFA samples and 9 corresponding relapse samples. Areas of low and high cell density were digitally identified with a cut-off of 8,500 cells/mm². Global DNA methylation and copy-number profiling was performed in 52/79 cases for the entire tumor area of the sample and in 15/79 cases for the cell-dense and less cell-dense regions, separately. Fluorescence-in-situ-hybridization was performed for 20 cases, and scRNA-Seq data were analysed for 12 cases. The proportion of cell-dense areas proved to be highly variable on a continuum ranging from 0 % to 100 % of the tumor area. It was significantly higher in relapses in comparison to the respective primary tumors (p=0.036). Also, cell-dense areas displayed a significantly higher proportion of proliferating tumor cells (p&lt;0.01). Global DNA methylation was similar, but not identical in different tumor areas. In 6/15 cases, the PFA subtype changed as determined by the current version of the brain tumor classfier (v12, www.molecularneuropathology.org). Chromosomal changes at 1q and 6q were only detectable in cell-dense areas in 5/12 and in 3/12 cases, respectively. Finally, scRNA-Seq data confirmed a widespread heterogeneity regarding 1q and 6q changes in PFA ependymoma cells. These data suggest that PFA ependymoma habor a previously unrecognized heterogeneity that has to be accounted for when selecting material for the analysis of clinically relevant DNA methylation profiles or copy number changes.
EPEN-14. A Phase 1, Safety and Dose Escalation Study of BXQ-350 in Patients with Advanced Solid Malignancies Demonstrates that BXQ-350 is Well Tolerated and Shows Signs of Potential Clinical Activity in Ependymoma Patients
Authors: Rixe Olivier , Morris John , Wesolowski Robert , Yilmaz Emrullah , Villano John , Muller Carolyn , Wise-Draper Trisha , Puduvalli Vinay , Curry III Richard , Takigiku Ray , Tapolsky Gilles 
Published: June 2022

Abstract
The significance of a dysregulated sphingolipid metabolism in cancer, including brain tumors, has been demonstrated and several enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers. Saposin C (Sphingolipid Activator PrO[S]etIN) is a human protein encoded by the Psap gene and is an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism. BXQ-350 is a nanovesicle of Saposin C that has broad anticancer activity, selectively inducing apoptosis of cancer cells by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations and inducing an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies including brain tumors (NCT02859857). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose, or the biological effective dose, of BXQ-350 administered intravenously at escalating doses from 0.7 mg/kg up to 2.4 mg/kg. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and potential biomarkers. This trial was performed at four US sites. Results indicate that BXQ-350 was safe and well-tolerated as no DLT was observed and an MTD was not reached. RANO or RECIST 1.1 criteria were used to evaluate tumor response. Analysis of plasma samples suggests that BXQ-350 modulates sphingolipid metabolism and impacts the immune system positively. Furthermore, potential signs of single agent activity were observed across tumor types, including in two ependymomas for which results will be presented.