bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-31. TARGETINGMIR-19B/PPP2R5E REGULATORY AXIS TO MAXIMISE ALKYLATING AGENT EFFICACY: A NEW AVENUE TO COUNTERACT TEMOZOLOMIDE RESISTANCE IN RECURRENT GLIOBLASTOMAS
Authors: Kashani Elham , Hlavackova Kristyna , Sadowski Martin , Maragkou Theoni , Krebs Philippe , Vassella Erik 
Published: November 2024

Abstract
Glioblastoma, IDH-wildtype (GBM), notorious for its inevitable recurrence despite aggressive multi-modal standard of care, presents a pressing need for novel treatment paradigms. The extensive DNA damage caused by the frontline DNA alkylating agent, temozolomide (TMZ) is counteracted by intricate or acquired survival mechanisms. Through functional microRNA screens we identified miR-19b-overexpressing clones possessing extra fitness in presence of escalating doses of TMZ. Our study uncovers a previously unrecognized TMZ resistance mechanism governed by miR-19b. Notably, miR-19b attenuation intensified DNA damage response and CHEK1 and CHEK2 phosphorylation, instigating persistent DNA lesions and consequently priming GBM cells for heightened TMZ cytotoxicity. Mechanistically, we showed that miR-19b exerts its function by targeting PPP2R5E, a subunit of protein phosphatase PP2A, frequently downregulated in GBM. We uncovered that the elevated DNA damage response in the miR-19b-attenuated cells was a consequence of enhanced nuclear and mitochondrial ROS production. This in turn, induced ROS-mediated senescence, and an intriguing susceptibility to ferroptosis, possibly due to increased ROS-mediated lipid peroxidation. Of note, all these phenotypes were reversed in GBM cells with concomitant miR-19b and PPP2R5E attenuation, demonstrating that miR-19b exerts its role in TMZ resistance by targeting PPP2R5E. In line with this finding, an orthotopic human-derived glioblastoma stem cell xenograft model confirmed that PPP2R5E attenuation not only decreases TMZ cytotoxicity in the brain, but also at the spinal metastatic location. Consistently, treating cells with the PP2A-activating drug FTY720 or knocking down endogenous PP2A-inhibiting proteins mirrored the effects of miR-19b attenuation in enhancing TMZ cytotoxicity. This intricate interplay between miR-19b and PPP2R5E underscores a novel strategy to modulate the TMZ response, highlighting promising results in our pre-clinical models. In conclusion, our findings advocate for the therapeutic targeting of the miR-19b/PPP2R5E regulatory axis as a potential novel strategy in the pursuit of effective therapeutic interventions for the formidable recurrent GBM tumours.
EXTH-33. COMBATING TUMOR HETEROGENEITY IN GLIOBLASTOMA WITH A NOVEL CAR-BASED PLATFORM
Authors: Wilkinson Daniel , Lerner Emily , Fecci Peter 
Published: November 2024

Abstract
Tumor heterogeneity is a major hindrance impeding success of antigen targeting immunotherapies, such as chimeric antigen receptor (CAR) T cells, in solid tumors. CAR T cells engineered to target EGFRvIII, IL13Rα2, and HER2 have mostly failed clinically to treat glioblastoma, because these antigens are typically only expressed on a subset of a tumor cells within a patient. Thus, finding a surface target that more universally characterizes tumor cells will likely be critical if antigen-specific immunotherapies are to succeed in glioblastoma and other solid tumors. Recently, we uncovered a mechanism whereby CD8 T cells can directly kill tumor cells independently of tumor-expressed major histocompatibility complex (MHC)-I. We found this mechanism to be dependent on NKG2D expression on T cells and NKG2D ligand (NKG2DL) expression on tumor cells. Interestingly, NKG2DL expression was not limited to MHC-I-deficient tumor cells, nor was it limited to gliomas, but NKG2DL expression characterized a variety of solid tumor types. Therefore, NKG2DL is potentially an ideal target for immune-based therapy. Here, we developed a bi-specific fusion protein comprised of the extracellular domain of NKG2D linked to an anti-CD3scFv. Thus, T cells will be redirected to target NKG2DL-expressing tumor cells. We have termed this fusion protein Bi-specific Engagers without Antigen Requirements (BEAR). To ensure local, intratumoral delivery of BEAR, we engineered an EGFRvIII-targeting CAR T cell to secrete BEAR (VIII CAR Engineered with BEAR; VIII “CARE-BEAR”). VIII CARE-BEAR demonstrated potent tumor kill in both in vitro and in vivo tumor heterogeneity models. Moreover, we engineered an EGFRwt-targeting (D2C7) CARE-BEAR to exemplify the potential utility of CARE-BEAR beyond glioblastoma.
EXTH-36. SHIFTING FROM EPIGENETICS TO THE EPICHAPEROME: HSP90 AS A THERAPEUTIC TARGET FOR H3K27M DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Sbergio Stefanie-Grace , Pajovic Sanja , Vadivel Arun Anguraj , Watanabe Jun , Sheth Javal , Canty Laura , Chiosis Gabriela , Nitz Mark , Hashizume Rintaro , Hawkins Cynthia 
Published: November 2024

Abstract
Diffuse midline gliomas (DMG) are lethal pediatric brain tumours, the majority of which have truncal histone (H3K27M) mutations. To investigate cellular vulnerabilities of histone mutant cells we generated oligodendrocyte precursor cells (OPC) isogenic cell lines and performed a high-throughput synthetic lethality drug screen (2400 small molecules). This identified HSP90 inhibitors as a potential therapeutic option for H3K27M DMG. We hypothesize that epichaperome HSP90 inhibitors present a new therapeutic approach targeting multiple aspects of DMG oncogenicity. HSP90 inhibitors, PU-H71 and PU-HZ151, effectively reduced viability of DMG lines in vitro in the low nanomolar range and result in caspase mediated cell death (p&lt;0.0001 1 uM, p&lt;0.05 500 nM, n=6). PU-HZ151 treated mice had a survival benefit vs control mice injected with orthotopic DMG xenografts (p=0.0012). In diseased cells, activated HSP90 forms a scaffold defined as the epichaperome. To unravel the molecular mechanisms of epichaperome inhibition in DMG cells, we performed epichaperomics – a pull down of epichaperome HSP90 with co-chaperones and clients followed by LC-MS/MS analysis. We identified an interactome enriched with proteins involved in cell cycling, RAS/MAPK signaling, immune response, and metabolic reprogramming. Proteomic and phosphoproteomic profiling of DMG cells post-PU-HZ151 treatment provided insights into the direct downstream effects critical for maintaining DMG viability, identified functional vulnerabilities primed by epichaperome inhibition including downregulation of cell cycling, and upregulation of HSF1 mediated cellular response to stress. In silico screening and kinase enrichment analysis highlighted CSNK2A1 as a top active kinase in DMG cells following PU-HZ151 treatment. To enhance the therapeutic efficacy of epichaperome inhibition, we employed the CSNK2A1 kinase inhibitor, CX-4945, in combination with PU-HZ151, resulting in the effective ablation of DMG patient cells in vitro. These data highlight the potential of epichaperome inhibitors for DMG treatment, as they target multiple DMG oncogenic pathways.
EXTH-42. GLIOMA-DERIVED CD200 PROMOTES TUMOR GROWTH AND SUPPRESSES NK CELL AND CD8 T CELL ANTI-GLIOMA ACTIVITY
Authors: Raphael Itay , Graner Michael , Moertel Christopher , Kohanbash Gary , Olin Michael 
Published: November 2024

Abstract
Immune-checkpoint inhibitors, such as anti-PD1 and anti-CTLA4, have emerged as promising therapeutic options for several malignancies yet show little efficacy against malignant brain cancers. CD200 is a newly recognized immune-checkpoint which is expressed by a marid of cell types, modulating immune homeostasis through multiple receptors. There is currently limited information regarding CD200 effects in brain tumors. Furthermore, while it is well accepted that CD200 binding to its inhibitory receptor induces a pro-tumorigenic environment through its ability to suppress immune responses, there are increasing evidence that CD200 could also have anti-tumor characteristics. Here we evaluated the role of tumor-derived CD200 on anti-glioma immunity. We demonstrate that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in serum of patients undergoing immunotherapy. Transcriptomic analysis of CD200 knockout (KO) glioma models reveals that glioma-derived CD200 significantly modifies the glioma tumor microenvironment (TME), not only through immune regulation but also through immune-independent pathways, such as tumor metabolism. Furthermore, we show that CD200 KO gliomas have reduced proliferation and are rejected by their hosts. Downstream analysis revealed that rejection of CD200 KO gliomas relied on a functional adoptive immune system, while decreased proliferation was linked to reduced CXCL10 production by the CD200 KO gliomas. Additionally, we demonstrate that glioma-mediated CD200 strongly suppresses anti-glioma NK cell function within the tumor microenvironment (TME), while secreted CD200 inhibits the priming of antigen-specific CD8 T cells in the lymphatic. Notably, NK cells were essential for the initial rejection of CD200 KO gliomas, while CD8 T cells played a critical role in establishing durable anti-tumor responses. Our work provides new mechanistic insights on glioma-derived CD200-mediated immunosuppression and an untapped potential for targeting CD200 by immunotherapies for malignant gliomas.
EXTH-75. IMMUNOVIROTHERAPY WITH PP2A AND PD-1 INHIBITION IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Kang Kyung-Don , Frederico Stephen , Fan Aaron , Gary Sam , Zhang Zhuo , Zhou Li , Markert James , Bernstock Joshua , Friedman Gregory 
Published: November 2024

Abstract
Pediatric high-grade gliomas (HGGs) represent a significant clinical challenge with poor survival rates. Engineered oncolytic herpes simplex virus (oHSV) has shown potential in several clinical trials at targeting HGGs through their direct lytic effect and induction of an immune response. We have learned from our clinical trial experience (NCT02457845) that a critical barrier to more durable response is augmenting and sustaining the anti-tumor immune response generated by oHSV. LB-100, a protein phosphatase 2A (PP2A) inhibitor, is known to enhance T-cell activity. We hypothesized that LB-100 with anti-PD-1 therapy would overcome the immunosuppressive barriers, enhancing the immunotherapeutic effects of oHSV and improve survival in an immunocompetent murine model. We investigated the therapeutic impact of clinically available, next-generation oHSV, M002, which expresses murine interleukin-12, combined with LB-100 and PD-1 inhibition compared to M002 with LB-100 or anti-PD-1 antibody, each therapy alone, or control by measuring median survival and changes in the tumor immune microenvironment. The triple combination of M002, LB-100, and anti-PD-1 antibody significantly extended median survival compared to control (45 days vs 22.5 days, P=0.001) or each treatment alone, and compared to M002 and LB-100 (44 days vs 28 days, P=0.017) or M002 and anti-PD-1 (45.5 days vs 41 days, P=0.023). This increase in survival was correlated with a robust increase in CD45+ immune cell infiltration and a reduction in T-regulatory cells. We will further investigate the changes in the tumor microenvironment to better understand the specific contributions of different immune cell populations. These data support the hypothesis that LB-100 enhances the efficacy of oHSV by amplifying T-cell-mediated immune responses against tumor cells. This combination therapy demonstrates a promising strategy that warrants further exploration and potential clinical application, emphasizing the critical role of targeting multiple aspects of immune regulation to enhance the efficacy of oncolytic virotherapy in pediatric tumors.
EXTH-83. CHARACTERIZATION OF SPLICING ABERRATIONS INDUCED BY PRMT5 INHIBITION IN GLIOBLASTOMA
Authors: Huo Longfei , Sharma Pratibha , Tsai Tsung-Lin , Chen Xiaohua , Yu Chunlei , Xu Jihong , Ju Zhenlin , Li Ziyi , Scherle Peggy , Vaddi Kris , Baiocchi Robert A , Sampath Deepa , Shukla Sachet , Puduvalli Vinay K 
Published: November 2024

Abstract
Glioblastoma (GBM) are lethal tumors with limited treatment options, with a high unmet need for novel therapies. PRMT5, an arginine methyltransferase that regulates several histone and non-histone targets, is overexpressed in cancers including GBM and is a promising therapeutic target given its role in promoting oncogenic processes. Here, we characterized the effects of pharmacological inhibition of PRMT5 by the brain-penetrant, orally bioavailable inhibitors, PRT811 and PRT808 on treatment-induced splicing aberrations using a panel of patient-derived glioma stem cells (GSC) and organotypic human glioma slice cultures. Changes in protein expression upon PRMT5 inhibition were assessed using reverse phase protein array (RPPA) analysis. Additionally, splicing aberrations due to PRMT5 inhibition in were tested in several GSCs using RNA-seq. We observed a potent reduction of symmetrical dimethylation of arginine (SDMA protein marks by both PRMT5 inhibitors across various GSC lines and ex-vivo brain tumor tissue slices. Notably, GSCs with both mutant and wild-type p53 displayed similar sensitivity to PRMT5 inhibition, independent of MTAP status. Moreover, PRMT5 inhibition elicited reduced cell proliferation, altered cell survival pathways, and apoptosis. RNA-seq analysis revealed that splicing alterations affecting numerous oncogenes and regulatory factors, encompassing 42 cancer driver genes, 80 splicing factors, and 42 transcriptional factors across these GSC lines, with specific splicing events observed in nuclear and cytoplasmic subcellular compartments. Additional analysis is ongoing to determine which of the aberrant transcripts are translated to yield tumor specific neoantigens that can be potential targets for tumor specific immune strategies. These results underscore the efficacy of pharmacological PRMT5 inhibition in genetically and epigenetically diverse GSCs, and highlight its potential for developing novel immune and non-immune therapeutic strategies against GBM.
QLTI-01. ASSESSING THE EFFECTIVENESS OF SUPPORT FROM ST. JUDE CHILDREN’S RESEARCH HOSPITAL TO VIETNAMESE TEAM IN TREATMENT FOR CHILDREN WITH BRAIN TUMORS
Authors: Nguyen Hoa Thi Kim , Bui Lan Ngoc , Phan Duy Canh , Dao An Thi Thanh , Nguyen Anh Hoang Mai , Hoang Thach Ngoc , Do Thanh Cam , Van Nguyen Dinh , Handayani Andini , Blair Sally , Lam Catherine G , Qaddoumi Ibrahim 
Published: November 2024

Abstract

BACKGROUND
Treatment for children with brain tumors requires multidisciplinary team (MDT) which is lacking in Vietnam which negatively impacts outcome. This study aims to describe the implementation and promotion of MDT approach in Vietnam with the support of St. Jude Children’s Research Hospital.

METHODS
We conducted a prospective descriptive study of St. Jude Children’s Research Hospital’s activities with the Vietnamese team between August 2023 and March 2024 and its impact on education, patient care and disseminating of MDC approach in Vietnam.

RESULTS
Onsite and online training were provided for the Vietnamese team during this time. The onsite training included exchange visits for both teams and St. Jude support for Vietnamese colleagues to attend regional and international neuro-oncology conferences. Online case discussions have been held every month from January 2024 and there are 40-60 participants each meeting from 5 main oncology centers in Vietnam. There are 3- 4 complex case discussions each meeting. A zalo group (a social media platform) for Vietnamese doctors (92 doctors) with multidisciplinary team members was established. After discussion, references and summaries of each case were distributed to the zalo group. For emergency cases, email consults are requested directly for timely input. In addition, key educational textbooks covering different disciplines of neuro-oncology (pathology, radiology and medical) were provided to different Vietnamese teams. All participants (92 doctors) found the online discussion (100.0%) benefical to further their knowledge in different fields (chemotherapy, radiation, pathology and surgery) and the outcome of consultations which guided teams to manage difficult cases. For some cases, pathology samples with local reports are sent to St. Jude to review the diagnosis and classification.

CONCLUSIONS
Training plays an important role in bringing knowledge and building team-based experience for Vietnamese clinicians in the treatment for children with brain tumor.
QLTI-05. EUROPEAN NEURO-ONCOLOGY QUALITY ASSURANCE (ENOQUA): AN EORTC BRAIN TUMOR GROUP STUDY
Authors: Razis Evangelia , Hau Peter , Gorlia Thierry , Andratschke Nicolaus , Baumert Brigitta , Lohmann Philipp , Vernadou Anastasia , Gempt Jens , De Vos Filip 
Published: November 2024

Abstract

INTRODUCTION
Neuro-Oncology, a complex and multidisciplinary field that is relatively recent, lacks well-established quality assurance measures and standards for patient care.

METHODS
We assessed the performance of 14 potential quality indicators across 19 EORTC Neuro-Oncology centers to validate these indicators as effective measures of quality. For each center, we abstracted records from 20 patients diagnosed with glioblastoma in 2018 who were not enrolled in an investigational study. We tested associations between patient survival, center characteristics, and the performance of these quality measures.

RESULTS
Most centers met several standard requirements, suggesting their potential acceptance for prospective validation. IDH expression data was universally recorded in the patients’ chart. Performing MRI within 72 hours of surgery and providing patient education for chemotherapy correlated with improved overall survival (OS). Standards met in the majority of centers were the presence of a multidisciplinary plan, a radiation plan and the extent of surgery recorded in the chart, as well as the referral for radiation within six weeks of diagnosis. Preliminary results indicate that academic centers outperformed others in most measures, although analysis is ongoing. Performance varied significantly across centers; some standards were consistently met poorly, highlighting areas needing improvement. Lack of universal acceptance of certain practices as necessary and/or important may render some standards inappropriate for further development. Final analysis will be presented at the meeting.

CONCLUSION
We are developing a comprehensive set of standards and measures for QA in neuro-oncology, which will require future prospective validation.
QLTI-08. PREDICTING POOR HIGH-VALUE CARE OUTCOMES FOLLOWING SURGICAL RESECTION OF MULTIFOCAL GLIOBLASTOMA
Authors: Chakravarti Sachiv , Pulya Ritvik , Oak Atharv , Ranganathan Sruthi , Jimenez Adrian , Mukherjee Debraj 
Published: November 2024

Abstract
Presenting with dismal prognoses, treatment of multifocal GBM (mGBM) requires extensive medical infrastructure. Individualized assessment for patients at risk of extended length of stay (LOS) and nonroutine discharge disposition, described as high-value healthcare outcomes, has not previously been described. To develop predictive models for extended LOS and nonroutine discharge disposition for mGBM patients. All mGBM patients undergoing surgical resection at our institution (January 1, 2009-December 31, 2020) were included. Predictive models for nonroutine discharge disposition (discharge to a non-home environment) and extended LOS [upper quartile of the LOS for all patients included in the present study’s cohorts (&gt;6 days)] were developed using multivariate logistic regression models. Optimism-corrected C-statistics for each model were calculated using 1000 bootstrapped samples in order to correct for potential bias associated with the limited population size. The Hosmer-Lemeshow test was used to evaluate model goodness of fit and calibration. A total of 137 mGBM patients were included in the present study. Most patients were male (40.1%), white (83.2%), not Hispanic/Latino (97.8%), not married (55.5%) and underwent elective surgery (85.4%). The average age among our patient cohort was 55.41 ± 13.17, the average KPS score was 77.23 ± 14.54 and the average mFI-5 was 0.613 ± 0.760. On bivariate analysis, older age (p=0.015) and decreasing Karnofsky Performance Status (KPS) score (p&lt;0.001) were significantly associated with nonroutine discharge disposition while emergency admission (p=0.010) and increasing frailty (mFI-5) score (p=0.003) were significantly associated with extended LOS. On multivariate analysis, increasing age (p=0.031) and decreasing KPS (p&lt;0.001) predicted nonroutine discharge while emergent admission (p=0.023) and greater mFI-5 (p=0.044) predicted extended LOS. Our models for nonroutine discharge and extended LOS had optimism-correct c-statistics of 0.7507 and 0.7309 respectively and displayed adequate calibration. Following external validation, our models may have utility as a risk stratification tool for this multifocal GBM patient populations.
QLTI-09. CLINICAL TRIALS IN NEURO-ONCOLOGY: DESIGN, LOGISTICS, CHALLENGES, AND PRACTICAL CONSIDERATIONS
Authors: Pawar Vikas , Roy Vijaylaxmi , Sreegiriraju Vijay , Goel Pallavi , Sadasivam Subhashini , Ghanekar Yashoda , Madiraju Surya , Ray Amit 
Published: November 2024

Abstract
Timely, secure and reliable transportation, precise handling and storage of biological specimens are critical for the success of clinical research. Research in neuro-oncology often involves complex assays such as next-generation sequencing where the integrityof brain tumor specimens is paramount. These challenges are pronounced in most Lower Middle-Income Countries (LMIC), due to climatic factors and infrastructure limitations, necessitating stringent measures to preserve sample quality and their genetic data integrity for downstream analysis. In this study, we conducted extensive cohort analysis on 80 tissues randomly picked samples of the 3600 samples collected across India to assess the impact of collection protocols, transportation logistics, and long-term storage on the genetic material of tissues. The quality and quantity of the isolated nucleic acids was determined by BioAnalyzer and Qubit parameters. Tissue samples were collected and stored at -80°C in RNAstable® within 4-12 hrs of collection. The DNA and RNA obtained from tissue samples stored for over one year was found to be of good quality with corresponding DNA Integrity Number (DIN) and RNA Integrity Number (RIN)between 7-9. Also, optimum quantity of DNA and RNA was obtained for whole exome and transcriptome sequencing. Upon sequencing, these samples showed good read coverage of 100X or more. These findings provide critical insights into the measures necessary for optimizing sample preservation and transportation to ensure accurate research outcomes. The results indicate that appropriate sample collection, transportation, and long-term storage of bio-specimens can be used effectively for future research. Additionally, the outcome underscores the potential for long-term studies in neuro-oncology using archived biological samples without compromising data integrity.