tbuckley/cabot-search huggingface dataset:
CSIG-09. BEYOND SINGLE AGENTS: EXPLORING THE POTENTIAL OF ABEMACICLIB IN COMBINATION WITH PANOBINOSTAT FOR IMPROVED GLIOMA TREATMENT
Authors: Namratha B Rao, Tracy A Miller, Daniel R Premkumar, Ian F Pollack
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma is the most common primary central nervous system tumour with a median survival of less than 15 months. Addressing the underlying redundant, and converging signaling pathways necessitates the utilization of small molecule inhibitors capable of simultaneous targeting and inhibition. In glioma, the aberrant CDK4/6-Rb pathway dysregulation resulting in disruption of cell cycle checkpoint progression can lead to uncontrolled cell division, a hallmark of cancer. The neuro-pharmacokinetics of abemaciclib, a Cyclin-dependent kinase inhibitor, is being currently investigated in phase 1 clinical trials by National Cancer Institue, [NCT05413304]. The importance of panobinostat as a Histone deacetylase inhibitor and potentiating the effects of various small molecular inhibitors in published literature is paramount. This study is based on investigating ways to overcome resistance by exploring the synergistic cytotoxic effects of abemaciclib in combination with panobinostat in glioma. METHODS We investigated the antiproliferative effects of abemaciclib and panobinostat on glioma cells using an MTS cell proliferation assay. Inhibitor combination analysis was done using, SYNERGYFINDER via zip-model. Flow cytometry with Annexin V staining further assessed cell death and apoptosis induced. RESULTS The antiproliferative effects of abemaciclib, alone and in combination with panobinostat, in pediatric lines (KNS 42, SJG2), and adult human glioblastoma line, SF188 exhibited lower IC50 as compared to adult high grade glioma lines (LN 18, LNZ 308). Synergy analysis revealed a strong cytotoxic effect in KNS 42 and SF 188 cells treated with the combination. Flow cytometric analysis indicated that the combination therapy induced significant cell death only in a subset of cell lines- KNS 42 and SF 188, suggesting underlying genetic heterogeneity influences treatment response, warranting further mechanistic studies. CONCLUSION Combination therapies using abemaciclib and panobinostat, targeting CDK4/6 and histone deacetylation pathways, show promise against aggressive and treatment-resistant gliomas. Further investigation into these combination approaches is crucial to understand resistant mechanisms, optimize efficacy, and establish their clinical efficacy for improving glioma patient outcomes.
EPCO-26. LONGITUDINAL SINGLE-CELL ANALYSES IDENTIFY DRIVERS OF GENETIC, EPIGENOMIC, AND CELLULAR EVOLUTION IN IDH-MUTANT GLIOMA
Authors: Kevin Johnson, Avishay Spitzer, Frederick Varn, Masashi Nomura, Luciano Garofano, Tamrin Chowdhury, Kevin Anderson, Fulvio D’Angelo, Lillian Bussema, Simon Gritsch, Young Taek Oh, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna-Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Anuja Lipsa, Frank Hertel, Zheng Zhao, Qianghu Wang, Tao Jiang, Beth Hermes, Nader Sanai, Anna Golebiewska, Simone Niclou, Jason Huse, W K Alfred Yung, Anna Lasorella, Mario Suvà, Antonio Iavarone, Itay Tirosh, Roel Verhaak
Journal: Neuro-Oncology (2024)

Abstract Despite standard treatment, IDH-mutant gliomas inevitably recur. Previous studies suggest that therapeutic resistance may result from a combination of intratumoral cellular heterogeneity, epigenetic evolution, and acquired genetic alterations. However, how these multilayered molecular features interact to influence the evolutionary paths of IDH-mutant gliomas remains incompletely understood. To chart this evolution, 75 glioma samples were longitudinally collected from 35 patients (n = 13 oligodendroglioma, n = 22 astrocytoma) and profiled using single nucleus RNA sequencing, ATAC sequencing, and bulk DNA sequencing. Analysis of 331,016 nuclei (snRNA) revealed eight tumor microenvironment cell types and five pan-IDH-mutant malignant cellular states. The malignant states were distributed along a cellular hierarchy of stem-like populations (neural progenitor cell-like, oligodendrocyte progenitor cell-like, and undifferentiated) and more differentiated populations (mesenchymal-like and astrocyte-like) with cycling cells enriched in the stem-like populations. Joint open chromatin accessibility data (snATAC) was available for a subset of malignant cells (71,088 nuclei) and state-specific differentially accessible peaks supported that these states are epigenetically encoded. Across both subtypes, higher tumor grade was associated with reduced malignant cell differentiation and increased cycling populations. Between the two time points, we identified that there was a longitudinal increase in the cycling, undifferentiated, and mesenchymal-like populations with a corresponding decrease in the astrocyte-like population. Longitudinal genetic analysis revealed that 19 of 35 tumors acquired at least one of the following genetic alterations: treatment-associated hypermutation, cell cycle alteration, or large changes in copy number alterations. Importantly, tumors that acquired these key genetic alterations demonstrated significant shifts towards reduced differentiation and increased cycling populations while those tumors that did not had more stable malignant profiles. Collectively, our results suggest a common cellular hierarchy across IDH-mutant gliomas with a shift towards reduced differentiation, increased cycling populations during disease progression that is driven by acquired genetic alterations.
BIOS-06. MACHINE LEARNING MODEL INDEPENDENTLY IDENTIFIES CLINICAL FEATURES ASSOCIATED WITH WILD-TYPE GLIOBLASTOMA VERSUS MUTANT GRADE 4 ASTROCYTOMA
Authors: Farida Abdelmoneum, Jared Stoller, Leslie Muldoon, Prakash Ambady, Ramon Barajas Jr
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, presents significant clinical challenges due to its invasive nature and high recurrence rates. Understanding the clinical demographic factors associated with IDH wild-type (IDH-wt) versus mutant grade 4 astrocytoma (IDH-Mut) is critical for prognosis and treatment strategies. This study aimed to utilize a novel machine learning method to identify key clinical and demographic factors linked to IDH status. METHODS The Cancer Imaging Archive dataset included 617 patients but required preprocessing and cleaning. The cleaning process ensured data completeness and consistency by removing non-relevant variables like date and time, resulting in 20 potential predictors and 317 observations. A random forest model using Gini impurity score was built to classify patient IDH status. The dataset was split into a training set (two-thirds) and a test set (one-third). A variable importance plot identified significant variables based on the mean decrease in the Gini index. RESULTS Our machine learning model achieved 98% accuracy on the test set, outperforming the previously published model of 80% accuracy. A variable importance plot identified age at diagnosis, gender, ethnicity, and race as key predictors of IDH status, with age being the most important. Age was the most important predictor, but race (Caucasian) and ethnicity (not Hispanic or Latino) were also significant. CONCLUSIONS We present a highly accurate machine learning model for differentiating glioma IDH molecular status based only on patient clinical and demographic factors; improving upon prior published models. Future work will use a generalized logistic model to explore variable interactions and predict IDH-wt versus IDH-Mut status. These steps are vital for enhancing predictive accuracy and supporting personalized treatment strategies. Furthermore, we will define associations and interactions between these variables with other biological and therapeutic variables in predicting clinical outcome.
QOL-02. SOCIAL NETWORKS CAN BE QUANTITATIVELY MEASURED AND NETWORKS WITH GREATER STRUCTURAL DIVERSITY ARE ASSOCIATED WITH HIGHER HUMAN FLOURISHING
Authors: John Rhee, Carissa Mastrangelo, Gilbert Youssef, Zachary Rothfeld-Wehrwein, Vrushali Dhongade, Vihang Nakhate, Tracy Batchelor, Amar Dhand
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In patients with glioblastoma, the predicted progressive deterioration in physical and cognitive abilities leads to decreased quality of life for patients and their caregivers. Research has shown that one’s social environment is a major contributor to health outcomes. However, in this population, study of the social environment is a gap in the literature. METHODS We examined the personal social networks of 25 adult glioblastoma patients at one time between initial diagnosis and first cycle of adjuvant chemotherapy from March to September 2023. We additionally collected demographic, tumor measures, and the European Organization for Research and Treatment of Cancer Quality-of-Life for Patients with Brain Tumors (EORTC QLQ-BN20) and the Harvard Human Flourishing Index (HFI) measures. RESULTS The average age was 64.5 years old, 56% were female, and 84% had a Karnofsky Performance Status (KPS) of 70 or higher. Patients had large network sizes (mean of 8.8). Patients reported high levels of flourishing despite the challenging diagnosis. Flourishing was statistically significantly associated with lower network constraint (networks in which alters are less likely to be connected to each other) in a patient’s social network (p=0.046) and less lower extremity weakness (p=0.025), controlling for age, gender, income, tumor at size of diagnosis, and KPS. CONCLUSION Our study indicates personal social networks with more contacts who are not connected to each other are associated with greater flourishing. Quantifying the social networks of patients with glioblastoma has implications as an objective measure for supportive care trials. Moreover, standard quality-of-life measures may not adequately capture what it means to meaningfully live and flourish. Therefore, future studies should include how social networks and flourishing change over the course of illness and how this may also impact overall survival.
EXTH-15. AN EGFRVIII RNA-LNP VACCINE PROTOTYPE ACHIEVES TUMOUR CLEARANCE IN A GBM MOUSE MODEL
Authors: Shannon Snelling, Robert Nechanitzky, Xueqing Lun, Kristofer Ellestad, Joanna Pyczek, Kirsten Olsen, Yu Wu, Yury Karpov, Jun Liu, Matthew Gold, Haritha Menon, Yilin Tan, Rajesh Krishnan, Douglas Mahoney, Natalia Martin-Orozco, Jennifer A Chan
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an aggressive high-grade glioma that is fatal despite standard-of-care therapy. Recurrent somatic alterations that form neoantigens represent opportunities for targeted therapeutic intervention. Using human EGFRvIII as a prototypical structural alteration and neoantigen, we tested the potential of a mRNA-LNP vaccine approach to improve the survival of mice with EGFRvIII-driven GBM. To generate the model, we used in vivo electroporation to introduce genetic alterations (EGFRvIII-OE/CDKN2A-KO/PTEN-KO) into periventricular cells of early postnatal C3H mice, then propagated cells from the subsequent tumours to create implantable cell lines. Following orthotopic implantation, the resulting syngeneic tumours faithfully recapitulate histologic features of GBM with infiltrative growth, mitoses, necrosis, and vascular proliferation. Also like human GBM, the models are sensitive to but not cured by temozolomide chemotherapy and are resistant to immune checkpoint blockade. We delivered mRNA-LNP vaccines against EGFRvIII into the thigh muscle of tumour-bearing mice on days 7, 10, 14, 21, and 36 after tumour cell implant. We observed no tumour in vaccine-treated mice compared to significant tumour burden in control vector-treated animals by MR imaging at day 30 post-tumour cell implant. By day 37, all control-treated mice had died, whereas vaccine-treated mice cleared their tumours with no tumour burden detectable by histology at day 150 (N= 5 per group, **p= 0.0023). In a follow-up experiment with vaccine or control treatment on days 10, 14, 18, and 25 post-cell implants, all control mice had died by day 39. Further, vaccine-treated surviving animals were re-challenged with tumour cell implant into the contralateral hemisphere on day 42 and remain alive as of day 90. Our ongoing proof-of-principle work demonstrates that neoantigen driver mutations in high-grade glioma models can be targeted with an mRNA lipid vaccine. We hope this pre-clinical work will lead to early-phase clinical trials.
TMOD-06. ESTABLISHMENT OF PITUITARY NEUROENDOCRINE TUMOR (PITNET) ORGANOID MODELS
Authors: Sachi Maeda, Fumiharu Ohka, Fumiaki Kanamori, Yuka Okumura, Kazuhito Takeuchi, Yuichi Nagata, Junya Yamaguchi, Hideyuki Harada, Hiroki Shimizu, Yuhei Takido, Ryuta Saito
Journal: Neuro-Oncology (2024)

Abstract Pituitary neuroendocrine tumors (PitNETs) are tumors that originate from the anterior pituitary gland. While they are mostly benign, they can cause various clinical symptoms due to hormonal secretion abnormalities. PitNET can be broadly categorized into three lineages, each of which has its differentiation controlled by specific transcription factors. Treatment options for PitNET include surgical resection and pharmacotherapy, but available drugs are limited, and their efficacy markers remain unclear. To develop novel drugs for PitNET and identify their efficacy markers, it is necessary to develop new research models. In recent years, organoid models have garnered attention as novel research models for various cancer types. In this study, we established novel organoid models derived from PitNET patients and analyzed their histological and endocrinological characteristics. Surgical specimens from 4 cases of somatotroph adenoma, 1 case of double adenoma, 1 case of gonadotroph adenoma, and 1 case of corticotroph adenoma were minced in dissection medium and embedded in Matrigel basement membrane matrix respectively. The organoids were cultured under 5% CO2 at 37°C using media supplemented with various growth factors. After 28 days of culture, formalin-fixed paraffin-embedded sections were prepared to examine histological homology with patient tumors. Hematoxylin and eosin staining results showed that all organoids maintained cell morphology and tissue structure similar to the original tumors. Immunohistochemical staining for markers specific to each PitNET revealed similar staining patterns between the organoids and the original tumors. Furthermore, analysis of hormone levels in the culture medium showed that hormone production capabilities, such as growth hormone and follicle stimulating hormone, were maintained even after long-term culture. In this study, we successfully established PitNET organoid models that retain histological and endocrinological characteristics. These models are expected to serve as useful research tools for elucidating the molecular mechanisms of PitNET and developing novel therapies targeting critical molecular abnormalities.
PATH-04. THE PROGNOSTIC IMPACT OF CDKN2A/B HETEROZYGOUS DELETIONS IN MENINGIOMA- INSIGHTS OF A MULTICENTER ANALYSIS
Authors: Franziska Maria Ippen, Thomas Hielscher, Areeba Patel, Kirsten Göbel, Dennis Friedel, Sybren L N Maas, Andreas von Deimling, Wolfgang Wick, Abigail K Suwala, Felix Sahm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Meningiomas are one of the most common primary brain tumors. Homozygous deletions of CDKN2A/B have reliably been shown to confer an increased risk of progression. However, the role of heterozygous CDKN2A/B deletions remains less clear. MATERIAL AND METHODS DNA methylation data, copy-number information and mutation data were generated on a multicenter cohort of meningiomas for a total of 970 samples. The CDKN2A/B locus was determined manually for each individual case in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan–Meier method. RESULTS A total of 970 meningioma cases were identified with 30 homozygous and 114 heterozygous CDKN2A/B deletion cases, 826 cases had balanced CDKN2A/B. Heterozygous CDKN2A/B deletions in general did not confer an increased risk of progression compared to CDKN2A/B balanced cases (p= 0.074). However, segmental heterozygous losses of 9p, encompassing CDKN2A/B, yielded a significantly worse prognosis when compared to meningiomas CDKN2A/B-balanced (p= 0.002) and in contrast to focal heterozygous deletions (p= 0.523). Segmental heterozygous 9p deletions encompassing CDKN2A/B were significantly more frequently associated with a higher amount of copy number variations (CNVs) than focal losses. CONCLUSION Segmental heterozygous CDKN2A/B deletions do confer an increased risk of progression, but focal heterozygous CDKN2A/B deletions do not. The signal for segmental deletions may not be locus-specific but just one representation of the generally instable genome of aggressive meningiomas.
DNAR-04. TUMOUR TREATING FIELDS (TTFIELDS) AND DNA DAMAGE RESPONSE (DDR) INHIBITORS ENHANCE GLIOMA CELL DEATH THROUGH CHEMO-/RADIOSENSITISATION
Authors: Callum Jones, Spencer Collis, Ola Rominiyi, Katie Myers, Aurelie Vanderlinden, Connor McGarrity-Cottrell
Journal: Neuro-Oncology (2024)

Abstract High grade gliomas are the most common primary brain cancer malignancies with ~300,000 global diagnoses each year with glioblastomas (WHO grade IV) conferring the worst prognoses. This arises from their treatment resistance, rationalised by the presence of glioma stem cell-like (GSC) tumour sub-regions and high intratumoural spatio-heterogeneity. TTFields are clinically approved alternating electric fields of intermediate frequency that exert anti-mitotic effects and invoke downregulation of the DDR. Therefore, TTFields alongside clinically developed, and blood brain barrier (BBB) penetrating DDR inhibitors (DDRi) could boost cell death and overcome treatment resistance through chemo-/radiosensitisation. Primary GSC cell lines were derived from surgically resected and clinically defined tumour core and invasive edge regions and grown in more biologically relevant 3D-printed AlvetexTM scaffolds, offering highly clinically relevant models. Cells were then pre-treated with DDRi, subjected to chemo-/radiotherapy and then incubated under TTFields (200 kHz, 72 hrs) with their survival measured by clonogenic assays after 3 weeks. Immunofluorescence and western blot analysis were used to analyse the combination treatment effects on the DDR. In multiple 3D-grown core/edge GSC models, western blot analyses revealed that the DDR was altered by TTFields and clonogenic survival assays revealed that TTFields alongside DDRi led to significant chemo-/radiosensitisation. TTFields alongside DDRi effectively enhances cell death by significant treatment sensitisation effects in clinically relevant 3D GSCs which exhibit extensive intra and intertumoral spatio-heterogeneity. Given that all the DDRi used are BBB penetrable and are either clinically approved or in clinical trials, TTFields could additionally compliment these treatment regimens in gliomas to boost their efficacy.
BIOM-51. MOLECULAR SUBTYPES, CLINICAL CHARACTERISTICS, AND THERAPEUTIC IMPLICATIONS FOR CNS TUMORS WITH<i>BCOR/BCORL1</i> FUSION/INTERNAL TANDEM DUPLICATION
Authors: Johannes Gojo, Aniello Federico, Neal Geisemeyer, Felix Schmitt-Hoffner, Monika Mauermann, Martin Sill, Katharina Bruckner, Andrey Korshunov, Damian Stichel, David Capper, Arnault Tauziede-Espariat, Pascale Varlet, Kenneth Aldape, Zied Abdullaev, Andrew M Donson, Jens Pahnke, Ulrich Schüller, Kristyn Galbraith, Matija Snuderl, Sanda Alexandrescu, Mariella Filbin, Dorothee Gramatzki, Tadeja Urbanic-Purkart, Fouzia Ziad, Helen Toledano, Kornelius Kerl, Martin Hasselblatt, Ludmila Papusha, Sebastian Brandner, Maria Łastowska, Evelina Miele, Jasper v d Lugt, Jens Bunt, Christof Kramm, Nicolas André, Romain Appay, Yassine Bouchoucha, Jordan Hansford, Michal Zapotocky, Mariette E Kranendonk, Sumihito Nobusawa, David Solomon, Christine Haberler, Barbara Jones, Dominik Sturm, Felix Sahm, Natalie Jäger, Stefan M Pfister, Katja v Hoff, Marcel Kool
Journal: Neuro-Oncology (2024)

Abstract Central nervous system (CNS) tumors with either BCOR internal tandem duplication (BCOR ITD) or gene fusions involving BCOR/BCORL1 (BCOR FUS) are recognized as tumor types with characteristic molecular and clinical features but lacking clear therapeutic guidance. In an extensive international effort, we compiled a retrospective cohort of 229 (148 BCOR ITD, 81 BCOR FUS) unique cases via molecular profiling of CNS tumors. By analyzing DNA methylation patterns of 220 tumors we confirmed distinct epigenetic profiles of BCOR ITD versus BCOR FUS. The majority (91 percent) of BCOR FUS primary tumors was localized in the supratentorial region whereas BCOR ITD were localized across all anatomical CNS compartments. Median patient age at diagnosis was 20 years for BCOR FUS and 4 years for BCOR ITD. Metastatic disease was rare in BCOR FUS patients but more common in BCOR ITD tumors where 10 percent presented with metastatic disease and one third showed CNS or (rarely) extra-CNS metastasis in the course of disease. This was also reflected in clinical outcome as 5-year overall survival (OS) was 89 percent in BCOR FUS but 61 percent in BCOR ITD. In contrast, 5-year progression-free survival (PFS) was comparable reaching 27 percent in BCOR FUS and 30 percent in BCOR ITD. Integrating treatment details we found a trend towards benefit of gross-total resection on OS (BCOR FUS, n=18, p&amp;lt;0.08; BCOR ITD, n=67, p&amp;lt;0.12) but not for PFS (BCOR FUS, n=16, p&amp;lt;0.33; BCOR ITD, n=64, p&amp;lt;0.59). Radiotherapy was associated with improved PFS (BCOR FUS, n=18, p&amp;lt;0.01; BCOR ITD, n=70, p&amp;lt;0.001) and OS (BCOR FUS, n=20, p&amp;lt;0.01; BCOR ITD, n=73, p&amp;lt;0.001). Further in-depth analyses of clinical outcome parameters (primary metastatic disease, radiotherapy approach, chemotherapy type, patient age) are currently ongoing. In summary, we provide first robust annotation of CNS BCOR tumor types, clinical outcomes and therapy.