tbuckley/cabot-search huggingface dataset:
OS06.6.A LOCAL DELIVERY OF HRBMP4 AS AN ANTICANCER THERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA: A FIRST-IN-HUMAN PHASE 1 DOSE ESCALATION TRIAL
Authors: E M Bos, E Binda, I S Verploegh, E Wembacher, D Hoefnagel, R K Balvers, A L Korporaal, A Conidi, E A H Warnert, N Trivieri, A Visioli, P Zaccarini, L Caiola, R van Wijck, P van der Spek, D Huylebroeck, S Leenstra, M L M Lamfers, Z Ram, M Westphal, D Noske, F Legnani, F DiMeco, A L Vescovi, C M F Dirven
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND This Phase 1 study evaluates the intra- and peritumoral administration by convection enhanced delivery (CED) of human recombinant Bone Morphogenetic Protein 4 (hrBMP4) - an inhibitory regulator of cancer stem cells (CSCs) - in recurrent glioblastoma. MATERIAL AND METHODS In a 3 + 3 dose escalation design, over four to six days, fifteen recurrent glioblastoma patients received, by CED, one of five doses of hrBMP4 ranging from 0·5 to 18 mg. Patients were followed by periodic physical, neurological, blood testing, magnetic resonance imaging (MRI) and quality of life evaluations. The primary objective of this first-in-human study was to determine the safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of hrBMP4. Secondary objectives were to assess potential efficacy and systemic exposure to hrBMP4 upon intracerebral infusion. Dynamics of BMP signaling were assessed by RNAseq, and differentiation induction was investigated by immunofluorescence. RESULTS Intra- and peritumoral infusion of hrBMP4 was safe and well-tolerated. We observed no serious adverse events related to this drug. Neither MTD nor DLT were reached. Three patients had increased hrBMP4 serum levels at the end of infusion, which normalized within 4 weeks, without sign of toxicity. One patient showed partial response and two patients a complete (local) tumor response, which was maintained until the most recent follow-up, 57 and 30 months post-hrBMP4. Tumor growth was inhibited in areas permeated by hrBMP4. CONCLUSION Local delivery of hrBMP4 in and around recurring glioblastoma is safe and well-tolerated. Three patients responded to the treatment. A complete response and long-term survival occurred in two of them. This warrants further clinical studies on this novel treatment targeting glioblastoma CSCs.
OS09.7.A GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB
Authors: A Lassman, B Alexander, D Berry, M Buxton, W Cavenee, H Colman, J De Groot, B Ellingson, G Gordon, E M V Hyddmark, M Khasraw, M Lim, I Mellinghoff, T Mikkelsen, J Perry, A Powell, E Sulman, K Tanner, M Weller, W K A Yung, N Blondin, A Brenner, O Butt, M I de la Fuente, J Drappatz, F Iwamoto, L Kim, E Lee, M Mantica, B Nabors, H Newton, D Schiff, T Walbert, S Weathers, T Cloughesy, P Y Wen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND GBM AGILE (NCT03970447;https://www.gcaresearch.org/research/gbm-agile) is a phase 3 Bayesian adaptive platform trial that efficiently tests multiple arms against common control, with 6 arms included to date. Primary endpoint is overall survival (OS). Stage 1 experimental arms are adaptively randomized against other arms. Demonstrated efficacy in stage 1 leads to fixed randomization stage 2. Stages 1 and 2 are combined for registration. Control randomization is fixed. Regorafenib, a multikinase-inhibitor, entered into GBM AGILE as the first arm and therefore was equally randomized against control. Regorafenib showed OS benefit in recurrent disease (RD) in randomized phase 2 REGOMA trial. MATERIAL AND METHODS Patient subtypes in GBM AGILE are newly diagnosed unmethylated (NDU), RD, and—not considered for regorafenib—ND methylated (NDM). Arm indications (signatures) are combinations of subtypes. Control is temozolomide (ND) and lomustine (RD). Efficacy is assessed by OS hazard ratio(HR), arm/control. Efficacy is demonstrated when Bayesian probability of benefit (HR&amp;lt; 1.00) ≥ 98% (roughly analogous P-value: 0.02). Futility occurs at any monthly analysis when Bayesian predictive power (PP) is &amp;lt; 25% for all signatures. Follow-up continues for 12 months after arm’s accrual stops. RESULTS When PP for all 3 pre-defined signatures was &amp;lt; 25%, regorafenib’s accrual was stopped for futility. Regorafenib/control sample sizes were 49/51, 127/128, 176/179 for signatures NDU, RD, and both. Respective PPs: 0.138, 0.030, 0.025—none close to 0.25. Respective mean HRs: 1.26, 1.25, 1.23. Probabilities of benefit (HR&amp;lt; 1.00): 0.35, 0.18, 0.17. At final analysis, mean HRs were 1.07, 1.08, 1.08 with final probabilities of benefit (HR&amp;lt; 1.00) equal to 0.421, 0.312, 0.296—none close to 0.98. CONCLUSION GBM AGILE efficiently and compellingly addressed regorafenib’s role in GBM, in RD and NDU. These findings are germane as they fail to confirm the REGOMA results in RD. GBM AGILE continues to efficiently assess other therapies, including utilizing concurrent and previously accrued controls. This abstract was accepted and previously presented at the 2023 SNO Annual Meeting and published in Neuro-Oncology, Volume 25, Issue Supplement_5, November 2023, Pages v97-v98.
P07.01.B ANDROGEN RECEPTOR SIGNALING MODULATES BOTH TUMOR AND IMMUNE CELLS IN GLIOBLASTOMA AND IMPACTS GLIOBLASTOMA GROWTH
Authors: C Birzu, L Scherer, E Chaskis, J Boussier, L Belin, E Quissac, T Da Costa Perreira, K Daddi, S Scuderi, A Laurenge, L Castro Vega, K Mokhtari, S Tran, B Mathon, M Verreault, A Idbaih
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is more frequent (sex ratio M:F=1.6) and exhibits worse prognosis in males compared to females suggesting a role of the hormonal macroenvironment including androgen signaling in biology of GBM. In the current study, we studied the impacts of androgen signaling in GBM cells and their immune tissue microenvironment (iTME). MATERIAL AND METHODS In vitro, we have investigated the impacts of androgen receptor (AR) modulation on: (i)the transcriptional programs of GBM-PDCLs and GBM associated myeloid cells -GAM-, (ii)the secretome of human GAM (hGAM) and murine GAM (mGAM) and, (iii)the metabolism of myeloid cells using co-culture systems with normal human monocyte-derived macrophages -nhMDMs- and Dihydrotestosterone -DHT- producing AR+ GBM patient derived cell lines (GBM-PDCLAR+). We investigated the impact of AR signalling in GBM in GBMAR+ from TCGA RNAseq data. In vivo, the impacts of AR stimulation was explored using DHT implants and castration in male immunocompetent murine GBM models. The iTME was characterized using multiplex immunohistochemistry (mIHC). RESULTS value is more pronounced in young patients (HR of 1.75 for males &amp;lt;45 years). In addition, we showed that both GBM tumor cells and GAM express AR. Human GBMAR+, from TCGA cohort, exhibit upregulation of type I interferon pathway but downregulation chemokine and cytokine production and receptor binding. In vitro, exposure of GBM-PDCLAR+ to DHT modulates genes involved in response to growth factors, cell differentiation, migration, metabolism (protein and glycosaminoglycan) and secretome (genes involved in macrophages differentiation). Pharmacological modulation of AR in hGAM identified (i) an AR-responsive cytokine signature including CCL2, CXCL10, IL-1ra, MIF, and IL-10, and of (ii) AR-associated mitochondrial respiration changes. Exposure of mGAM, from adult immunocompetent GBM-bearing mouse (Nfpp10), to DHT, is associated with a similar pro-inflammatory but dysfunctional cytokines profiles in males. In immunocompetent GBM-bearing mice, neither DHT exposure nor the androgen deprivation (i.e. castration) modulated significantly tumor growth or mice survival. However, DHT exposure is associated with more undifferentiated GBM tumor cells in castrated males. The castration doesn’t impact significatively the myeloid cell infiltration but lowers the T-cells count (p= 0.03). DHT appears to reverse this phenotype back to intact male level. In addition, the DHT exposure increased AR expression on myeloid and GBM cells but not on T-cells. CONCLUSION Our study brings preclinical evidence that androgens signaling modulates both tumor cells and iTME cells in GBM. Further explorations should establish the role of AR blockade in reprogramming the GAM towards a more anti-tumorigenic phenotype.
P07.02.A SEX-SPECIFIC EVALUATION OF EMOTIONAL PROBLEMS, UNMET NEEDS AND PSYCHIATRIC COMORBIDITY IN PATIENTS WITH HIGH-GRADE GLIOMAS - A MULTI-CENTER STUDY
Authors: M Renovanz, M Hippler, R Kuchen, L Doerner, D Rieger, J Steinbach, M Ronellenfitsch, A Kessler, M Misch, J Onken, M Rapp, M Nadji-Ohl, M Mehlitz, J Meixensberger, M Fehrenbach, N Keric, F Ringel, J Coburger, C Weiss Lucas, J Wehinger, F Schmidt-Graf, J Gempt, M Tatagiba, G Tabatabai, M Schranz, S Singer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients diagnosed with high-grade gliomas (HGG) often experience considerable emotional distress. However, not all of them actively seek professional psychosocial support even when clearly needed and so far, gender aspects are not considered in clinical routine. We evaluated differences between female and non-female patients regarding emotional functioning and psychiatric comorbidity. METHODS In this multi-center study involving 13 centers, emotional functioning was assessed in patients with high-grade glioma during their visits to the outpatient clinic with the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), using thresholds of clinical importance following Giesinger to define increased problems. Unmet psychosocial care needs were ascertained with study specific questions and psychiatric comorbidity with the Structured Clinical Interview according to DSM (SCID). Analyses employed chi-square tests and multivariate binary logistic regression. RESULTS In total, 763 patients were enrolled of whom n=691 could be interviewed with the SCID. About half of them (57%, n= 396) were male, 294 (43%) female and 1 (0.1%) identified as diverse. For the following analyses, females were compared with non-females (male and diverse). Emotional functioning was poor in 67% of female and 57% of the non-female patients (unadjusted odds ratio (OR) 1.5, 95% CI 1.1-2.1, p=0.01; adjusted OR=1.4, 95% CI 0.9-2.1, p=0.11). About 22% of the women and 20% of men/diverse expressed the wish for support by a psychologist (p=0.54); additional support by social workers was wished for by 9% of all sexes (p=0.90), and additional emotional support by oncologists from 11% of the women and 6% of the men/diverse. According to the SCID interview, a total of 217 patients (31%, CI 28%-35%) were diagnosed with at least one common mental disorder (male: 115, 29%; female: 102, 35%). There was no evidence that gender was a predictor of comorbid mental disorders (adjusted OR=1.2; 95% CI 0.9-1.8, p=0.25). CONCLUSION Patients diagnosed with a high-grade glioma are at risk of comorbid mental disorders independently of gender though women might express their support needs and emotional problems more openly. Therefore, support should be offered to all genders low-threshold and equally.
P02.08.A HERV-W ENVELOPE PROTEIN IS PRESENT IN MICROGLIAL CELLS OF THE HUMAN GLIOMA TUMOR MICROENVIRONMENT AND DIFFERENTIALLY MODULATES NEOPLASTIC CELL BEHAVIOR
Authors: L Reiche, B Plaack, M Lehmkuhl, V Weyers, J Gruchot, D Picard, H Perron, M Remke, G Reifenberger, P Küry, C Knobbe-Thomsen, D Kremer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioma is the most common and aggressive primary tumor of the central nervous system (CNS). With regard to its still unclear etiology, several recent studies focused on human endogenous retroviruses (HERVs) as potential new pathogenic factors in various neurological diseases. Although HERVs account for up to 8 % of the human genome, these retroviral elements are epigenetically silenced but can be reactivated by environmental factors such as infection with modern viruses. The resulting production of viral particles and/or proteins exerts effects on cellular processes such as inflammation, proliferation and migration in neurological diseases such as amyotrophic lateral sclerosis (ALS), schizophrenia, chronic inflammatory polyneuropathy (CIDP) and multiple sclerosis (MS). In previous studies, we demonstrated that in MS, the human endogenous retrovirus type-W envelope protein (HERV-W ENV) interferes with lesion repair through the activation of microglia (MG), the innate myeloid immune cells of the CNS. In this study, we investigated whether HERV-W ENV is expressed in gliomas. In particular, we aimed to understand how and to what extent HERV-W ENV modulates neoplastic cell behavior. MATERIAL AND METHODS We used immunohistochemical staining to detect HERV-W ENV in human gliomas. The mRNA expression of HERV-W ENV in tissue samples of human gliomas was quantified via qRT-PCR. Using the human glioblastoma cells T98, A172 and LN229 we investigated the effects of HERV-W ENV on various molecular and cellular markers, including gene and protein expression, proliferation and migration. RESULTS We show that HERV-W ENV is present in the microglial cells of the tumor microenvironment (TME) of human glioma. It modulates the behavior of human glioblastoma (GBM) cell lines in GBM/MG cocultures by altering their gene expression, secretome, morphology, proliferation, and migration properties and could thereby contribute to key tumor properties. CONCLUSION This study shows that HERV-W ENV is a relevant player in the interplay between glioma and microglial cells within the tumor microenvironment. In vitro evidence suggests that HERV-W ENV modulates the drivers of glioma progression via microglia. Whether this can be used therapeutically by blocking HERV-W ENV with the monoclonal antibody temelimab will have to be investigated in future studies.
P02.09.B HYPOXIA MODULATES DIFFUSE ASTROCYTOMA TUMOR MICROENVIRONMENT THROUGH CELL-TYPE-DEPENDENT RESPONSES
Authors: A Tiihonen, I Salonen, I Koivisto, A Ritamäki, S Jaatinen, T Hyvärinen, J Kreutzer, M Mohammadlou, M Valkonen, P Ruusuvuori, S Parkkila, P Kallio, S Hagman, J Kesseli, V M Ravi, H Haapasalo, A Jukkola, K Joseph, K J Rautajoki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse astrocytomas, especially glioblastomas (GBs), are aggressive brain tumors with a poor prognosis despite the efforts to improve their treatment. In diffuse astrocytomas, myeloid immune cells, notably monocyte-derived macrophages and brain-resident microglia are pivotal in the immunoregulation of tumor microenvironment (TME). GBs, characterized by higher macrophage frequencies, often exhibit hypoxia in the TME. In this work, we investigated how hypoxia affects the regulation of myeloid immune cells. MATERIAL AND METHODS We analyzed 222 diffuse astrocytoma patient samples using multiplex immunohistochemistry, 45 GBs with single-cell RNA sequencing (SCS) data, and 30 diffuse astrocytoma samples using spatial transcriptomics. The resulting data was analyzed with QuPath as well as R and Python-based tools and scripts. RESULTS Our findings reveal that hypoxia generates distinct spatial and gene expression responses in macrophages and microglia. Microglia decrease in highly hypoxic areas, while macrophages increase gradually compared to normoxia. In SCS data, macrophages show the highest proportion of cells under hypoxia, and the responding differentially expressed genes in macrophages and microglia are associated with different biological processes. Our results are further validated with spatial transcriptomics and cell culture models. CONCLUSION Hypoxia is significantly shaping the TME and immunosuppression in diffuse astrocytomas.
P02.10.A IDENTIFYING NOVEL HEXOKINASE-2 ASSOCIATED PROCESSES IN THE GLIOBLASTOMA TUMOUR MICROENVIRONMENT
Authors: C L Edwards, M Morris, S P Shivakumar, T Richards, B Small, K Butcher, T Dawson, T Warr, K Karakoula
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GB) is the most common and aggressive type of adult brain tumour. With a median patient survival of only 16 months, new therapies for GB are desperately needed. Deregulation of cellular metabolism is a hallmark of cancers, where they upregulate glycolysis and preferentially ferment glucose to lactate (over pyruvate) in the ‘Warburg effect’. Upregulation of hexokinase 2 (HK2), which catalyses the first rate-limiting step of glycolysis, is key to Warburg metabolism. Several studies have shown HK2 to be selectively overexpressed in GB, while normal human brain tissue (NHBT) relies upon its isoform HK1. As a result, HK2-orientated therapies may selectively target GB tumours while limiting toxicity to normal metabolising healthy tissue. In this study we sought to identify HK2-associated tumour processes in GB which could serve as potential therapeutic co-targets. MATERIAL AND METHODS High HK2 expressing (&amp;gt;20-fold upregulation vs NHBT) established and patient-derived GB cell cultures (U87-MG, IN859) were identified by RT-qPCR. HK2 expression was knocked down in these cultures by transfection with targeted siRNA, while non-targeting siRNA was used as a negative control (NC). Expression profiles of HK2 knockdown (HK2KD) and NC cultures were compared using RNAseq. Differentially expressed genes (DEGs) found to be associated with HK2KD were analysed for gene ontology category enrichment (GOSeq) and protein-protein interactions (STRING). DEGs shared between HK2KD cultures were validated by RT-qPCR. RESULTS HK2KD was associated with significantly (padj ≤0.05) enriched GO biological processes (BPs) in both U87-MG (117) and IN859 (109). BPs related to glycolysis or glucose metabolism were not enriched. Large clusters of enriched BPs related to inflammatory and immune response were prominent in both HK2KD-U87-MG and HK2KD-IN859. Notable members of these clusters included ‘regulation of neuroinflammatory response’, ‘activation of innate immune response’, and ‘response to bacterium’. Numerous enriched BPs linked to the recruitment of immune cells, such as ‘leukocyte migration’ and ‘granulocyte chemotaxis’, were also evident. STRING analyses further revealed clusters of interacting DEG-encoded cytokines (i.e. CSF2, IL1A/1B/6, TNF) and chemokines (i.e. CCL3, CXCL1/2/3/5/6/8) associated with HK2KD. Several angiogenesis related BPs were also enriched, which corresponded with the downregulation of the major angiogenic regulators HIF2A, VEGF and FGF2 in these HK2KD cultures. CONCLUSION These findings highlight potential non-canonical roles for HK2 in regulating inflammatory, immune and angiogenesis related processes within the GB tumour microenvironment. Agents targeting HK2 may thus improve the efficacy of existing preclinical immuno/anti-angiogenic therapies against GB, which warrants further investigation.
OS09.6.A METHYLATION CLASSIFICATION AND MOLECULAR LANDSCAPE OF H3 WILDTYPE SPINAL CORD GLIOMA
Authors: R Chai, H Chen, Q Chang, Y Wang, J Wang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Spinal cord H3-K27M-wildtype gliomas (H3WT-SCG) are rare and heterogeneous tumors whose pathological classification remain challenging. MATERIAL AND METHODS We comprehensively characterized 55 H3WT-SCG patients through DNA methylation array, whole-exome/transcriptome sequencing, proteomics, and single-cell RNA sequencing. RESULTS Methylation-based classification revealed six molecular classes in the enrolled cohort, including spinal cord pilocytic astrocytomas (PA-SPINE, n=29), normal-like (high-immune, n=10), Diffuse leptomeningeal glioneuronal tumour (DLGNT, n=10), subependymaoma (SUBEPN-SPINE) (n=3), glioblastoma-like (GBM-like, n=2), and pleomorphic xanthoastrocytoma-like (PXA-like) (n=2). To our surprise, the molecular classification is inconsistent with traditional histologic diagnoses in 61.8% of cases, and the most traditional diffuse astrocytoma classified into PA-SPINE (14/24) or normal-like (5/24). We found that compared to traditional methods, methylation-based classification more accurately reflects the molecular features and patient prognosis in H3WT-SCGs, evidenced by the enrichment of BRAF fusions in PA-SPINE and DLGNT (p-value 0.04), and the enrichment of chromosomes 1p loss (p-value 6.5e-08) and 1q gain (p-value 3.6e-05) in DLGNT. The largest subclass, PA-SPINE, can be further divided into adult (older than 18 year old) and pediatric subtypes, with differences in DNA methylation profile. The adult case has lower BRAF fusion frequency (p-value = 1.4e-03), shorter tumor length (p-value = 3.7 e-04) and longer progress-free- survival (p-value = 0.062). Moreover, adult PA-SPINE neoplastic cells exhibited a less differentiated status, characterized by higher expression of EGFR and neuronal markers, as well as lower expression of cytokines and chemokines than pediatric cases. Single cell analysis showed that adult cases demonstrated reduced infiltration of monocyte-derived macrophages and proliferative myeloid cells compared to pediatric cases. CONCLUSION This study revealed molecular classes of H3WT-SCGs that precisely reflect the clinical and molecular characteristics of these tumors and further highlight the differences in clinical, molecular, biological, and cellular features between adult and pediatric PA-SPINE.
OS07.4.A INTERLEUKIN-6 INCREASES STRUCTURAL AND ELECTROPHYSIOLOGICAL CONNECTIVITY IN GLIOMA
Authors: T Picart, S Krishna, A Daniel, A Dada, S Oten, J Hyer, S Hervey-Jumper
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In the setting of glioblastoma (GBM), the pleiotropic cytokine interleukin-6 (IL-6) upregulates PD-L1 expression through STAT3-dependant mechanisms. This leads to local immunosuppression, sustains tumor progression and may explain the limited efficacy of immune checkpoint inhibition. Consistently, IL6 knock-out in orthotopic murine glioma models diminishes tumor growth and increases survival. IL-6 increases synaptogenesis during development and contributes to neuronal network remodeling following focal spinal cord or brain injury. Yet, the contribution of IL-6 to glioma-induced circuit remodeling from a structural and electrophysiological perspective is poorly understood and is investigated herein. MATERIAL AND METHODS The expression of IL-6 was compared in magnetoencephalography (MEG)-based intratumoral regions of High- (HFC) and Low-Functional Connectivity (LFC) from GBM patients using bulk and single-cell RNA sequencing and immunofluorescence staining in a panel of gliomas with biological replicates (n=44 samples). In mouse postnatal cortical neurons and primary patient-derived glioblastoma cell co-cultures, the effects of exogenously applied recombinant human IL-6 and the humanized anti-IL-6 receptor (IL6R) antibody TOCILIZUMAB (TCZ) on Ki67, GAP43, and synaptic marker expression, tumor connectivity and neuronal activity were monitored. Co-culture analysis were validated with human and mouse cortical organotypic glioblastoma slices. RESULTS IL-6 was overexpressed in HFC compared to LFC regions, independently of tumor grade. In neuron and GBM co-cultures, the number of tumor microtubes per cell was significantly increased by the addition of recombinant IL-6 and decreased by TCZ treatment. The addition of recombinant IL-6 increased the expression of the tumor microtube marker, GAP43 and modified the expression profile of synaptic markers. Electrophysiological recordings, from multielectrode array (MEA), showed a significant increase in the neuronal activity metrics, such as weighted mean firing rate, network burst frequency and duration, and also the neuronal synchrony index following the addition of recombinant IL-6. Additionally, the proliferation index of GBM cells was significantly increased by exogenous recombinant IL-6 and decreased by TCZ treatment. CONCLUSION These findings suggest that IL-6-signaling increases structural and electrophysiological connectivity in gliomas and may contribute to neuronal network hyper-excitability and synchrony. Additional experiments are required to more precisely understand the IL-6-driven molecular mechanisms promoting glioma-induce circuit remodeling. These data will help to design new therapeutic options likely to improve the oncological and functional outcomes of patients treated for diffuse gliomas.