tbuckley/cabot-search huggingface dataset:
EPCO-44. SPATIAL TRANSCRIPTOMICS ENABLES STATISTICAL MODELING OF SEX DIFFERENCE IN GENE CO-EXPRESSION NETWORK AND IMMUNE LANDSCAPE OF GLIOBLASTOMA
Authors: Yue Hao, Angela Baker, George Reid, Jingqin Luo, Brian Hilbush, Marcos Otero, Christopher Streck, Karen L Fink, George J Snipes, Bruce E Mickey, Andrew E Sloan, Jill S Barnholtz-Sloan, Michael E Berens
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is characterized by inter- and intra-tumor molecular heterogeneity and demonstrated cell plasticity. Sex differences have been observed in various aspects: a male:female GBM incidence ratio is 1.6:1; standard of care treatments (debulking, radiation, and temozolomide) benefit females more than males. 14 human GBM samples from two study sites were subject to spatial profiling on the Vizgen Merscope platform to examine whether distinct biological and therapeutic niches in GBM were evident, to understand how the tumor microenvironments (TME) contributed to the heterogeneity of GBM, and to interrogate sex difference in the immune landscape of GBM. Multiple sets of spatial probes were designed to capture the cell identities (cancer stem cells, astrocytes, oligodendrocytes, microglia, macrophages, etc.) and the spatially-resolved expression patterns of genes with different functions. Two of the 14 GBM samples were also profiled on another FISH-based spatial platform (Veranome). The data from the two platforms exhibited a linear correlation. We explored the gene-gene co-expression network, and calculated the interaction probabilities between genes which were then compared for sex difference. We found that female samples showed significantly lower (two-fold) CD4+/CD8A+ T-cell count ratios than male samples. We also observed sample-specific spatial niches of different GBM cell subtypes and immune cell populations. Our large-scale spatial transcriptomics study revealed intrinsic sex-based differences in immune response to tumor and illuminated microenvironmental influences on GBM.
EXTH-46. TESTING PRECISION GENOMICS-GUIDED THERAPY IN A MODEL OF ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA: DUAL INHIBITION OF CDK4/6 AND MEK
Authors: Jenna Koenig, M Reza Saadatzadeh, Barbara J Bailey, Pankita H Pandya, Erika A Dobrota, Kathryn Coy, Felicia M Kennedy, Anthony L Sinn, Jignesh K Tailor, Steven P Angus, Nur P Damayanti, Karen E Pollok
Journal: Neuro-Oncology (2024)

Abstract Typical survival for pediatric high-grade gliomas remains less than 18 months despite recent improved understanding of the molecular drivers of these tumors. Hyperactivating MAPK and CDK4/6 pathway mutations are common and targetable alterations implicated in tumorigenesis and malignant transformation in pediatric glioma. We have established and characterized a novel patient-derived xenograft (PDX) model, RHT128, from a pediatric patient diagnosed with the high-grade glioma anaplastic pleomorphic xanthoastrocytoma (APXA). The molecular landscape of PDX RHT128 exhibits molecular fidelity to the patient’s tumor. Clinical precision genomics analysis of the tumor revealed a novel BRAF chromosomal rearrangement and CDKN2A/B deletion. Based on this molecular signature, the patient was treated with MEK inhibitor trametinib as a monotherapy and, following progression of disease, with CDK4/6 inhibitor ribociclib. However, the tumor continued to progress. In this study our objective is to simultaneously target the CDK4/6 and MAPK pathways in RHT128 and determine to what extent this combination therapy minimizes emergence of therapeutic resistance. Single-agent efficacy assessments in a subcutaneous RHT128 model, showing significant dose-dependent reduction in tumor volume after treatment with abemaciclib (p&amp;lt;0.05), palbociclib (p&amp;lt;0.01), and the blood-brain barrier-permeable MEK inhibitor mirdametinib (p&amp;lt;0.0001). Analysis of the global kinome in CDK4/6 inhibitor-treated PDX tissues compared to vehicle treatment using multiplexed-inhibitor bead chromatography–mass spectrometry demonstrated effective inhibition of CDK4/6. Moreover, this analysis revealed dose-dependent alterations in the MAPK and PI3K pathways and modulation of critical neurotransmitter pathways in treated tissues. Future studies will explore efficacy of these MEK and CDK4/6 inhibitors in combination and in our BRAF wild-type and BRAF V600E variant APXA models to gain further mechanistic insights. The pervasiveness of alterations to the MAPK and CDK4/6 pathways in pediatric gliomas make this approach promising for further study in a broader range of these deadly tumors.
EPCO-28. UNVEILING INVASIVE MECHANISMS OF GLIOBLASTOMA CELLS THROUGH MULTIMODAL SINGLE-CELL SEQUENCING
Authors: Yiyan Wu, Benson Wu, Yosef Ellenbogen, Sheila Mansouri, Joan Kant, Xuyao Li, Olivia Singh, Parnian Habibi, Pathum Kossinna, Sandra Ruth Lau Rodriguez, Andrew Gao, Gelareh Zadeh, Federico Gaiti
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common malignancy of the central nervous system, characterized by a dismal prognosis and inevitable recurrence despite aggressive standard-of-care therapy. Extensive colonization of the surrounding brain parenchyma precludes complete surgical resection, posing a significant therapeutic challenge. While well-studied in model systems, the molecular features and epigenetic regulators of invasive GBM cells remain under-explored directly in clinical samples. To address this gap, we performed a multimodal single-cell sequencing characterization of GBM tumor samples from anatomically distinct regions collected using MRI guidance. Our results demonstrate an enrichment of progenitor-like (neural- and oligodendrocyte-like) malignant states and neurons at the tumor margins. In contrast, differentiated-like states and myeloid cells were more abundant in the tumor core. Peri-tumoral progenitor-like malignant states expressed a unique neuronal signature associated with synaptic signaling, neurogenesis, and Notch signaling. Further, the expression of this neuronal signature was correlated with increased invasiveness. Analysis of matched primary-recurrent GBM patient cohorts revealed an expansion of this neuronal activity program, which was associated with worse overall survival. Motifs of proneural transcription factors implicated in neuronal lineage differentiation were also found to be differentially accessible in progenitor-like malignant states marked by the neuronal invasive signature, potentially contributing to the remodeling of cell states at the invasive margin. Further, cell-cell interaction analysis predicted greater communication between neurons and peri-tumoral progenitor-like malignant states, mediated predominantly through neurexin-neuroligin trans-synaptic signaling, facilitating synaptogenesis and the integration of tumor cells into neural circuits. Altogether, these findings suggest a model in which GBM invasive cells communicate with normal brain neurons in peri-tumoral regions, exploiting neurodevelopmental pathways to facilitate invasion and potentially seed recurrence. Our characterization of invasive GBM cells provides insight into the mechanisms of brain invasion and highlights potential therapeutic vulnerabilities of malignant invasive cells. Understanding these mechanisms opens new avenues for targeted therapies aimed at curtailing the invasive and adaptive capabilities of GBM.
EXTH-49. DEVELOPMENTAL ANTIGENS CAN TARGET EMBRYONAL PEDIATRIC BRAIN CANCERS IN ADOPTIVE CELLULAR THERAPY
Authors: Christina Pham, Mathew Sebastian, Alexandra Reid, Caitland Love, Jeffery Drake, Duane Mitchell, Catherine Flores
Journal: Neuro-Oncology (2024)

Abstract Mutations in tumor neoantigens have shown promise in immunotherapies for many cancers, yet pediatric brain tumors, which typically have a lower mutational burden, offer fewer opportunities to capitalize on these targeted therapies. Studies indicate that medulloblastoma (MB) and brain stem gliomas (BSG) originate from abnormal reactivation of post-natal developmental processes. This led us to investigate whether proteins expressed during the early post-natal development of the mouse cerebellum and brainstem could be powerful antigens to fight MB and BSG, respectively. We performed both in vitro and in vivo studies in mice with the RNA of developmental antigens from the brain stem and cerebellum in an adoptive cellular therapy (ACT) platform. We evaluated the reactivity and therapeutic efficacy of these treatments as sustainable antigenic targets against BSG and MBs. We demonstrate that T cells activated towards these non-mutated, tissue-specific developmental antigens can recognize distinct subtypes of MB and BSG, and activate specifically without cross-reacting to the normal brain. This conferred a survival benefit in established orthotopic models of these pediatric brain tumor types. Our research exhibits the value developmental antigens can offer when serving as tumor rejection antigens in MB and BSG.
TMIC-23. INVESTIGATING THE FUNCTIONAL ROLE OF SECRETED FERRITIN FROM GLIOBLASTOMA CELL TYPES
Authors: Emily Tufano, Kondaiah Palsa, Rebecka Serpa, James Connor
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a survival rate ~5%. Our laboratory previously showed the inhibitory effect of iron and ferritin-bound iron on migration and spheroid formation in GBM cells. Furthermore, studies have shown the release of extracellular vesicles (EVs) and their iron-related cargoes are regulated by cellular iron concentrations. Building on these findings, this study aims to investigate the impact of EV-associated ferritin on migration in GBM. To achieve this, we examined the influence of iron on EV release from four GBM cell lines, comprising two cancer stem cells (CSCs) and two non-CSCs: T387, T3691, LN229, and T98G. Using Nanoparticle tracking analysis (NTA), we demonstrated that 100 μM of ferric ammonium citrate (FAC) significantly increases EV release in the CSC line after 24 hours (p-value &amp;lt;0.01). Conversely, there was no significant impact on the non-CSC line under the same conditions. Based on these results, the ability of iron to regulate EV release is dependent on CSC versus non-CSC status. Given the functional role of ferritin on migration potential in GBM, we used immunoblotting to examine ferritin release from cells following iron treatment. We observed a reduction in ferritin release from CSCs following FAC treatment compared to the control, while non-CSCs, in contrast, released more ferritin after treatment. Interestingly, ferritin released from CSCs was predominantly within EVs, whereas ferritin released from non-CSCs was not associated with EVs. To assess the functional impact of ferritin release on migration, we utilized a Transwell migration system, and observed that EVs from iron-treated cells reduced migration in the recipients. Together, these findings expand our understanding of differential responses of ferritin in CSC and non-CSC EVs to iron treatment and will allow us to identify new targets and strategies for managing GBM progression.
EXTH-81. A RARE CASE OF RELENTLESSLY PROGRESSIVE METASTATIC PINEOCYTOMA MANAGED WITH SEQUENTIAL MULTIMODAL THERAPY
Authors: Allison Valerius, Anna Thomsen, Ugur Sener, Fredric Meyer, Anita Mahajan, Michael Link, Daniel LaChance, Michael Ruff, Timothy Burns, Caterina Giannini
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pineocytoma is a rare pineal parenchymal WHO grade 1 tumor, typically well-managed with surgical resection alone. With gross total resection (GTR), 91% 1-year and 84% 5-year survival rates have been reported. Recurrent pineocytoma is rare and optimal management in that setting is unknown, in part owing to the rarity of the condition. METHODS We report an atypical course of pineocytoma in a 58-year-old male involving metastatic disease. RESULTS A pineal mass was identified upon MRI of the brain obtained for vision changes. Patient underwent GTR, pathology was consistent with pineocytoma, WHO grade 1. Ki-67 labeling index was low at 1-2%. Despite low-grade pathology, two years later, surveillance imaging demonstrated recurrence in the pineal region and a second lesion in the right thalamus. The patient underwent gamma knife surgery (GKRS) to both lesions. Three years later, he developed three new lesions in the right cerebellum and again underwent GKRS. Subsequent surveillance imaging identified new lesions in the right cerebellum and along ventricular walls, treated with further GKRS. Nine years after initial diagnosis, focal nodular leptomeningeal metastases were discovered, along with progression at the primary tumor site. Patient was treated with GKRS to the nodular deposits followed by pembrolizumab. Further disease progression as noted despite immunotherapy. Patient was treated with 6 cycles of temozolomide chemotherapy and at further progression 3 cycles of lomustine. Upon additional progression, further radiation therapy was administered with bevacizumab to reduce risk of radiation necrosis. Patient remains on surveillance 13 years after initial diagnosis with visual changes and mild headache representing only clinical issues. CONCLUSIONS Although exceedingly rare, pineocytoma is capable of metastasizing to brain parenchyma and the leptomeninges, as demonstrated in our patient. However, our case demonstrates prolonged survival is possible even in the setting of relentlessly progressive metastatic disease with utilization of multimodality treatment.
CTIM-23. A PHASE II STUDY OF RETIFANLIMAB (PD-1 INHIBITOR) AND EPACADOSTAT (IDO1 INHIBITOR) IN COMBINATION WITH BEVACIZUMAB AND HYPOFRACTIONATED RADIOTHERAPY FOR RECURRENT GLIOBLASTOMA: NCT03532295
Authors: Abeer Butt, Jingqin Luo, Yu Tao, Omar Butt, Kelsey Etter, Leslie Nehring, Deanna Hissim, Cole McKean, George Ansstas, Albert Kim, Christopher Abraham, Sani Kizilbash, Roy Strowd, Tanner Johanns, Jiayi Huang, Matthew Ciorba, Jian Campian, Milan Chheda
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Immunotherapy has not improved survival in recurrent GBM (rGBM). Indoleamine 2,3 dioxygenase 1 (IDO1), highly expressed in ~90% of patients with malignant glioma, is a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn) and enables immune escape. METHODS We hypothesized combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies would overcome tumor-related immunosuppression. This was an open-label Phase II study of two regimens: Arm A consisted of retifanlimab (anti-PD1, 500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B added the IDO inhibitor, epacadostat (400mg po BID), initiated prior to HFRT. Key inclusion criteria included dexamethasone ≤ 4 mg/day. The primary endpoint was overall survival (OS) at 9 months (OS-9). 24 evaluable patients were required to detect an OS-9 of 60% with 80% power, compared to 38% in historical controls (bevacizumab alone) by 1-sided 1-sample log rank test at alpha=0.1. RESULTS We previously reported Arm A. Here, we present results from Arm B. 25 of the 27 patients enrolled to regimen B were evaluable: median age 58years (23-71); 28% female; 23% MGMT promotor methylated; median KPS 90 (70 - 100); a median of 6 cycles of epacadostat as of May 2024 (1 - 13). 18 of 25 died with a median follow up 9.23 months. Median PFS was 7.52 months (95%CI: 5.52-9.43). Median OS was 9.5 months (95%CI 8.08-11.96). Regimen B met its primary endpoint with OS-9 of 61.07% (95%CI: 38.23-77.65%). There were 5 possible immune-related grade 3+ toxicities to date (2 ALT/AST increase; 3 rash). CONCLUSIONS Retifanlimab, epacadostat, HFRT, and bevacizumab in rGBM is well-tolerated, with encouraging OS and PFS at the time of submission. Arm B met its primary endpoint. Further studies are warranted to identify biomarkers to predict long-term responders.
RADT-18. DEDICATED 3D-FSE SEQUENCE-BASED RADIOSURGERY REDUCES DISTANT INTRACRANIAL RELAPSE RATES IN A HISTOLOGY-AGNOSTIC PATIENT COHORT
Authors: Eyub Y Akdemir, Muni B Rubens, Selin Gurdikyan, Kevin J Abrams, Charif Sidani, Robert H Press, Matthew D Hall, D Jay Wieczorek, Cecillia Lee, Ranjini Tolakanahalli, Alonso N Gutierrez, Michael W McDermott, Minesh P Mehta, Rupesh Kotecha
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) is a cornerstone in the treatment of brain metastasis (BM), despite a known risk of distant intracranial failure (DIF). Recent imaging advances, specifically, sensitive 3D-FSE sequences, have started to be incorporated into SRS practice; however, comparisons of outcomes to historical imaging approaches are limited. We evaluated the impact of adding 3D-FSE to MPRAGE in BM detection and prolongation of DIF in a histology-agnostic patient group. METHODS Outcomes of patients treated with SRS for BM between 01/2019-01/2024 were evaluated. MPRAGE sequences were obtained for all; 3D-FSE sequences were implemented in 02/2020. Median times to DIF were estimated using the Kaplan-Meier method. RESULTS 215 patients underwent 332 SRS courses for 1456 BM imaged with MPRAGE and 3D-FSE (primary cohort), compared to the control cohort (92 patients, 135 SRS courses, 462 BM). MPRAGE sequences revealed 1636 lesions in 307 patients (462 in 92 control cohort, 1174 in 215 primary cohort). In the primary cohort, an additional 282 lesions were identified with 3D-FSE (24% increase) by neuroradiologists and multidisciplinary review. There was a statistically significant prolongation in the median time to DIF between the cohorts (11.4 vs. 6.8 months, p=0.029), most pronounced in the 1-4 metastases subgroup (14.7 vs. 8.1 months, p=0.008) and in those with a single BM (36.4 vs. 10.9 months, p=0.001). While patients relapsing on immunotherapy or targeted therapy did not significantly benefit from 3D-FSE (7.2 vs. 5.7 months, p=0.280), those who relapsed on chemotherapy or were off systemic therapy at least four weeks prior to SRS (including synchronous metastases) exhibited a trend towards longer time to DIF with 3D-FSE (14.7 vs. 7.9 months, p=0.057). CONCLUSIONS 3D-FSE added to MPRAGE lengthens time to DIF via improving BM detection, especially for limited BM, and those relapsing on systemic therapy with limited intracranial penetration or no systemic therapy.
CNSC-55. UNCOVERING THE ROLE OF COLLAGEN EXTRACELLULAR MATRIX IN GLIOBLASTOMA BRAIN MICROENVIRONMENT TRANSFORMATION
Authors: Melika Hashemi, Durgadevi Selvam, Reid J Hale, Katelynn Shockley, Ailin Zhyrgalbekovna, Andrea Comba
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is a highly malignant brain tumor characterized by diffuse infiltration and significant heterogeneity, without effective treatment. Mesenchymal-like (MES) glioma cells drive tumor aggression by promoting brain invasion and tumor microenvironment remodeling. Previous spatial transcriptomic analyses identified Collagen, particularly COL1A, as a key extracellular matrix (ECM) component, enriched in MES areas termed oncostreams. Depletion of COL1A1 disrupted oncostreams, influencing the tumor microenvironment to support cell survival, and migration. Reactive astrocytes and macrophages, essential components of the brain microenvironment, impact glioma progression. However, the interplay between glioma-secreted collagen and the brain microenvironment remains poorly understood. To elucidate this, we generated orthotopic mouse glioma models with high-collagen (NPD) and low-collagen (NPDshCol1A1). Our data revealed that downregulation of COL1A1 in glioma cells alters the abundance and spatial distribution of reactive astrocytes and macrophages/microglia. Immunofluorescence and flow cytometry analysis showed that tumors with low-collagen had decreased GFAP+ reactive astrocyte cells at the invasive edge and perivascular niche compared to high-collagen gliomas. Moreover, our results shows that high collagen levels may activate astrocytes through distant communication, as evidenced by the higher presence of reactive astrocytes in the contralateral cortex of NPD tumors. However, low-collagen tumors exhibited an increase in astrocytes (GFAP+) in the tumor core. Furthermore, high-collagen gliomas demonstrated increased macrophage infiltration, promoting an immunosuppressive environment. Using multiplex immunohistochemistry assays, we observed that reactive astrocytes along the invasive tumor edge were associated with glioma cells expressing elevated levels of COL1A1 and TGF-β ligand. In summary, our results show that glioma cell-expressed COL1A1 promotes the activation of peritumoral and perivascular brain-resident astrocytes and macrophages. The interactions of reactive astrocyte with glioma cells enriched in collagen form a feedback loop that enhances tumor invasion and vascular proliferation, suggesting that targeting the ECM-astrocyte interactions could disrupt these processes and offer a therapeutic avenue for GBM.
PATH-11. TECTAL GLIOMA: CLINICAL, PATHOLOGICAL, AND MOLECULAR FEATURES
Authors: Ryoji Imoto, Yoshihiro Otani, Joji Ishida, Shuichiro Hirano, Naoya Kemmotsu, Yasuki Suruga, Ryo Mizuta, Yasuhito Kegoya, Yohei Inoue, Kana Washio, Hiroyuki Yanai, Shota Tanaka, Kaishi Satomi, Koichi Ichimura, Isao Date
Journal: Neuro-Oncology (2024)

Abstract Tectal glioma (TG) is a rare lower-grade glioma (LrGG) that occurs in the tectum, mainly affecting children. The clinical course is usually indolent, with common symptoms including headache, gait disturbance, and ataxia resulting from obstructive hydrocephalus. TG shares pathological similarities with pilocytic astrocytoma (PA), but recent genetic analyses have revealed distinct features, such as alterations in KRAS and BRAF. Here, we report the clinical, radiological, pathological, and molecular characteristics of TG cases in our hospital. We conducted a retrospective review of cases clinically diagnosed as TG and surgically treated at our institute between January 2005 and March 2023. Molecular analysis, including genome-wide DNA methylation profiling, was performed. Six cases were identified and the median age at diagnosis was 30.5 years (range: 6–45 years). The mean tumor diameter was 22.8 mm (range: 14.7–33.2 mm), with obstructive hydrocephalus observed in all cases. Contrast enhancement of the tumor was noted in four cases and cyst formation occurred in two cases. Four patients underwent biopsy or biopsy with endoscopic third ventriculostomy, and two patients underwent tumor resection. Postoperatively, three patients received radiotherapy and two were treated with chemotherapy. The median overall survival was 6.2 years (range: 1.4–7.3 years), and the median progression-free survival was 3.4 years (range: 1.4–7.3 years). Histological diagnoses included three cases of PA, one case of astrocytoma, and two cases of high-grade glioma. Among the three patients who underwent molecular evaluation, including genome-wide methylation analysis, two had KRAS mutation and one had H3-3A K27M mutation. Our results demonstrate the diverse histological and molecular characteristics of TG distinct from other LrGGs. Given the heterogeneous pathological background and the risk of pathological progression in TG, we emphasize the importance of comprehensive diagnosis, including molecular evaluation.