tbuckley/cabot-search huggingface dataset:
DISP-08. GBM PATIENTS FACE TTF ACCESS AND INFORMATION INEQUITY THAT MAY IMPACT PATIENT OUTCOMES AND QUALITY-OF-LIFE
Authors: Quinn T Ostrom, Fabio M Iwamoto, Lakshmi Nayak, Kelli Duprey, Ed Pilkington, Jacob Ellen, David Robles
Journal: Neuro-Oncology (2024)

Abstract We evaluated the quality and accessibility of healthcare for Glioblastoma (GBM) patients across the United States through an online survey distributed to the OurBrainBank community and partners and promoted on social media. A total of 297 patients or caregivers completed the survey (85% caregivers; 15% GBM patients). Median age at diagnosis was 57, lower than the national average. 78% described having some college education, and 69% reported commercial insurance coverage. Our preliminary findings highlight that 82% of respondents reported that their treating doctor recommended the standard-of-care for GBM consisting of tumor resection, 3-6 weeks of chemo/radiation, and 6 months of chemotherapy and sometimes Tumor-Treating-Fields (TTF), per the Comprehensive- Cancer-Network (2021) guidelines. 40% reported no discussion of TTF as an option. Of those offered TTF, nearly half (46%) received it as part of their initial treatment combined with standard chemotherapy and 36% received it as a subsequent option. For those attempting to access TTF, 29% encountered difficulties, often due to financial constraints linked to insurance denials. These findings illuminate significant concerns regarding dissemination of information on treatment options, as well as access to treatments. Access to these treatments can have a significant influence on survival and quality of life of GBM patients. The substantial number of patients not offered TTF, combined with challenges to accessing treatments due to insurance issues, highlight critical obstacles to engaging in informed and shared decision-making. Compared to the general GBM-affected population, our survey respondents tend to be younger and from urban areas, indicating a possible selection bias in survey participation. This skew could lead to an underrepresentation of the challenges encountered by patients facing additional barriers. We are adopting measures to engage a more diverse participant group, especially from rural communities Ongoing targeted recruitment will further elucidate barriers to patient-centered care in GBM, with the potential for significant improvements in survival and QOL.
EXTH-58. BLOCKING IMMUNE CHECKPOINT— LAIR1: DISRUPTING THE LAIR1—FXIII-A—COLLAGEN IMMUNOSUPPRESSIVE CIRCUIT FOR ENHANCED ANTITUMOR THERAPEUTICS
Authors: Haipeng Tao, Dongjiang Chen, Changlin Yang, Duy T Nguyen, Ruixuan Liu, Tianyi Liu, Avirup Chakraborty, Alicia Y Hou, Nicole A Petit, Christina Von Roemeling, Tuo Lin, Robert W Davis, Janie Zhang, Alfonso Pepe, Diego Ivan Pedro, Hector Mendez-Gomez, Frances Weidert, Dan Jin, Kaytora Long-James, Paul C Castillo, John A Ligon, Ashley Ghiaseddin, Elias J Sayour, Maryam Rahman, Loic P Deleyrolle, Betty Y S Kim, Duane A Mitchell, W Gregory Sawyer, Jianping Huang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recent evidence indicates that tumor-associated myeloid cells (TAMCs), including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), play a crucial role in glioblastoma (GBM) immunosuppression and progression. These cells can constitute up to 50% of the total mass in GBM tumors and are pivotal in dampening the immune response, which negatively impacts patient survival. Targeting TAMCs represents a promising strategy to overcome the limitations of current cancer treatments. However, drug development in this area remains limited. Our study focuses on Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR1), a novel immune checkpoint overexpressed on TAMCs within GBM. We comprehensively analyze LAIR1’s inhibitory role in cancer progression, highlighting its potential as a therapeutic target. METHODS Both in vitro and in vivo experiments were conducted. LAIR1 wild-type (LAIR1+/+) and knock-out (LAIR1-/-) tumor models were tested for antitumor response and intratumoral immune landscape. We also utilized 2D and 3D cultures to evaluate the effects of antibody blockade (aLAIR1) alone and in combination with CAR-T therapy (8R-70CAR) in both human and mouse GBM models. RESULTS We have uncovered a previously unrecognized immunosuppressive LAIR1→ Factor XIII A (FXIII-A)→ Collagen IV circuit across cancer types. Inhibiting LAIR1, either through genetic LAIR1-/- or aLAIR1, effectively disrupts this immunosuppressive pathway and results in enhanced peripheral and tumor-infiltrating memory CD8 T cell populations, a phenotypic shift of TAMs towards an M1 profile, and a decrease in tumor collagen deposition. These collective effects contribute to the normalization of the TME and facilitate improved interactions between T cells and tumor cells, leading to a more effective antitumor response. Notably, using aLAIR1 as a standalone intervention or combined with CAR T cell therapy demonstrates enhanced antitumor efficacy in preclinical models resistant to chemo-radiation and anti-PD-1 treatments. CONCLUSIONS We discovered a novel mechanism by which LAIR1 contributes to GBM progression. LAIR1 blockade holds promise in reversing suppressive TME and serving as a therapeutic strategy.
SURG-39. LONG-TERM RESULTS OF INTERVENTION FOR GROWING INCIDENTAL MENINGIOMAS OR CONTINUED ACTIVE SURVEILLANCE, A PROSPECTIVE COHORT STUDY
Authors: Torbjørn Strømsnes, Morten Lund-Johansen, Maziar Behbahani, Geir Olve Skeie, Bente Sandvei Skeie
Journal: Neuro-Oncology (2024)

Abstract Incidental meningiomas are common findings. They represent a clinically challenging cohort, without a detailed consensus on their management. The risk of tumor progression and that of intervention must be considered. Long-term prospective data on incidental meningiomas are sparse. We aimed to evaluate the long-term effect of Gamma Knife Radiosurgery (GKRS), surgical resection and continued observation for growing incidental meningiomas. A prospective database of 62 patients (70 tumors) commenced under active surveillance was established in 2009. Radiological and clinical data was obtained until sept 2023. The results of long-term observation (group 1) and intervention with GKRS (group 2) or surgery (group 3) at progression was analyzed. Due to growth, 41 (58.6%) tumors were treated. The mean growth rate was higher prior to GKRS (2.1 cm 3 /y) and surgery (0.4 cm 3 /y) than during long-term active surveillance (0.009 cm 3 /y) (p &amp;lt; 0.001). The meningiomas became in mean 31.3% and 99.1% smaller after GKRS and resection, respectively. In comparison, tumors under long-term surveillance increased in mean 27.2% (p &amp;lt; 0.001). According to the RANO response criteria, the complete, partial, and minimal response versus stable disease rates were higher following intervention, the overall progressive disease rates were similar (Group 1; 20.7%, group 2: 11.4% and group 3: 16.7%) (p = 0.232). Treatment versus no-treatment did not affect overall survival (Group 1; 10.3 y, group 2: 11.8 y and group 3: 13.5 y (p = 0.264). No symptom development was registered in group 1. In group 2, 2.9% experienced transient (grade 2) adverse events, and in group 3, 50% suffered permanent (grade 4) adverse events according to the Common Terminology Criteria for Adverse Events (CTCEAv5). Intervention reduces tumor volume; however, the clinical significance remains uncertain and side effects are not negligible. Active surveillance is safe, saves &amp;gt; 40% of patients from unnecessary interventions and does not compromise future treatments. The optimal timing of intervention should be further explored.
DDDR-43. ERAS-801 IS A SELECTIVE BRAIN-PENETRANT EGFR INHIBITOR WITH IMPROVED ACTIVITY AGAINST EGFR EXTRACELLULAR DOMAIN-MUTANT GLIOBLASTOMA
Authors: Quincy Okobi, Dimitri Cadet, Lorenz Urner, Michael Jung, Timothy Cloughesy, David Nathanson
Journal: Neuro-Oncology (2024)

Abstract Epidermal growth factor receptor (EGFR) is a driver of nearly 50% of glioblastoma (GBM), yet EGFR inhibitors have failed in GBM (e.g., erlotinib, lapatinib, neratinib, gefitinib, and afatinib) due to poor CNS penetration and/or an inability to inhibit EGFR in its wildtype and extracellular domain (ECD) mutated forms (e.g., EGFRvIII). Here we describe ERAS-801, a reversible and selective EGFR tyrosine kinase inhibitor with unique binding properties that enable potent activity for amplified and ECD mutant EGFR. ERAS-801 demonstrated the highest nonclinical CNS penetration out of all tested EGFR inhibitor comparators. Accordingly, relative to other EGFR inhibitors tested in GBM trials (e.g., erlotinib, lapatinib, and osimertinib), ERAS-801 showed superior survival benefit in EGFR altered orthotopic PDX models. Finally, further characterization of ERAS-801 in a preclinical trial of glioma orthotopic PDX models that capture the molecular heterogeneity of GBM, ERAS-801 demonstrated a significant survival benefit at a 25 mg/kg QD dose in the vast majority of EGFR-driven orthotopic GBM PDX models, with FDG-PET imaging serving as a non-invasive biomarker of response. Based on these nonclinical data, ERAS-801 is currently under clinical investigation for GBM.
CNSC-40. GTP SIGNALING PATHWAY PROMOTES NHEJ REPAIR BY INDUCING NUCLEAR ACTIN POLYMERIZATION IN GLIOBLASTOMA
Authors: Weihua Zhou
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVES We recently identified that GTP promotes non-homologous end joining (NHEJ) by triggering a GTP-Rac1-PP5-Abi-1/S323 cascade and we sought to define the molecular mechanisms. METHODS Crispr/Cas9, CDNA overexpression and immunoblot were used to modulate and confirm protein levels. Cellular fractionation and immunofluorescence (IF) were used to determine the localization of proteins. Laser micro-irradiation was used to induce DNA damage and monitor the recruitment of DNA repair proteins. RESULTS We found that GTP-activated protein Rac1 and Abi-1, the two key components of the newly identified pathway, shuttled into the nucleus post-RT in glioblastoma (GBM) cells. These effects were further enhanced by the GTP precursor guanosine but blocked by GTP depletion. Furthermore, Abi-1 and Rac1 accumulated in the nucleus of the cells expressing constitutively active Rac1 but not dominant negative Rac1 after RT, which suggests that Rac1/Abi-1 nuclear translocation is Rac1 activity dependent. We previously discovered that GTP-Rac1 promotes DNA repair by facilitating the dephosphorylation of Abi-1 (S323). Here, we discovered that dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D) shuttled into nucleus after RT. Because Rac1 canonically binds to Abi-1 and promotes actin polymerization in the cytosol, we next wanted to determine if RT-induced nuclear Rac1/Abi-1/S323A could enhance nuclear actin polymerization, which could enhance NHEJ repair. We found that Abi-1/S323A but not Abi-1/S323D increases nuclear filament actin formation post-RT and activating the GTP-Rac1-Abi-1/S323A axis (through guanosine supplementation, expression of constitutively active Rac1 or expression of dephosphomimetic Abi-1/S323A) enhanced the recruitment and stability of KU80 at sites of DNA damage, which could be blocked by actin polymerization inhibitor cytochalasin D. Furthermore, inhibiting actin polymerization overcame radiation resistance in GBM cells with an active GTP-Rac1-Abi-1/S323A axis. CONCLUSIONS GTP-Rac1-PP5-Abi-1/S323 cascade promotes NHEJ repair by inducing the nuclear assembly of filament actin and disrupting this regulation could improve treatment responses in GBMs.
CSIG-08. AGGRESSIVE HIGH-GRADE NF2 MUTANT MENINGIOMAS DOWNREGULATE ONCOGENIC YAP SIGNALING VIA THE UPREGULATION OF VGLL4 AND FAT3/4
Authors: Abigail Parrish, Sonali Arora, H Nayanga Thirimanne, Dmytro Rudoy, Sebastian Schmid, Philipp Sievers, Felix Sahm, Eric Holland, Frank Szulzewsky
Journal: Neuro-Oncology (2024)

Abstract Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Furthermore, decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 in NF2 mutant meningiomas.
TMET-02. CELL-INTRINSIC METABOLIC PHENOTYPES IDENTIFIED IN GLIOBLASTOMA PATIENTS USING MASS SPECTROMETRY IMAGING OF 13C-LABELED GLUCOSE METABOLISM
Authors: Anastasia Tsyben, Andreas Dannhorn, Gregory Hamm, Dominique-Laurent Couturier, Mayen Briggs, Richard Mair, Kevin Brindle
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GB) is an inherently heterogeneous and invasive primary brain cancer. Genomic and transcriptomic studies have attempted to classify GB into subtypes that predict survival and that have different therapeutic vulnerabilities. An outstanding question and technical challenge is to visualize the metabolism of a tumour within its native microenvironment and understand to what extent its metabolism is driven by the microenvironment. Patients with GB tumours were infused with [U-13C]glucose and intra-operative multi-regional tumour samples were rapidly snap frozen for analysis using mass spectrometry imaging (MSI). Tissue microenvironment was assessed using multiplexed antibodies in immunocytochemistry (IMC) of contiguous sections. Isotope tracking in human-derived neurospheres and patient-derived xenografts were used to confirm the presence of metabolic phenotypes detected in the human samples and to test the susceptibility of each phenotype to a panel of drugs targeting cellular metabolism. Three metabolic signatures were identified in patient tumours: glycolytic, oxidative and a mixed glycolytic/oxidative phenotype. The phenotypes did not correlate with microenvironmental features, including proliferation rate, immune cell infiltration, and vascularisation. The phenotypes were retained when patient-derived cells were grown in vitro, or as orthotopically implanted xenografts, and were robust to changes in oxygen concentration, demonstrating their cell intrinsic nature. The spatial extent of the regions occupied by cells displaying these distinct metabolic phenotypes are large enough to be detected using clinically applicable metabolic imaging techniques. The phenotypes also demonstrate differential drug sensitivities, suggesting imaging of these phenotypes may be used to stratify patients for personalised therapy trials. This is the first report to demonstrate high resolution imaging of metabolic fluxes in a human tumour in vivo and the presence of different metabolic phenotypes within GB that are tumour cell intrinsic and largely independent of the tumour microenvironment.
NIMG-11. DISCOVERING POSTOPERATIVE APHASIA RECOVERY IN GLIOMA PATIENTS: THE ROLE OF THE RIGHT BROCA’S HOMOLOG AND VERIFICATION
Authors: Shimeng Weng, Peng Wang, Shengyu Fang, Tao Jiang
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE This study aimed to elucidate the neurological mechanisms that support the recovery of postoperative aphasia by examining alterations in language and extended networks in patients with glioma. Additionally, we sought to determine the causal relationship between the right Broca’s homolog and language recovery using neuro-navigated repetitive transcranial magnetic stimulation (nrTMS). METHODS Sixty-two patients with left hemisphere gliomas were retrospectively analyzed and categorized into aphasia and non-aphasia groups based on Aphasia Quotient (AQ) scores. Resting-state functional MRI (rs-fMRI) data were collected and analyzed to investigate differences in functional connectivity (FC) and topological properties of language-related networks. Additionally, eight patients with surgery-induced aphasia were prospectively treated with nrTMS, targeting the node identified from the retrospective analysis. RESULTS Significant increases in FC between the left auditory cortex and the right inferior frontal gyrus in the Executive Control Network were observed in the non-aphasia group. Nodal properties, such as the nodal efficiency of the right Broca’s homolog, were independently associated with postoperative language function. The nrTMS treatment group demonstrated significant improvements in AQ scores, with correlations between increased nodal efficiency and positive language outcomes. CONCLUSION The right hemisphere, specifically the right inferior frontal gyrus, plays a compensatory role in maintaining language function after glioma resection. These findings suggest the therapeutic potential of nrTMS for enhancing postoperative language recovery, offering insights into individualized patient care and rehabilitation strategies for patients with glioma.
IMMU-28. LOW-INTENSITY PULSED ULTRASOUND COMBINED WITH POLY-ICLC AND INTERLEUKIN-2 UNLOCKS THE IMMUNE PRIVILEGE OF THE BRAIN BY PROMOTING EPITOPE SPREADING AND ACTIVATION OF CNS-SPECIFIC NAÏVE T CELLS
Authors: Marco Gallus, Akane Yamamichi, Victor Andres Arrieta, Atsuro Saijo, Pavlina Chuntova, Su Phyu, Lan Phung, Jeffrey Haegelin, Haoyu Long, Senthilnath Lakshmanachetty, Takahide Nejo, Kaori Okada, Li Chen, Karl Habashy, Andrew Gould, Christina Amidei, Catalina Lee Chang, Roger Stupp, Michael Canney, Adam M Sonabend, Hideho Okada
Journal: Neuro-Oncology (2024)

Abstract Immunotherapies targeting glioma, such as chimeric antigen receptor (CAR) T cell therapies, offer new therapeutic avenues; however, their application has yielded limited success in clinical trials so far. Due to the antigenic heterogeneity of gliomas, targeting a few or several antigens still results in recurrence with “antigen-loss” tumors, indicating the need to engage the endogenous immune system to eliminate these therapy-resistant tumor cells. However, natural anatomical barriers and an immunosuppressive environment allow brain tumors to evade detection by the endogenous immune system. Low-intensity pulsed ultrasound combined with microbubbles (LIPU/MB) has recently been shown to transiently open the blood-brain barrier (BBB), enabling penetration of cells and drugs into the CNS. Using intravital two-photon imaging, two-photon microscopy, multiparametric spectral flow cytometry, and bone marrow chimera mice, alongside blood samples from glioblastoma patients treated with LIPU/MB, we observed that LIPU/MB promotes migration of CNS antigen-presenting cells from the perivascular space into the periphery. To assess the immunological relevance of LIPU/MB-mediated CNS antigen presentation to the peripheral immune system, we have developed new transgenic mice (GFAP-minigene mice) with an intact BBB expressing four immunogenic peptides under the CNS-specific GFAP promoter. In GFAP-minigene mice, LIPU/MB combined with toll-like receptor 3 agonist poly-ICLC and Interleukin-2 promoted priming, activation, and homing of naïve CNS-specific T cells into the brain parenchyma. Cytotoxic T cell activity in the brain was accompanied by MHC-I and MHC-II epitope spreading, mirrored by the occurrence of endogenous T cells in the brain, deep cervical lymph nodes, and spleen harboring other CNS-(minigene) antigen-specific T cell receptors. Collectively, our findings suggest that LIPU/MB combined with poly-ICLC can overcome inherent limitations of immunotherapy by enhancing CNS epitope spreading and activation of naïve CNS-antigen-specific T cells within the context of an intact blood-brain barrier.
TMOD-05. GLIOMA-ASSOCIATED OLIGODENDROCYTE PROGENITOR CELLS’ DYNAMIC PATTERNS SUGGEST FUNCTIONAL ADAPTATIONS DURING GLIOMA PROGRESSION IN A UNIQUE MOUSE MODEL
Authors: Claudia K Petritsch, Lulu Xing, Brandon Bui
Journal: Neuro-Oncology (2024)

Abstract Gliomas account for more than one-third of brain tumors in children, with high fatality rate despite aggressive adjuvant treatment. Two-thirds of survivors suffer from health conditions due to the toxicity of conventional therapies. Notably, gliomas with the BRAFV600E mutation, occurring in ~20% of all glioma cases, are difficult to treat and have a high risk for progression, especially when combined with CDKN2A deletion. The mechanisms for glioma progression remain unclear and unraveling them could lead to therapies that inhibit glioma progression, preventing high-grade gliomas. Objectives: To gain mechanistic insights into glioma progression and exploit therapeutically for preventing progression. We developed two novel mouse models for BRAFV600E mutant progressive gliomas – one at high genetic risk for progression and one at intermediate genetic risk for progression. Expression of genetic alterations were induced by injecting compound transgenic mice with adenovirus-Cre. Our new mouse models therefore more faithfully recapitulated the genetic changes accompanying glioma formation and progression from low- to high-grade than earlier mouse models which used the RCAS system to overexpress the oncogene (PMCID: PMC11112369 ). Glioma formation was followed non-invasively by magnetic resonance imaging. Single cell RNA sequencing and spatial transcriptomics were performed and immunofluorescence was used for validation (PMCID: PMC10619673 ). We present new data showing that animal subject survival is significantly shorter in the high risk model than in the low risk model. Our two models with distinct latency can be used for preclinical studies and studies of the changes associated with progression, including in the glioma microenvironment. Analyses revealed temporal, functional, and spatial changes in glioma-associated oligodendrocyte progenitor cells (GA-OPCs) at distinct stages (initiation, expansion, progression) and grades. Our findings that GA-OPCs closely interact with glioma cells and their morphological transformation as gliomas progress, suggest changing functions, including potential roles in phagocytosis and immunomodulation. Understanding the unclear role of glioma microenvironment OPCs in promoting glioma progression could reveal an Achilles heel for targeted therapies.