tbuckley/cabot-search huggingface dataset:
ANGI-07. A CASE OF HYPERBARIC OXYGEN USED AS A TREATMENT MODALITY FOR ANAPLASTIC ASTROCYTOMA
Authors: Catherine Boldig, Muhammad Jaffer, Yolanda Pina, Sepideh Mokhtari
Journal: Neuro-Oncology (2024)

Abstract Although its precise mechanism is unclear, hyperbaric oxygen is thought to impede the growth of tumor cells by inhibiting tumor hypoxia, a known driver for angiogenesis. We present a case of a 32-year-old pilot who developed sudden onset aphasia and disorientation which led to hospitalization and imaging. He was diagnosed with anaplastic astrocytoma and underwent resection, radiation, and chemotherapy with temozolomide. Approximately one year later, MRI showed enlarging non-enhancing T2/FLAIR hyperintense mass in the right temporal lobe. He received 4 cycles of lomustine. Four months later, MRI showed slight increase in the size of ring enhancement around the treatment area. These findings were thought to be related to treatment-related changes. After 4 doses of bevacizumab every 2 weeks, there was improvement in surrounding vasogenic edema. However, after 7 doses, his MRI brain demonstrated increase in treatment-related changes with more vasogenic edema. He also had worsening left-sided weakness, unable to lift his left arm against gravity, dysarthria, and cognitive slowing. MRI perfusion supported treatment-related changes rather than tumor growth. He then started hyperbaric oxygen treatments and after 20 sessions of treatment, his vasogenic edema and his left-sided weakness improved. After 60 sessions of hyperbaric oxygen, he noticed further improvement in his strength and short-term memory. Four months after completion of his hyperbaric oxygen, he was found to have increasing size of ring-enhancing lesion and was restarted on hyperbaric oxygen treatments in addition to bevacizumab and low-dose temozolomide. He completed a total of 100 rounds of hyperbaric treatments. MRI showed improvement and stability. His left-sided weakness continued to improve. Hyperbaric oxygen alone or combined with other treatment modalities may be a promising therapy to improve quality of life. Further research will assist with mechanisms through which hyperbaric oxygen works and patient outcomes.
SURG-49. INVESTIGATING LITT-BASED COMBINATION THERAPIES IN PRECLINICAL GLIOMA MODELS
Authors: Timothy Woodiwiss, David Giles, Rowland Han, Derek Li, Colin McCornack, Loren Beck, Yiwei Fu, Will Leidig, Markus Anzaldua-Campos, Ryan Cleary, Albert Kim
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Laser interstitial thermal therapy (LITT) is a minimally invasive means of tumor cyto-destruction with the potential for additional clinical benefits, such as altering the blood-brain barrier or the brain tumor microenvironment (TME). Using a murine model of GBM, we utilized a clinically relevant laser ablation model to identify and exploit immune TME changes after LITT to generate therapies that improve mouse survival, with the potential for rapid clinical translation. METHODS Right frontal lobe implantation of the immune “cold” SB28 murine glioma cells were performed in C57BL/6J mice. Tumor location was verified by MRI followed by stereotactic insertion of a paired fiberoptic laser and thermocouple to perform real-time hyperthermic ablation with temperature monitoring. Pulsed laser application maintained a peri-lesional temperature of 44°C for 150-180 seconds. Following LITT (or sham surgery), spectral flow cytometry was used to profile the immune TME. Survival studies were performed using a combination of LITT and immune modulating therapies. RESULTS Laser ablation alone provided a survival benefit compared to sham surgery (median survival: 29 vs 22.5 days, P&amp;lt;0.0001) in in glioma-bearing mice. Survival studies combining LITT with anti-PD1 lacked a significant response in the SB28 model but showed some long-term survivors. Flow cytometry performed on brain tissue post-LITT days 3 and 7 demonstrated little to no change in CD4+/CD8+ T cell responses but did show an increase in neutrophils, which expressed TLR2 and 4. The TME showed negligible numbers of phagocytic cells with obvious tumor cell uptake post-LITT. Using these results, we generated strategies for LITT-based combination immune therapies. Survival studies are ongoing using combinations of LITT/anti-PD1 with neutrophil depletion, inhibition of anti-CD47, and addition of broad TLR2/4 agonists as a neutrophil stimulus. CONCLUSIONS A clinically relevant immunocompetent murine LITT model enables the generation of novel treatment strategies with potential for rapid clinical translation.
CNSC-44. TARGETING OF THE YAP/TAZ-TEAD AXIS DIMINISHES VIABILITY AND DIFFERENTIATION POTENTIAL IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Jorge Luis Jimenez Macias, Se-Yeong Oh, Zhengang Hu, Kevin Yin, Nisan Sele, Nikki Boon, Anson Sing, Steven A Sloan, Renee D Read
Journal: Neuro-Oncology (2024)

Abstract Pediatric high-grade gliomas (pHGGs) are invasive and fast-growing brain malignancies. They account for up to 40% of all brain tumor-related deaths in childhood. Genetic alterations that characterize these gliomas include H3 onco-histone mutations and genetic alterations in receptor-tyrosine kinases (RTKs), including amplification, mutation, and gene fusions in RTKs. However, direct targeting with tyrosine kinase inhibitors (TKIs) has shown at best partial responses in patients due to the molecular heterogeneity within these tumors and the lack of pharmaceutical penetration into the central nervous system (CNS). Thus, alternative therapeutic approaches to treat pHGGs are urgently needed. The YAP/TAZ transcription factors, which cooperate with TEAD co-factors to promote target gene expression, orchestrate stem-cell fate decisions and proliferation downstream of growth factor signaling pathways, such as RTKs. We observed that YAP expression is upregulated in RTK mutant and H3 mutant pHGGs. Depletion of YAP via RNAi methods decreased proliferation, inhibited pHGG stem cell self-renewal, and induced apoptosis of pHGG cells. Use of Verteporfin (VP), a FDA-approved YAP/TAZ small molecule inhibitor, mimicked the effects seen by YAP genetic depletion. Using an in vitro human cortical organoid-tumor model in which tumor cells are engrafted to human brain cortical organoids, we screened for responses in tumor cells and in non-tumor cells in the neural microenvironment upon VP treatment, using single-cell RNA-sequencing and immunofluorescence to visualize responses. These organoid models offer improved models for modeling how the neural CNS microenvironment shapes responses of tumor cells to YAP/TAZ inhibition and VP treatments. Results from our work showing that YAP/TAZ-TEAD inhibition is a promising therapeutic avenue for management of pHGGs will be presented. Further pre-clinical work will follow to correlate observation and understand the therapeutic efficacy of YAP/TAZ-TEAD inhibition for pHGG treatment.
ANGI-08. SPATIAL TRANSCRIPTOMIC COMPARISONS OF GLIOBLASTOMA TISSUE REVEAL UPREGULATION OF NEURODEVELOPMENTAL PATHWAYS AND SYNAPTIC GENES IN INFILTRATING TUMOR CELLS
Authors: Dylan Harwood, Vilde Pedersen, Nicolai Bager, Ane Schmidt, Tobias Stannius, Aušrinė Areškevičiūtė, Knud Josefsen, Dorte Nørøxe, David Scheie, Hannah Rostalski, Maya Lü, Alessio Locallo, Ulrik Lassen, Frederik Bagger, Joachim Weischenfeldt, Dieter Heiland, Kristoffer Vitting-Seerup, Signe Michaelsen, Bjarne Kristensen
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, chemotherapy, and radiotherapy. Malignant cells escape surgical resection by migrating into the surrounding healthy brain tissue, where they give rise to the recurrent tumor. Gene expression profiling allows glioblastoma tumor cores to be classified into mesenchymal, proneural, and classical subtypes, each with distinct genetic alterations and cellular compositions. In contrast, the adjacent brain parenchyma where infiltrating malignant cells escape surgical resection is less characterized in patients. Using single-cell and multicellular resolution spatial transcriptomics on tissues from both the tumor core and infiltrated brain tissue (n = 11), we compared the transcriptional profiles of malignant cells in these regions. Malignant cells near regions with microvascular proliferation showed increased expression of genes related to vascular homeostasis. Within tumor cores, proneural and mesenchymal subtypes exhibited distinct spatial gene expression patterns, although these differences were reduced in the infiltrated brain tissue, apart from gene expression due to chromosomal alterations specific to the proneural subtype. We identified two transcriptional patterns of brain infiltration, with the dominant pattern showing a transition from mesenchymal to proneural states. This transition was accompanied by increased expression of genes linked to neurodevelopmental pathways and glial cell differentiation. Additionally, one gene module upregulated in infiltrating malignant cells was predictive of poor patient survival and enriched for genes associated with differentiated neuronal cells. Together, our findings provide an updated view of the spatial landscape of glioblastomas and infiltrated brain tissue, furthering our understanding of the malignant cells that invade healthy brain. This insight offers new avenues for targeted therapy after surgical resection of the primary tumor.
EXTH-02. MODIFYING CAR T CELL EPIGENETIC PROGRAMS TO IMPROVE THEIR PERSISTENCE AGAINST GROUP 3 MEDULLOBLASTOMAS
Authors: Meghan Ward, Linda Senaoui, Ben Youngblood, Martine Roussel, Giedre Krenciute
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Safe, effective therapies are desperately needed to improve outcomes for patients with medulloblastoma (MB), a malignant pediatric brain cancer. Chimeric antigen receptor (CAR)-T cells are a promising therapeutic option as they target T-cell cytotoxicity exclusively to tumor associated antigens. B7 homolog 3 (B7-H3) is an ideal target for CAR-T cell therapy as all MB subtypes express B7-H3 but healthy tissues do not. However, a major roadblock to tumor clearance and control is the inability of CAR-T cells to persist, suggesting that improving persistence will improve therapeutic efficacy. The goal of this study was to compare head-to-head the impact of knocking out TET2 and DNMT3A negative epigenetic regulators of CAR-T cell persistence against group 3 MB (G3MB), the most malignant MB subtype. METHODS We generated B7-H3 CAR-T cells with CD28ζ signaling domain and performed CRISPR/Cas9 knockout (KO) of TET2, DNMT3A, and AAVS1 as a control. We compared resulting CAR-T cell persistence via repeat stimulation assays in vitro against G3MB cell lines with varying B7-H3 antigen density (D341low, HDMB03mid, and D425high). We further compared KO CAR-T cells in vivo against D341low, HDMB03mid, and D425high orthotopic xenografts. RESULTS Our data shows that DNMT3A KO, but not TET2 KO, consistently improves the persistence and expansion of CAR-T cells against G3MB in vitro. In vivo, KO of epigenetic regulators, improves CAR-T cell therapy against highly aggressive D341low, HDMB03mid, and D425high but is insufficient to elicit curative responses. CONCLUSIONS Our study demonstrates that genetic KO of negative epigenetic regulators of CAR-T cell persistence can improve anti-tumor function against G3MB. We conclude that for the B7-H3.CD28ζ CAR, DNMT3A KO is superior for improving persistence over TET2 KO, but that DNMT3A KO is insufficient in vivo.
NIMG-85. RADIATION DOSE IS ASSOCIATED WITH CHANGE IN MAGNETIC RESONANCE FINGERPRINTING PROPERTIES OF ANATOMICALLY DISTINCT REGIONS OF INTEREST IN GLIOBLASTOMA MULTIFORME PATIENTS
Authors: Joan Lee, Theodore Arsenault, Sree Gongala, Tiffany Hodges, Dan Ma, Herbert Newton, Chaitra Badve, Prashant Vempati
Journal: Neuro-Oncology (2024)

Abstract Magnetic Resonance Fingerprinting (MRF) is an investigational imaging technique that provides spatially-resolved quantification of tissue properties, in contrast to qualitatively weighted conventional MR imaging. Intentional sequential variation of acquisition parameters throughout the MRF acquisition produces a unique quantitative signal timecourse for each tissue, which generates a spatial “fingerprint” for individual voxels. This study applies MRF to quantitatively correlate radiation dose with MR signal intensity changes, specifically T1, T2, and M0 maps across regions of interest (ROIs) that are involved in cognitive speed and processing. Three patients who underwent radiation therapy for resected glioblastoma multiforme participated in this study. MRF scans were conducted at pre-radiotherapy (pre-RT), mid-radiotherapy (mid-RT), and post-radiotherapy (post-RT) timepoints. ROIs (bilateral hippocampi, amygdalae, dorsolateral prefrontal cortices, and corpus callosum) were contoured and radiation dose to the ROI contours at mid-RT and post-RT timepoints were obtained using MIM treatment planning software (MIM Software, Beachwood, OH). Spearman’s rank correlation test was conducted in MATLAB (MATLAB R2024a, Natick, MA) for mean radiation dose to ROIs against MRF T1 relaxation time, T2 relaxation time, and M0 proton density. Mean radiation dose exhibited statistically significant correlation with absolute changes from pre-RT to post-RT T1 relaxation time, T2 relaxation time, and M0 proton density values across the ROIs. Mid-RT scans showed intermediate changes, suggesting a progressive alteration in tissue characteristics with accumulating radiation dose. The hippocampus and amygdala received lower radiation doses than other ROIs and exhibited less pronounced changes in T1, T2, and M0 values. These results demonstrate a novel application of MRF in quantitative characterization of imaging changes in anatomically distinct ROIs. The correlation between radiation dose and absolute changes in MRF signal values from pre-RT to post-RT MRF scans reflect progressive changes as a result of radiation exposure.
TMET-28. RECIPROCAL LINKS BETWEEN METHIONINE METABOLISM, DNA REPAIR AND THERAPY RESISTANCE IN GLIOBLASTOMA
Authors: Navyateja Korimerla, Kari Wilder-Romans, Jie Xu, Isra Haq, Weihua Zhou, Peter Kalev, Nathan Qi, Charles Evans, Maureen Kachman, Zitong Zhao, Angelica Lin, Andrew J Scott, Alexandra O’Brien, Ayesha Kothari, Sravya Palavalasa, Erik Peterson, Marc L Hyer, Katya Marjon, Costas A Lyssiotis, Taryn Sleger, Daniel R Wahl
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance.Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor-specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.
CSIG-14. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS THROUGH THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION
Authors: Pin-Yuan Chen, Pei-Yu Liu, Chy-In Huang, Hsiang-Tsui Wang
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.
CNSC-12. IMMUNOLOGICALLY TARGETING U1 MUTANT SHH MEDULLOBLASTOMA
Authors: Michelle Kameda, Rong Zheng, Nabil Ahmed, Chonghui Cheng, Michael Taylor
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVES Medulloblastoma (MB) is the most common malignant pediatric brain tumor representing a significant burden of morbidity and mortality in the US. MB is comprised of four subgroups: Wnt, Shh, Group 3, and Group 4. Shh tumors represent 25% of cases and subdivides into Shh-beta and Shh-gamma, Shh-alpha, and Shh-delta. Half of Shh MB carry an identical somatic point mutation in a non-coding small nuclear RNA (snRNA) called U1 (r.3A&amp;gt;G) which is found in 97% of Shh-d tumors, and in most Shh-alpha tumors with TP53 mutations. Current therapies for patients with TP53 and U1 mutant Shh-alpha MB observe rare survivors, and adult Shh-delta patients continue to experience significant morbidity and mortality calling for urgent prioritization of these tumors for targeted therapy. METHODS Cryptic exons were identified in both Shh-delta U1 snRNA mutant samples and Shh-delta U1 wildtype (WT) samples using CryEx pipeline. In-house scripts were utilized for selecting for cryptic exons that are uniquely expressed in Shh-delta U1 snRNA mutant compared to wildtype (WT) samples. RESULTS Analyzing 180 Shh MB RNA-seq samples, we identified 23% Shh-alpha, no Shh-beta, 97% of Shh-delta and 3% Shh-gamma harbored the U1 mutation. The splicing landscape was then interrogated comparing Shh-delta U1 snRNA mutant samples to WT samples. Expressed exons were filtered to exclude known exons to identify novel or cryptic exons. To select for Shh-delta U1 snRNA mutant induced cryptic exons, CryEx arising from introns, not identified in Shh-delta U1 WT and included &amp;gt;10% of their inclusion rates measured by percent spliced in (PSI) in Shh-delta U1 snRNA mutant samples were filtered. Of the middle CryEx, we identified 43,188 that were U1 mutant induced. Further filtering for cell surface Middle CryEx, three of the 75 middle CryEx overlapped. CONCLUSION The PTCH1 neoantigen formed from the CryEx insertion translates a protein that is unique to the tumor cells (i.e., not in normal tissue) was identified as a juxtamembrane for therapeutic drug discovery.
CNSC-11. INVESTIGATION OF GLIOBLASTOMA NEURON-TUMOR NETWORKS WITH RABIES-BASED RETROGRADE TRACING
Authors: Svenja K Tetzlaff, Ekin Reyhan, C Peter Bengtson, Julian Schroers, Julia Wagner, Marc C Schubert, Nikolas Layer, Maria C Puschhof, Anton J Faymonville, Nina Drewa, Rangel L Pramatarov, Niklas Wissmann, Obada Alhalabi, Alina Heuer, Nirosan Sivapalan, Joaquín Campos, Berin Boztepe, Jonas G Scheck, Giulia Villa, Manuel Schröter, Felix Sahm, Karin Forsberg-Nilsson, Michael O Breckwoldt, Claudio Acuna, Bogdana Suchorska, Dieter Henrik Heiland, Julio Saez-Rodriguez, Varun Venkataramani
Journal: Neuro-Oncology (2024)

Abstract Glioblastomas are primary brain tumors known for their whole-brain invasion and high therapeutic resistance. In previous studies, neuron-to-glioma synapses have been shown to promote glioblastoma progression. A deep characterization of this communication and of tumor-connected neurons has not been possible due to technological limitations. We adapted a rabies virus-based retrograde tracing approach to investigate and manipulate neuron-tumor networks. Interestingly, we found that glioblastoma cells rapidly integrated into neural circuits across the brain, engaging with distal neurons of diverse subtypes in very early stages of tumor development. Beyond glutamatergic neurons, we identified cholinergic neurons as drivers of glioblastoma cell invasion. We revealed patient- and tumor cell state-dependent differences in the expression of synaptogenic genes which also correlated with neuron-tumor connectivity and tumor cell invasivity. Notably, radiotherapy led to increased neuron-tumor connectivity mediated via neuronal hyperexcitability. The anti-epileptic drug perampanel alongside radiotherapy mitigated this effect and enhanced treatment efficacy by simultaneous neuronal activity inhibition. Utilizing our rabies-based approach, we genetically ablated tumor-connected neurons leading to a significantly decreased tumor progression offering a potential novel therapeutic avenue. Taken together, we developed a framework for dedicated analysis of multicellular neuron-tumor networks and propose our methodology as a versatile and adaptable approach to tackle glioblastoma.