tbuckley/cabot-search huggingface dataset:
TMIC-05. AGING-SPECIFIC MICRORNA EXPRESSION SIGNATURE IN ELDERLY GLIOBLASTOMA
Authors: Daisuke Yamashita, Yoshihiro Ohtsuka, Haruna Takeda, Kosuke Kusakabe, Masahiro Nishikawa, Satoshi Suehiro, Akihiro Inoue, Hideaki Watanabe, Toru Kondo, Hozumi Motohoshi, Takeharu Kunieda
Journal: Neuro-Oncology (2024)

Abstract PURPOSE The rise in aging population worldwide is increasing death from cancer, including glioblastoma. MicroRNAs (miRNAs/miRs) are small non-coding RNAs that mediate the posttranscriptional silencing of specific target mRNAs and that are currently recognized as important regulators of tumorigenesis and development. Here, we explore the impact of brain aging and aging-specific miRNAs on elderly glioblastomas. METHODS We comprehensively analyzed miRNAs expression using the TCGA dataset and identified miRNAs that are specifically expressed in elderly glioblastomas. To create the Ehime Glioma Genome Atlas (EGGA), RNA sequencing was performed using tumor tissues from 8 glioblastoma patients (4 elderly and 4 non-elderly). First, we evaluated the impact of the identified miRNAs on prognosis using TCGA and CGGA datasets and searched for target genes of specific miRNAs using TargetScan. The expression patterns of the identified target genes were verified using EGGA, TCGA, and CGGA datasets. RESULTS We divided the TCGA dataset into elderly and non-elderly groups based on three ages (75 years-old, 70 years-old, and 65 years-old) and analyzed the expression of miRNAs in tumor tissues. There were 3 miRNAs that showed abnormalities (1 increased miRNA, 2 decreased miRNAs), and among these, miR-210 (increased expression) and miR-507 (increased expression) were identified as miRNAs related to prognosis. Next, we analyzed the expression of EGGA and identified 410 mRNAs (368 increased mRNAs, 42 decreased mRNAs) that showed significantly abnormal expression in the elderly group. The target genes searched using TargetScan were 4,048 genes for miR-210 and 4,704 genes for miR-507. When compared with the 410 genes identified using EGGA, PLA2G3, a target gene to miR-507, was identified. The expression of PLA2G3 was also specifically increased in elderly glioblastoma in the TCGA dataset, and it had a strong influence on prognosis. CONCLUSION Our results found an aging-specific miRNA “miR-507” and its target gene “PLA2G3” that suggested as potential new therapeutic target molecules for improving the prognosis of elderly glioblastomas.
TMET-21. METABOLIC PROFILING OF MENINGIOMA REVEALS NOVEL SUBGROUP-SPECIFIC BIOLOGIC INSIGHTS AND OUTCOME DEPENDENCIES
Authors: Alexander Landry, Justin Wang, Jeff Liu, Vikas Patil, Wen-Jiang Zhang, Yosef Ellenbogen, Chloe Gui, Andrew Ajisebutu, Thomas Kislinger, Eric Chen, Farshad Nassiri, Gelareh Zadeh
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Prior studies have elucidated the presence of four consensus molecular groups (MGs) of meningioma, with unique underlying biology and outcomes. The hyperactivation of metabolic pathways may be associated with tumour growth in so-called hypermetabolic (MG3) tumours, and there is a need to better understand the metabolic profiles of these tumours. This study is the first to study the global metabolon of meningioma in the context of modern molecular subgroups. METHODS We performed untargeted metabolic profiling of 53 meningiomas representing each MG and WHO grade. Prognostic biochemicals were identified using Cox regression and further investigated using RNA and protein-based pathway analyses. A larger cohort with available RNA sequencing (n=121) was used to further explore the prognostic influence of relevant pathways, and biochemicals of interest were validated on a subset of these samples (n=35) using targeted high performance liquid chromatography (HPLC). RESULTS Our untargeted approach identified 560 unique biochemicals for downstream analysis. The abundance of N6-trimethyllysine was associated with significantly earlier time to recurrence highly prognostic on our whole cohort (HR [95%CI] = 3.18 [1.45-26.23], p = 0.004) and within hypermetabolic (MG3) tumours (HR [95%CI] = 6.73 [1.72-6.97], p = 0.006); pyruvate was with worse outcomes in proliferative (MG4) tumours specifically (HR [95%CI] = 5.65 [1.073-29.71], p = 0.041). Analysis of implicated gene pathways demonstrated that upregulation of the oxidative phosphorylation pathway portends worse outcomes in the hypermetabolic subgroup but better outcomes in the proliferative subgroup. By contrast, upregulated lactate transporters were associated with worse outcomes in proliferative, but not hypermetabolic, meningiomas. CONCLUSIONS This is the first study to demonstrate a subgroup-specific prognostic role of N6-trimethyllysine and pyruvate in meningioma, offering increasingly granular outcome predictions using a widely accessible technique (HPLC). In addition, we demonstrated key differences in energy utilization between hypermetabolic and proliferative tumours suggesting fundamental differences in preferred energy utilization and reinforcing a need for subgroup-specific therapies.
CNSC-31. INVESTIGATING THE THERAPEUTIC POTENTIAL OF STK17A INHIBITION IN GLIOBLASTOMA
Authors: Jesus Castro, Deepa Seetharam, Sana Chaudhry, Jay Chander, Justin Taylor, Ashish Shah
Journal: Neuro-Oncology (2024)

Abstract For decades, the survival rate for glioblastoma (GBM) has remained nearly stagnant, with a 5-year survival rate of only 5%. There is an unmet medical need for therapeutic development, because while GBM is the most common primary brain tumor, only four FDA approved drugs have been developed for GBM over the last century. By taking advantage of RNA sequencing, a potential target for GBM has been identified: the kinase STK17A (Serine/Threonine Kinase17A). We confirmed that STK17A is overexpressed in gliomas by analyzing public databases and single-cell RNA sequencing from our own GBM patients, and further associated it with poor patient outcome. Little is known about STK17A, but it has been found to be involved in cell proliferation and tumorigenesis. The role of STK17A in GBM pathophysiology and its therapeutic potential as a drug target remains a critical knowledge gap. To better understand STK17A’s role in GBM pathophysiology, we first knocked down STK17A in GBM cell lines and determined that STK17A had functional roles in proliferation and morphology. Similar conclusions were drawn after removing STK17A in GBM xenograft mouse models. These findings support STK17A as a viable therapeutic target. We then designed and optimized novel STK17A inhibitors for evaluations through kinase enzymatic and biological assays, in vitro proliferation and toxicity assays, and in vivo Drug Metabolism and Pharmacokinetics (DMPK) assays. We then used these potent, selective, and highly brain penetrant STK17A inhibitors to investigate the anti-tumor effects of STK17A inhibition in GBM and demonstrate the efficacy of our novel STK17A inhibitors in vivo. In conclusion, this work seeks to contribute to the field of targeted therapies for GBM by optimizing and examining a novel brain penetrant STK17A inhibitor, initiating studies for the treatment of GBM in vitro and in vivo, and providing proof of efficacy for further studies in GBM patients.
STEM-16. EXPLORING THE ROLE OF HYPOXIA AND MACROPHAGES ON GLIOBLASTOMA QUIESCENCE AND STEMNESS AS MEDIATORS OF RADIORESISTANCE
Authors: Puja Pradhan, Luis Agudelo, Victor Karwacinski, Nicole Constante, Cheryl Olson, Jiabo Li, Ling-kai Shih, Tatiana Carneiro-Lobo, Daniel Brat
Journal: Neuro-Oncology (2024)

Abstract Our ultimate goal is to identify, characterize and therapeutically target the glioma cell population that is responsible for treatment resistance and recurrence following chemoradiation. Two cell types that may have overlapping phenotypes and are known to influence radioresistance are 1) quiescent cells and 2) glioblastoma (GBM) stem cells (GSCs). The extent of overlap between these populations is unknown as are the influence of hypoxia and immune cells on their radioresistant properties. We have shown that hypoxia and co-culturing with THP-1 macrophages dramatically increases the percentage of GSCs. Using the Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI) system expressed in patient-derived gliomas, we used flow cytometry to distinguish cells based on their cell cycle status (G1/G0 and G2/M) and classified them as quiescent (high p27, low Ki67) or GSC (high CD133/CD44 co-expression). We found that the fraction of cells in G0 expressed high p27 and low Ki67, indicating cell cycle suppression and low proliferation, respectively. G0 glioma cells also contained a high percentage of GSCs, but GSCs were also distributed in G1 and G2/M. Following exposure to hypoxia, flow cytometry of FUCCI GBM cells showed an increase of cells in G0. After 3 Gy radiation under normoxic conditions, GBM cells demonstrated a shift to increased levels of G2/M cells compared to non-irradiated cells. In hypoxia, however, GBM cells sustained their population of cells in G0 and did not exhibit such cell cycle shifts. Our results indicate that both hypoxia and macrophages cause GSC enrichment and that hypoxia increases the proportion of quiescent cells in G0. Additional study is necessary to determine the extent of overlap between the GSCs and quiescent cells and to identify the intrinsic cell properties that drive tumor recurrence.
BIOM-61. CSF CTDNA ANALYSIS OF PATIENTS WITH DIFFUSE GLIOMAS REVEALS DIAGNOSTIC MOLECULAR ALTERATIONS
Authors: Srividya Arjuna, Daniel H Wang, Ashish Balar, Mauli Shah, Antonio Dono, Alexander Sanchez-Espitia, Dzifa Duose, Sophia Nguyen, Chirag B Patel, Sujit S Prabhu, Frederick F Lang, Yoshua Esquenazi, Leomar Y Ballester
Journal: Neuro-Oncology (2024)

Abstract There is a critical need for better strategies to diagnose and monitor patients with diffuse gliomas. Liquid biopsies are less invasive than tissue biopsies and are amenable to serial collection at multiple timepoints. However, analysis of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) in patients with diffuse gliomas remains underutilized in clinical practice due to technical challenges and a scarcity of studies demonstrating clinical utility. We evaluated ctDNA in 49 CSF samples from patients with various types of diffuse gliomas with a next generation sequencing (NGS) panel interrogating 613 cancer-related genes. Cell-free DNA concentration obtained from CSF (0.4-5mL) ranged from 0.009 to 60ng/µL. Input DNA concentration ranged from 0.12-30ng. Mutations were detected in 29/49 (59.2%) samples including 22/49 (44.9%) with single nucleotide changes, 14/49 (28.6%) with copy number changes, and 1 fusion (2.0%). The majority of samples without mutations detected (n=20) had suboptimal DNA input (&amp;lt;30ng): 17/20 (85%). We identified diagnostic alterations in CSF including mutations in IDH1 (3/5 IDH-mutant gliomas), TERTp and EGFR amplification (7/34 glioblastomas), H3-3A (4/6 pediatric high-grade gliomas). Some of these mutations, in combination with other clinical parameters, allowed us to identify specific CNS tumor types based on the 2021 WHO classification of CNS tumors, resulting in the reclassification of 2 patients. Matched tumor tissue sequencing results were available for 23/49 (46.9%) patients and the results showed good concordance with CSF ctDNA analysis. In summary, our results suggest that the NGS analysis of CSF-ctDNA can provide clinically relevant information in patients with diffuse gliomas.
RADT-01. PRE-OPERATIVE SINGLE FRACTION VERSUS FRACTIONATED STEREOTACTIC RADIOTHERAPY: A SINGLE-INSTITUTION ANALYSIS OF 299 RESECTED METASTASES
Authors: Haley Perlow, Sydney Luu, Sohil Reddy, Jared Bradshaw, Sarah Hennings, Jennifer Matsui, Brett Klamer, Rituraj Upadhyay, Alexandria Oliver, John McGregor, Russell Lonser, Daniel Prevedello, James Elder, Kyle Wu, Roshan Prabhu, Simeng Zhu, Raj Singh, Sasha Beyer, John Grecula, Dukagjin Blakaj, Evan Thomas, Raju Raval, Joshua Palmer
Journal: Neuro-Oncology (2024)

Abstract The treatment standard for patients with large or symptomatic brain metastases and limited intracranial disease is surgical resection followed by post-operative (post-op) stereotactic radiosurgery (SRS). The multicenter PROPS-BM cohort showed how pre-operative (pre-op) SRS may lead to a reduced incidence of radiation necrosis (RN), local failure (LF), and meningeal disease (MD) compared to historical controls. Fractionated treatments can deliver a higher biological effective dose and may reduce the incidence of LF and MD. We hypothesize that pre-op fractionated stereotactic radiation therapy (FSRT) will reduce the incidence rate of RN, MD, and LF when compared to patients who receive pre-op SRS. Patients who had surgical resection and pre-operative radiation to at least one brain metastasis at a single institution were retrospectively analyzed. Outcomes were evaluated on a per-lesion basis. The primary outcome was a composite endpoint defined by 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. 260 patients with 299 resected brain metastases were eligible for analysis. 64 metastases received SRS and 235 metastases received FSRT. 38 patients had multiple metastases resected pre-operatively. The median gross tumor volume was 4 ccs for SRS and 10 ccs for FSRT (p&amp;lt;0.001). Overall, 4 (6.3%) SRS and 6 (2.6%) FSRT patients experienced LF. 4 (6%) SRS and 21 (8.9%) FSRT patients experienced Grade 2 or higher RN. 3 (4.7%) SRS and 11 (4.7%) FSRT patients were diagnosed with MD. 14% of both SRS and FSRT patients experienced the composite endpoint. There were no statistically significant differences in outcome between these two treatment groups. In our study, pre-op SRS and FSRT both appear to be safe and effective options to treat resectable brain metastases. It is important to prospectively compare pre-op SRS and FSRT in matched cohorts to assess any differences in treatment efficacy and toxicity.
STEM-02. INSIGHTS INTO STEM CELL THERAPIES FOR GLIOBLASTOMA: A SYSTEMATIC REVIEW
Authors: Olivier UWISHEMA
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma accounts for the majority of gliomas, which are the most common brain tumors. Classified as grade 4 by the WHO, it carries a poor prognosis. Various stem cell therapies have been tested and analyzed for their efficacy in treating glioblastoma. The aim of this review is to examine the type, efficacy, and future considerations for different stem cell therapies in glioblastoma treatment. MATERIALS AND METHODS A literature review was conducted using Boolean operators in the form of Stem Cell Therapy AND Glioblastoma; Neural Stem Cells AND Glioblastoma; Cord Blood AND Glioblastoma. Electronic databases including Cochrane Library, PubMed, and Scopus were searched. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement. RESULTS Targeting Cancer Stem Cells (CSCs) may be crucial for effective GBM treatment, as these cells are considered key drivers of tumor initiation, progression, and therapeutic resistance. Future research and clinical trials in this area are necessary to fully understand the potential of stem cells in combating glioblastoma. CONCLUSIONS While some stem cell therapies have shown promising initial results, it is important to consider the complexity of targeting Glioblastoma Stem Cells (GSCs), including malignant transformation, the heterogeneity of glioblastoma, and glioma-associated mesenchymal stem cells.
STEM-01. SHARED ASTROCYTE-LIKE GLIOMA STEM CELLS DRIVE HETEROGENEITY AND IMMUNE DYNAMICS IN ADULT-TYPE DIFFUSE GLIOMAS
Authors: Ashraf Zaman, Walter Muskovic, Emily Holton, Madhavi Pandya, Rachael Zekanovic, Venessa Chin, Eric Lam, Catia Moutinho, Jacky Yeung, Charlie Teo, Michael Sughrue, Joseph Powell
Journal: Neuro-Oncology (2024)

Abstract Adult-type diffuse gliomas present significant treatment challenges due to their complex cellular composition and evolving nature. Understanding this heterogeneity is critical for the development of effective, targeted therapies. We conducted single-cell and single-nucleus RNA sequencing on a unique cohort of 66 tumours (single surgery) and 54 paired samples (two surgeries). This comprehensive dataset of approximately 900,000 cells allows us to dissect conserved cellular landscapes and dynamic evolution across diverse glioma subtypes. Using a novel phylogeny-based approach, we identified an astrocyte-like glioma stem cell (GSC) as the root of diverse glioma lineages. This discovery transforms our understanding of glioma development, pinpointing the GSC as a potential therapeutic target. The GSC’s similarity to healthy adult neural stem cells provides clues as to the origin of glioma heterogeneity and the shared basis of intratumoural diversity. Our analysis uncovered a shared cellular architecture across astrocytomas, oligodendrogliomas, and glioblastomas (GBMs). This architecture encompasses seven recurring malignant cell states: neuro-, oligo-, neuro-oligo-lineage, cycling (G1/S, G2/M), hypoxia-associated, and a quiescent astrocyte-like GSC. Importantly, these cell state proportions vary significantly between glioma subtypes. Additionally, we demonstrate that GBMs display substantially higher T-cell and myeloid cell infiltration than IDH-mutant gliomas. Counterintuitively, this correlates with a poorer prognosis, implying profound T-cell dysfunction and intricate myeloid cell-tumour interactions. Longitudinal analysis further highlights the dynamic nature of glioma cell populations and the immune landscape. Subtype-specific T-cell and myeloid gene expression profiles were identified, including potential targets such as PARD6G (GBM) and CXCL13 (IDH-mutant-astrocytoma), laying the groundwork for tailored immunotherapies and prognostic biomarkers. This study presents a comprehensive model of glioma heterogeneity and evolution. The model reveals a shared astrocyte-like GSC that fuels cellular diversity, coupled with distinct, dynamic immune landscapes in different glioma subtypes. These findings hold extraordinary potential for developing transformative treatment strategies. Future research functionally validating the GSC and its impact on tumour dynamics will be essential for translating these insights into improved patient outcomes.
TMET-30. ONCOLYTIC HSV REWIRES METABOLISM TO PROMOTE ANTITUMOR IMMUNITY THROUGH REDUCTIVE CARBOXYLATION AND FERROPTOSIS
Authors: Upasana Sahu, Matthew P Mullarkey, Sara Murphy, Miguel Diaz, Junhyoung Park, Abu Hena Mustafa Kamal, Benny Abraham Kaiparettu, Tae Jin Lee, Joshua Charles Anderson, Ashok Sharma, Nagireddy Putluri, Pamela Wenzel, Christopher Wiley, James M Markert, Balveen Kaur
Journal: Neuro-Oncology (2024)

Abstract Cancer cells autonomously rewire metabolism to meet increased bioenergetic demands. Oncolytic HSVs (oHSVs) are attenuated Herpes simplex type 1 derived viruses that lyse tumor cells releasing damage-associated molecules triggering antitumor immunity. Currently one oHSV-1 derived virus is approved for melanoma treatment in the USA and another for recurrent GBM in Japan. While several other viruses are being evaluated in clinical trials for safety and efficacy, an understanding of the impact of oHSV therapy on cancer cell metabolism is largely unexplored. A detailed understanding of how oHSV impact tumor cell metabolism and oxidative stress is important to understand the unique susceptibilities that can further be exploited to improve the therapeutic index. Here, we analyzed transcriptomic changes in tumor biopsies of recurrent high-grade glioma patients treated with oHSV. RNA-seq data obtained from pre- and post-G207 treated biopsies from phase-Ib study patients (NCT00028158) revealed enrichment in pathways related to citric acid cycle, oxidative phosphorylation, and glutamate metabolism. We confirmed these changes by RNA sequencing of oHSV-infected patient derived GBM cells. Mechanistically, oHSV hijacked cellular glucose metabolism to increase oxidative phosphorylation and modulated cellular glutamine metabolism towards reductive carboxylation and reduced free glutathione, collectively contributing to increased ROS generation. Kinome profiling revealed PKC activation upon treatment with oHSV. Increased ROS combined with reduced glutathione, and PKC activation promoted ferroptotic cell death characterized by increased lipid peroxidation and smaller, ruptured mitochondria, and contributed to immunotherapy by this treatment. IDH mutant tumors that block reductive carboxylation were resistant to oHSV-induced ferroptotic cell death and did not benefit from oHSV-induced antitumor benefit. Together, this study presents avenues to enhance antitumor immunity by oHSV therapy.
RADT-32. FREQUENT MULTIFOCAL INTRATUMORAL HEMORRHAGE IN MULTIPLE BRAIN METASTASES FROM HEPATOCELLULAR CARCINOMA
Authors: Yukitomo Ishi, Kentaro Nishioka, Shigeru Yamaguchi, Michinari Okamoto, Hiroaki Motegi, Sogo Oki, Takashi Mori, Hidefumi Aoyama, Miki Fujimura
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Brain metastasis (BM) rarely occurs in hepatocellular carcinoma (HCC); however, it frequently causes intratumoral hemorrhage (ITH). We investigated the clinical manifestations of ITH in patients with multiple BMs from HCC (HCC-BM). METHODS Patients who underwent treatment for multiple BMs with more than two metastatic sites were retrospectively reviewed and those diagnosed with HCC-BM were further analyzed. The multifocality of hemorrhage was classified into two groups, spatial and temporal multifocality, according to the radiological findings. The characteristics of multifocal hemorrhage in HCC were compared with those of BMs from other cancer types. RESULTS Fifteen out of 636 (2.36%) cases of multiple BMs were due to HCC metastasis. Out of 15 HCC-BM cases, 13 (86.7%) presented multifocal hemorrhage and 1 presented unifocal hemorrhage during the follow-up period. Spatial and temporal multifocality were observed in 9 and 5 cases, respectively, among 13 cases of multifocal hemorrhage. Among 636 cases of multiple BMs, HCC cases showed the highest frequency of multifocal hemorrhage, and HCC was significantly associated with multifocal hemorrhage compared with other primary-site cancer types (30/621 cases, 4.8%). Out of 15 patients with multiple HCC-BMs, 12 underwent whole-brain irradiation (WBI), and their median overall survival was 147 days. In one patient (8.3%), although treatment was stopped due to neurological deterioration by ITH, local BM control was favorable after the completion of WBI, and the only cause of death in six patients who completed WBI and were radiologically followed up until death was the progression of extracranial lesions. CONCLUSIONS Multiple HCC-BMs frequently present with multifocal ITH compared with BMs from other cancer types. Despite poor treatment outcome, WBI may show favorable local control considering the potential hemorrhagic event by tiny metastases that would not be detected radiologically. Immediate commencement of treatment before hemorrhage progression will be required for the treatment of multiple HCC-BMs.