tbuckley/cabot-search huggingface dataset:
CTNI-29. A PHASE 1B STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND OBJECTIVE RESPONSE OF LP-184 ALONE AND IN COMBINATION WITH SPIRONOLACTONE IN IDH WILD TYPE GLIOBLASTOMA AT FIRST PROGRESSION
Authors: Karisa Schreck, John Laterra, Aditya Kulkarni, Kishor Bhatia, Reginald Ewesuedo, Marc Chamberlain
Journal: Neuro-Oncology (2024)

Abstract LP-184 is a fully synthetic small molecule alkylator of the acylfulvene therapeutics class that induces DNA double-strand breaks and improves survival in orthotopic GBM xenograft models. In preclinical studies, LP-184 is brain penetrant with a brain tumor/plasma concentration ratio of 0.2. DNA damage induced by acylfulvenes is repaired via transcription-coupled nucleotide excision repair (TC-NER) mediated by ERCC complexes. GBM with intrinsic or pharmacologically induced DNA Damage Repair deficiency (dDDR) may preferentially respond to LP-184, independent of MGMT status. LP-184 is currently under investigation in a first-in-human Phase 1a dose-escalation safety study (NCT05933265) in adult patients with advanced solid tumors including GBM, with no dose-limiting toxicities to date at dose level 6. Following determination of the Maximum Tolerated Dose and/or Recommended Phase 2 Dose from Phase 1a, the selected expansion dose will be assessed in a Phase 1b study to evaluate the safety, pharmacokinetics, and objective response of LP-184 alone and in combination with spironolactone in IDH wild type glioblastoma at first progression. Spironolactone is a brain penetrant FDA approved agent that proteolytically degrades the TC-NER component ERCC3, thereby creating dDDR. Two rGBM cohorts will be enrolled according to a Simon’s 2-stage optimal design: (i) LP-184 alone (days 1 and 8 in a 21-day cycle, as intravenous infusion over 30 minutes) and (ii) combination of LP-184 and spironolactone (200 mg orally daily in conjunction and before the LP-184 infusion). In the first stage, 10 response evaluable subjects will be enrolled. If 1 or more of the first 10 response evaluable subjects achieve an objective response, 19 further subjects may be accrued in the second stage. In each cohort, at least 5 subjects will undergo planned tumor resection and will be treated with LP-184 or the combination the day prior to surgery to evaluate PK/PD.
IMMU-54. THERAPEUTIC TARGETING OF STING IN MENINGIOMAS
Authors: Mark Youngblood, Shashwat Tripathi, Hinda Najem, Mateo Gomez, Nishanth Sadagopan, Thomas Sears, Lisa Hurley, Wenxia Wang, Harrshavasan Congivaram, Abrar Choudhury, Alicia Steffens, Daniel Oyon, Luis Fernandez, Ashley Selner, Jawad Fares, Matthew Hagan, Aaron Palmer, Constantine Karras, Joy Trybula, Peng Zhang, Alexander Stegh, Michael Curran, David Ashley, Stephen Magill, Craig Horbinski, James Chandler, Maciej Lesniak, Jason Miska, Gavin Dunn, David Raleigh, Amy Heimberger
Journal: Neuro-Oncology (2024)

Abstract Up to one-quarter of meningiomas recur within five years of resection; however, there are currently no established adjuvant therapies for lesions that are intractable to surgery and radiation. To identify novel treatment approaches, scRNA-sequencing datasets were reanalyzed from thirteen meningiomas and nine adjacent dura samples including &amp;gt;30,000 immune cells from varying WHO grades and molecular subtypes. In contrast to gliomas, immune-inducing STING (stimulator of interferon genes) was expressed within the meningioma tumor cells, consistent with DNA methylation profiling that showed hypomethylation of the STING promotor in 93% of cases (267 of 288 meningiomas; beta &amp;lt; 0.2). Meningiomas in the immune-enriched subgroup additionally exhibited significant hypomethylation in the 3’ UTR of this gene (p = 1.9 x 10-9). Using sequential multiplex immune fluorescence, STING expression was confirmed in neoplastic, myeloid, and endothelial cells within all grades of meningiomas, but not in adjacent dura and brain. Downstream STING pathway activation markers such as p-IRF3 were partially expressed, suggesting that further activation of the STING pathway may offer therapeutic benefits. Ex vivo single-cell suspensions of resected human meningiomas treated with the STING agonist 8803 induced 25-45% growth inhibition in 7/8 cases within 72 hours (p &amp;lt; 0.001; two-way ANOVA). There was no growth inhibition of the meningioma cell lines IOMM-LEE and CH157 treated with 8803, which lack immune cells and contain only clonal neoplastic cells. However, when the IOMM-LEE meningioma cells were implanted in vivo, a single dose of 8803 induced a &amp;gt;50% reduction in tumor volume relative to the vehicle control injection at multiple time points (p &amp;lt; 0.001; two-way ANOVA) indicating that the immune system is an essential component of STING efficacy in these tumors. Our results reveal widespread expression of STING in neoplastic and myeloid populations in meningiomas and clarify a new treatment indication for use of the STING agonist 8803.
EXTH-76. REDIRECTING STROMAL CELLS TO IGNITE ANTI-TUMOR IMMUNITY AGAINST GLIOBLASTOMA
Authors: Anna DeVries, Christina von Roemeling, Rachel Moor, Brandon Wummer, Frances Weidert, Jonathan Chardon-Robles, John Ligon, Paul Castillo, Hector Mendez-Gomez, Elias Sayour
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The dismal prognosis of high-grade gliomas demands novel treatment approaches. Through the development of a novel mRNA lipid particle aggregate (RNA-LPA) vaccine, our lab has shown anti-tumor efficacy in preclinical murine studies and promising immunological responses in canine glioma models and human studies (Cell. 2024 May 9;187(10):2521-2535.e21). The translational potential necessitates further investigating the immune activation mechanism to allow greater applicability of this therapy in the future. OBJECTIVE We sought to unravel mechanistic cross-talk for immune initiation following intravenous administration of RNA-LPAs. METHODS We used Ai14 reporter mice to determine RNA-LPA transfected cellular subsets and dual reporter mice to assess cellular infiltration into murine glioma models. Murine gliomas were generated via implantation of K2 or KR158b-luc cell lines. RESULTS Following intravenous administration, we found fibroblastic reticular cells in secondary lymphoid organs take up RNA-LPAs. We show that FRCs have direct contact with antigen presenting cells and mediate release of full-length proteins following RNA-LPA transfection. Similar to the periphery, there is transfection of stromal cells in the brain tumor microenvironment (TME) and recruitment of infiltrating leukocytes. In response to RNA-LPAs, transfected stromal cells release type I interferon (IFN-I), which is requisite for anti-tumor efficacy. IFN-I mediates upregulation of CD69 on lymphocytes leading to sequestration following co-localization with RNA-LPAs. IFN-I is necessary for LFA-I expression on T cells, which is important for T cell trafficking across the blood-brain barrier. In preclinical models to track antigen specific immunity, we find systemic RNA administration elicits an increase in tumor reactive T cells with decreased S1P1 expression suggestive of a ‘locked-in’ response within the TME. CONCLUSION While stromal cells are regulatory niches in glioblastoma ecosystems, we show they can be leveraged for immunologic cross-talk that facilitates T cell recruitment, trafficking and sequestration in the TME critical for immunologic reprogramming and long-lasting immunotherapy.
NIMG-67. THE CURRENT STATE OF LARGE LANGUAGE MODELS AND NEURO-ONCOLOGY IMAGING
Authors: Daniel Aaronson, Nathan Zwagerman
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Large language models (LLM), such as chatGPT by OpenAI, exist at the intersection of machine learning and natural language processing, and are poised to transform healthcare with rapid growth in recent years. The ability of these models to process visual data has also advanced in recent years, with GPT-4 being the first model to publicly process visual data, and GPT-4o adding additional capabilities. There has been significant interest in the application of GPT-4o to healthcare image processing. OBJECTIVE This study sought to examine the ability of GPT-4o in determining a final diagnosis based on a single MRI image of an intracranial neoplasm. We then compared the performance to GPT-4, as well as to humans including neurosurgery residents, fellow, and attendings. METHODS GPT-4 and GPT-4o were given a standard prompt and an accompanying image requesting the most likely diagnosis for 20 brain MRI images, including 5 gliomas, 5 meningiomas, 5 pituitary tumors, and 5 sham non-tumor images. These were compared to a survey of neurosurgery attendings, fellows, senior residents, and junior residents. RESULTS GPT-4 supplied correct diagnoses in just 40% of the cases, while GPT-4o correctly identified the pathology in 70% of cases. Neurosurgeons yielded correct responses in 92% of cases, with neurosurgery senior residents faring the best (albeit with a small sample size). CONCLUSION GPT-4 and GPT-4o underperformed neurosurgery residents, fellows, and attendings in correctly identifying CNS malignancies. Still, with no additional training, GPT-4o yielded significantly better results than GPT-4, showing rapid advancement in the LLM over is predecessor in identifying intracranial neoplasms via single-image MRIs.
QOL-16. POSTOPERATIVE MOTOR FUNCTION AND PROCESSING SPEED PREDICT QUALITY OF LIFE IN PATIENTS WITH GLIOBLASTOMA AT CHRONIC-PHASE
Authors: Mitsutoshi Nakada, Riho Nakajima, Masashi Kinoshita
Journal: Neuro-Oncology (2024)

Abstract The quality of life (QOL) in patients with glioblastoma (GBM) should be paid attention. The aim of this study is to identify brain functions that influence the QOL of patients with GBM by objectively assessing neurocognitive functions. Data from 40 patients with newly diagnosed GBMs were analyzed. All patients completed the assessment of various neurological and neurocognitive functions and QOL at 6 months postoperatively. QOL was assessed using the 36-Item Short Form Survey (SF-36). In the SF-36, the physical, mental, and role and social component summary (PCS, MCS, and RCS, respectively) scores were calculated. Multiple logistic regression analyses and chi-square tests were used to evaluate the association between SF-36 scores and brain functions. The MCS was maintained, whereas the PCS and RCS scores were significantly lower in patients with GBMs than in healthy controls (p=0.0081 and p&amp;lt;0.0001, respectively). Among a variety of brain functions, motor function and processing speed were significantly correlated with PCS and RCS scores, respectively (p=0.0048 and p=0.030, respectively). Patients whose PCS or RCS remained stable had a higher probability of motor function or processing speed preservation than those whose RCS or PCS decreased (p=0.0026). Taken together, motor function and processing speed may be predictors of QOL in patients with GBMs.
BIOM-02. A HIGH-GRADE GLIOMA, NOT ELSEWHERE CLASSIFIED IN AN OLDER ADULT WITH DISCORDANT GENETIC AND EPIGENETIC ANALYSES
Authors: Carlen Yuen, Silin Bao, Xiao-Tang Kong, Merryl Terry, Melike Pekmezci
Journal: Neuro-Oncology (2024)

Abstract World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) uses integrated diagnoses, which incorporates both histologic and molecular features of the neoplasms. With each new iteration, there is refinement and expansion of the diagnostic categories. DNA methylation profiling is a powerful technique to diagnose existing CNS tumors and define new tumor types. However, challenging diagnostic cases that do not conform to the updated WHO classification remain. We present a case of a 72-year-old male with a high grade glioma (HGG) suggestive of high grade astrocytoma with piloid features (HGAP), but it did not “match” to HGAP on DNA methylation profiling, which is essential diagnostic criterion for HGAP. This resulted in an HGG, not elsewhere classified (NEC) diagnosis. This lack of classification posed additional challenges for treatment decision-making.
EXTH-80. A NOVEL BISAMINOQUINOLINE DERIVATIVE NANOPARTICLE (BAQ13-NP) FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Orin Bloch, Dullei Min, Tzu-Yin Lin, Yuanpei Li
Journal: Neuro-Oncology (2024)

Abstract Aminoquinolines, such as hydroxycholoquine, are known to inhibit autophagy and slow cancer cell growth, improving survival in preclinical models of glioblastoma. Unfortunately, they failed to demonstrate benefit in clinical trials due to a lack of sufficient potency and BBB penetration. We have developed a novel bisaminoquinoline derivative packaged in a nanoparticle (BAQ13-NP) with improved potency and intratumoral accumulation after systemic administration, confirmed by distribution and toxicity studies in animals. In this study, we evaluated the impact of BAQ13-NP on tumor cell autophagy and survival using patient-derived glioma cell lines and murine models. GBM patient-derived cell lines (n=4) and murine glioma cells (GL261, CT-2A) were treated with BAQ13-NP (1-4 µM) in culture, demonstrating growth restriction to less than 50% of control at 5-7 days (p&amp;lt;0.01) by MTT assay. Cells treated with BAQ13-NP also demonstrated reduced autophagy with significant increases in accumulation of LC3B and p62 (p&amp;lt;0.01) and reduced IL-6 dependent STAT3 phosphorylation in tumor cells, T cells, and myeloid cells (p&amp;lt;0.01). In addition, treatment of tumor cells with BAQ13-NP reduced IL-6 production over 50% (p&amp;lt;0.01). Mice with orthotopic GL261 or CT2A tumors were treated with BAQ13-NP by tail vein injection (25 mg/kg q2 days) starting 7 days post implantation. Significantly increased survival was observed in BAQ13-NP treated GL261 (HR 0.75, p=0.030) and CT2A (HR 0.78, p=0.033) bearing mice compared to vehicle control treated animals. Reduced tumor size at specific intervals was also observed with BAQ13-NP treatment, corelating with improved survival. BAQ13-NP can inhibit autophagy and slow glioma tumor growth, improving survival in preclinical models. Given the excellent distribution and low toxicity of this novel agent when delivered intravenously, we believe it has great potential to improve outcomes for GBM patients. Our drug has recently received IND approval and will soon be tested in a phase I clinical trial.
TMOD-15. TOWARD BRAIN CANCER ORGANOID-INFORMED PRECISION MEDICINE FOR GLIOBLASTOMA
Authors: Claire Storey, Lucy Gately, Kate Drummond, Andrew Gogos, Dmitri Mouradov, Michael Christie, Helen Brasier, Emma Priest, Alana Fakhri, Peter Gibbs, Oliver Sieber
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Improved preclinical models for glioblastoma are urgently needed to enhance the translation of research to clinical applications. Patient-Derived Tumor Organoids (PDTOs) offer a promising model that can be generated quickly. Here we explored their feasibility. METHODS Primary (n=16) and recurrent (n=2) PDTOs were established using the method described in Jacob et al. Cell. 2020 by dissecting tumours into small fragments, preserving their cytoarchitecture. Histological features of the parent tumour were compared to the matched PDTOs by a neuropathologist. To assess the molecular fidelity, comprehensive whole genome sequencing compared matched tumor tissue, PDTOs, and corresponding normal blood samples (n=11), along with RNA sequencing of matched tumor tissue and PDTOs (n=10). We assessed PDTO responses to regorafenib (n=18) and conventional TMZ (n=9), lomustine (n=9) and 10 Gy of ionizing radiation (IR) (n=6) using the automated imaging system IncuCyte S3® to evaluate whole spheroid brightfield and invasion areas following drug/IR treatment and assess viability. RESULTS We achieved a 100% establishment rate of primary GBMs using same-day procedures and an 80% rate if held under 3 days. Histological features were retained in the PDTO. Molecular overlap was greater than 90%, along with a high concordance in gene expression. PDTOs exhibited notable resistance to temozolomide and lomustine, however, showed a very modest response to IR and a moderate response to regorafenib. IncuCyte S3® analysis revealed discernible changes in whole spheroid brightfield and invasion area for regorafenib-treated PDTOs. Clinically relevant concentrations of regorafenib reduced GBM cell proliferation (Ki67 staining). Beyond this concentration, regorafenib exhibited efficacy in eliminating GBM cells. CONCLUSION PDTOs recapitulate the molecular and histological features of the original tumor and may enable the prediction of individual patient responses to therapies and guide more effective treatment selection. We are now applying our established methodology to assess a new set of promising drug candidates.
CTNI-82. BELZUTIFAN TREATMENT OF VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA
Authors: Anna Thomsen, Allison Valerius, Joon Uhm, Michael Ruff, Duru Baykal, Samantha Caron, Jessica White, Mason Webb, Pavel Pichurin, Bryan Neth, Ugur Sener
Journal: Neuro-Oncology (2024)

Abstract Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.
BIOM-48. UTILITY OF CIRCULATING TUMOR DNA (CTDNA) FROM CEREBROSPINAL FLUID (CSF) FOR PROGNOSIS OF PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA
Authors: Alexandra M Miller, Subhiksha Nandakumar, Bridget M Holle, Christoph Kreitzer, Timothy Song, Marlene Tartaro, Charli Ann J Hertz, Johnathan Rafailov, Carl Campos, A Rose Brannon, David B Solit, Luca Pasquini, Alicia Meng, Anne Reiner, Robert Young, Nicholas D Socci, Maria E Arcila, Michael F Berger, Nikolaus Schultz, Ingo K Mellinghoff
Journal: Neuro-Oncology (2024)

Abstract High-grade gliomas (HGGs) are the most aggressive primary brain tumors, and molecular characterization is vital for their diagnosis and treatment. Due to their location, tumor sampling is often challenging. Therefore, developing minimally invasive diagnostic methods is urgently needed. Here we report that circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) can identify key genomic alterations and track clonal evolution in HGGs. Detection of CSF ctDNA correlates with leptomeningeal disease and overall survival, indicating its potential for integration into clinical decision-making. Our study includes 313 samples from 253 patients with recurrent glioma treated at MSKCC who underwent CSF collection using the MSK-IMPACT targeted sequencing assay. 37% of genomic alterations were detected using our less stringent variant calling criteria and Gaussian Mixture Model to call copy number events. CSF ctDNA positivity was determined by the presence of at least one oncogenic disease-defining alteration or any shared alteration with the tumor. We found 212 CSF ctDNA positive (68%) and 101 CSF ctDNA negative (32%) samples. CSF ctDNA positivity was the highest amongst histone mutant tumors (96%). We noticed 44% of alterations shared between the tumor and the CSF, additionally, we noted considerable tumor evolution particularly within the growth signaling pathways (e.g. PDGFRA). Our cohort demonstrated that patients with positive CSF ctDNA had a significantly shorter overall survival compared to those who were CSF ctDNA negative (4.83 months vs 14.14 months, HR 2.4, p &amp;lt; 0.001). Radiographic findings such as enhancing disease and contact of the tumor with the ventricular space were positively associated with CSF ctDNA positivity. Additionally, CSF ctDNA was associated with positive cytology in 12/12 cases (100%). With our improved pipeline, we hypothesize CSF ctDNA may be used as a prognostic biomarker for survival, but confirmation requires further validation in a prospective study.
IMMU-04. G-AMINOBUTYRIC ACID DRIVES GLIOBLASTOMA IN FEMALES IN AN IMMUNE-DEPENDENT MANNER
Authors: Asmita Pathak, Sravya Palavalasa, Erika Ciervo, Maxon Berg Van Den Knott, Nikola Susic, Khushi Hemendra Shah, Bruno Colon, Diana Chin, Yadi Zhou, Feixiong Cheng, Costas Lyssiotis, Dionysios C Watson, Daniel Wahl, Michele Ceccarelli, Ashish Shah, Justin D Lathia, Defne Bayik
Journal: Neuro-Oncology (2024)

Abstract Communication with a neuronal network and accumulation of myeloid-derived suppressive cells (MDSCs) support GBM growth and therapeutic resistance. GBM incidence and outcomes differ between males and females. We previously demonstrated that granulocytic (gMDSCs) drive GBM in females. However, a lack of understanding of the host factors regulating distinct MDSC subset function remains to be a major obstacle for therapeutically targeting these cells in GBM. In this study, we identified γ-aminobutyric acid (GABA) pathway as a modulator of gMDSC activity. gMDSCs from both healthy adults and glioma patients, expressed significantly higher levels of GABA receptor B1 (GABBR1) and GABA receptor B2 (GABBR2) compared to monocytic MDSCs (mMDSCs). On contrary, GABA receptor A (GABAAR) subunits were not expressed in either MDSC subtype. Given these differences, we investigated the effect of GABA on MDSC metabolism and found an increase in L-arginine metabolism specifically in female gMDSCs following GABA treatment while no significant metabolic changes were observed in any other groups. In MDSCs, L-arginine can be metabolized via nitric oxide synthase (NOS2) or Arginase-1 (Arg-1). While treatment with GABA or the GABBR agonist baclofen increased NOS2 production in specifically in female gMDSCs, Arg-1 was not affected. Mechanistically, baclofen enhanced gMDSC-mediated T cell suppression in females. In preclinical models of GBM, baclofen treatment resulted in a truncated survival only in immunocompetent female mice, which was reversed by pharmaceutical inhibition of NOS2. Clinically, female patients on GABA analogs (pregabalin, gabapentin) had significantly lower 12-month survival probabilities compared to control population. This effect was not observed in male patients. Conversely, inhibition of GABBR with CGP35348 prolonged survival in female GBM models and reprogramed the immunosuppressive tumor microenvironment. Collectively, these results highlight that GABA alters anti-tumor immune response in a sex-specific manner. These results support the future assessment of GABA pathway inhibitors as potential immunotherapy agents in GBM.