tbuckley/cabot-search huggingface dataset:
NCOG-07. SAFETY OF ONC201 TREATMENT IN PATIENTS WITH PREVIOUSLY TREATED H3 K27M-MUTANT GLIOMA: RESULTS FROM ONC028, AN ONGOING COMPASSIONATE USE PROGRAM
Authors: Akansha Sharma, Robert Aiken, David N Korones, Carl Koschmann, Jourdan Lubes, Sharon L Gardner, Marion Morrison, Samuel C Ramage, Rohinton S Tarapore, Yazmin Odia
Journal: Neuro-Oncology (2024)

Abstract PURPOSE H3 K27M-mutant diffuse midline glioma (DMG) has a poor prognosis, with a median overall survival of 1 year and no proven treatments beyond radiotherapy. ONC201 (dordaviprone), a first-in-class imipridone, previously demonstrated durable responses in patients with recurrent H3 K27M-mutant DMG. The present analysis reports safety data from ONC028, a compassionate use program (CUP) for patients with previously treated H3 K27M-mutant glioma. METHODS ONC028 is an expanded access program that provides ONC201 monotherapy to patients with H3 K27M-mutant glioma. Eligible patients are adults or pediatric patients with H3 K27M-mutant glioma, prior therapy including at least radiation, and adequate organ function. Patients must be ineligible for enrollment in other ongoing clinical studies evaluating ONC201. ONC201 is administered orally once weekly at 625 mg or dose-equivalent based on body weight for pediatric patients. MRIs are performed every two 28-day cycles for the initial 12 months, thereafter every 2-3 cycles. Treatment continues until disease progression, unacceptable adverse events (AEs), or withdrawal of consent. Treatment may continue post-progression at the discretion of the treating physician. Bevacizumab use for radiation necrosis or symptom management is acceptable. AEs are assessed by NCI CTCAE v5.0 criteria. RESULTS The 422 enrolled patients include 191 adults (45.2%) and 231 children (54.7%); 87.1% had a performance score ≥60 and the most common tumor location was the pons (57.3%). Any-causality Grade ≥3 AEs have been reported in 200 patients (47.4%). Grade ≥3 treatment-related AEs (TR-AEs) were reported in 19 (4.5%) patients; the commonest was decreased lymphocyte count, occurring in 3 (0.7%) patients. Any-causality serious AEs (SAE) were reported in 43.1% (n=182) patients. There were 10 (2.4%) patients with reports of treatment-related SAEs, the commonest were ascites, nausea, vomiting, and seizure, each occurring in 2 patients (0.2%). CONCLUSIONS ONC028 provides expanded access to ONC201 treatment for patients with previously treated H3 K27M-mutant glioma who are ineligible for enrollment in ongoing trials of ONC201. ONC201 treatment remains well-tolerated.
TMET-23. MASS SPECTROMETRY-BASED METABOLIC PROFILING AND IMAGING OF ASTROCYTE AND GLIOBLASTOMA INVASIVE MARGIN CELLS
Authors: Une Kontrimaite, Phoebe McCrorie, Sandra Martinez-Jarquin, Harry Porter, Kei F Carver Wong, Stuart Smith, Dong-Hyun Kim, Ruman Rahman
Journal: Neuro-Oncology (2024)

Abstract Despite multimodal treatment, 90% of patients diagnosed with isocitrate dehydrogenase (IDH) wild-type glioblastoma experience tumour recurrence within 5 years. Poor prognosis is in considerable part attributed to the ability of cancer cells to infiltrate a healthy brain. We hypothesise that metabolic changes underpinning cellular crosstalk between astrocytes and glioblastoma cells isolated from the invasive margin within a physiologically representative in-vitro tumour microenvironment may reveal therapeutic targets to prevent or delay glioblastoma recurrence. This study used advanced analytical techniques to establish baseline metabolomic profiles for eGFP-tagged primary glioblastoma cells isolated from the invasive margin and healthy human cortical astrocytes. Liquid chromatography-mass spectrometry (LC-MS) enabled detailed analysis of biochemical pathways, and Atmospheric Pressure-Matrix Assisted Laser Desorption/Ionisation (AP-MALDI) imaging offered spatial localization of metabolites, critical for mapping their distribution within tumour microenvironments. Metabolites were extracted using a biphasic method (methanol:chloroform:water) for LC-MS analysis, and metabolic profiling was conducted using a ZIC-pHILIC column coupled with a Q-Exactive Orbitrap Mass Spectrometer. Additionally, AP-MALDI imaging facilitated the generation of high-resolution spatial distribution maps of selected metabolites, achieving a resolution of 10 µm. Both multivariate and univariate statistical analyses were applied to identify significant metabolic alterations. Metabolic profiling identified distinct pathways altered in glioblastoma cells compared to astrocytes, including alterations in aspartate, glycine and serine, and lipid metabolism. High-resolution imaging outlined the spatial distribution of metabolites involved in these pathways, revealing regions of metabolic heterogeneity. Furthermore, this methodology facilitated an expanded identification range of essential biomolecules, notably lipids and amino acids, thereby augmenting our understanding of their dynamic functions across diverse cellular contexts. By leveraging the complementary strengths of LC-MS and AP-MALDI imaging, this research enhances our understanding of spatial metabolite distribution in glioblastoma cells isolated from the invasive margin and suggests potential applications in patient tissue, offering a deeper exploration of disease mechanisms.
DDDR-37. OHSV AND RADIATION THERAPIES SENSITIZE GLIOBLASTOMA TO IGF1R-TARGETED THERAPY AND SYNERGIZE IN TRIPLE COMBINATION THERAPY
Authors: Alexandra A Miller, Min Hye Noh, Jin Muk Kang, Grace Nguyen, Min Xin Huang, Yoshihiro Otani, Hiroshi Nakashima, E Antonio Chiocca, Tae Jin Lee, Ji Young Yoo
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) continues to have a dismal prognosis despite remarkable advances in the field due to both tumor-intrinsic factors (i.e., IDH1 or EGFRvIII mutations) and extrinsic factors (i.e., relating to the tumor microenvironment (TME)), necessitating therapeutic innovation. Oncolytic herpes simplex virus-1 (oHSV) is an FDA-approved therapy that has shown promising results in clinical trials; however, therapeutic efficacy is limited to a small subset of patients. Thus, elucidating both the tumor-TME interplay and feedback/feedforward tumor-cell signaling in the context of viro-immunotherapy is essential in augmenting therapeutic outcomes. We recently discovered a novel mechanism of resistance to oHSVs, in which infection increases secretion of Insulin-like growth factor 2 (IGF2), activating the Insulin-like Growth Factor-1 Receptor (IGF1R). Upregulation of the IGF1R signaling pathway in GBM is correlated with poor prognosis and has been implicated in resistance to conventional therapies including radiotherapy (RTx). Herein, we further elucidate the impact of oHSVs on IGF1R activation, demonstrating a dose-dependent enhancement of downstream signaling. While IGF1R targeting therapies (e.g., OSI-966, Picropodophyllin (PPP)) have displayed limited efficacy in clinical trials, they significantly increased oHSV-induced cytotoxicity in all tested primary GBM cells compared to either agent alone in vitro and in vivo, resulting in a dose-dependent increase in PARP and caspase 3 activity by western blot and immunohistochemistry. We further found that RTx-induced IGF1 secretion and subsequent IGF1R activation were enhanced when combined with oHSV treatment. Triple combination therapy with oHSV, IGF1R inhibition, and RTx significantly increased tumor cell killing in vitro and improved survival of orthotopic GBM tumor-bearing mice. Collectively, our study provides preclinical evidence of enhanced therapeutic efficacy of oHSVs and RTx in combination with IGF1R blockade, supporting future use of IGF1R inhibitors in combination with the standard of care and FDA-approved oHSV therapies in patients with GBM.
SURG-55. NOVEL IQ-DOME APPROACH FOR SUPERIOR SEMICIRCULAR CANAL DEHISCENCE REPAIR REDUCES REVISIONAL SURGERY RATE
Authors: Laila Khorasani, Mahlet Mekonnen, Anubhav Chandla, Aryan Pandey, Quinton Gopen, Isaac Yang
Journal: Neuro-Oncology (2024)

Abstract Superior Semicircular Canal Dehiscence (SSCD) is characterized by a thinning of the bony ceiling of the superior semicircular canal, manifesting in auditory and vestibular deficits. Surgical repair is the standard treatment modality of SSCD, with conventional methods including plugging or recapping the defective canal with bone wax, bone chips, muscle, and others. Previous research has shown multiple complications with these conventional materials, including a high rate of failure of the primary repair and the need for revisional surgeries. To address this challenge, we investigated a novel surgical sealing technique using IQ-Dome, a titanium mesh plate overlying the arcuate eminence. We aim to assess the efficacy of IQ-Dome in the repair of SSCD compared to conventional material while evaluating outcome measures including postoperative symptom resolution, complication, and revisional surgery rates. We performed a retrospective analysis of patients undergoing SSCD repair via the middle cranial fossa approach at UCLA between 2017 and 2021. We compared demographics and post-operative outcomes between the application of IQ-Dome and conventional materials. A total of 160 patients undergoing SSCD repair were included in our study, with 80 patients receiving IQ-Dome and 80 patients receiving non-IQ-Dome approaches. 60% of patients in the IQ-Dome cohort and 66.7% of patients in the non-IQ-Dome cohort were female. The mean ages of patients were 45.7 years (range 13-78) in the IQ-Dome cohort and 48.9 years (range 17-69) in the non-IQ-Dome cohort. The surgical revision rates for the IQ-Dome and non-IQ-Dome cohorts were 5.7% and 8.5%, respectively. There was no significant difference in postoperative complications between groups. Thus, IQ-Dome is a safe approach for the surgical management of SSCD, decreasing failure and revision rate by nearly 3% in our patient population and offering an alternative surgical sealing repair intervention. Future studies with larger sample sizes are warranted to further assess the efficacy of IQ-Dome.
TMIC-19. EXCESSIVE LIPID PRODUCTION SHAPES GLIOMA TUMOR MICROENVIRONMENT
Authors: John Paul Aboubechara, Haitham Maraqah, Mones Abu-Asab, Han Sung Lee, Orwa Aboud
Journal: Neuro-Oncology (2024)

Abstract Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n=18) and IDH1 mutant (IDH1-mt) astrocytoma (n=12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature has lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.
IMMU-08. PRECLINICAL EVALUATION OF GAL-1-SPECIFIC CAR-T CELL FUNCTION IN AN IN VITRO AND EX VIVO MODEL OF GLIOBLASTOMA
Authors: Arabinda Das, Alicia M Zukas, Jaime Martinez Santos, Heather R Stephens, Joseph Mark, Penny Sekerak, Libby Kosnik Infinger, William A Vandergrift III, Abhay K Varma, Sunil J Patel, David Cachia, Scott M Lindhorst
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Human glioblastoma (GBM), especially those exhibiting anti-VEGF resistance, overexpress the carbohydrate-binding protein galectin-1 (Gal-1). To develop novel anti-GBM approaches, we developed Gal-1 targeted CAR-T cells to investigate potential antitumor effect with in vitro and ex vivo slice culture models. METHODS Uniform GBM brain slice cultures were collected using NICO’s Myriad resection tool and their Automated Preservation System (APS), designed to obtain fresh brain tumor samples maintaining tumor cytoarchitecture and microenvironment. To prepare Gal-1 CAR-T cells, we used creative laboratory to utilize a third-generation Gal-1-CAR construct with high binding and codon optimized scFv-Gal-1 fragment fused with CD3ζ and co-stimulatory cytoplasmic domains of CD28 and 4-1BB (Gal-1 scFv-CD28-4-1BB-CD3ζ). We then transfected into the T cells, from peripheral blood, mononuclear cells using a lentiviral system. The anti-tumor capabilities of CAR-T cells were evaluated by co-culturing with GBM cells and ex vivo APS-GBM slices. RESULTS The collected APS- GBM slices samples were clear of debris and blood product, not requiring post-surgical mechanical slices, and exhibited viability up to 12 days over traditionally prepared ex vivo cultures. With this, we found Gal-1-CAR-T cells grew exponentially in the presence of cytokines and maintained phenotypic and biological attributes such as cell viability, potency, migration, and T cell activation. Gal-1 scFv-CD28-4-1BB-CD3ζ -CAR-T cells killed more than 80% of GBM tumor cells within 24 hours in Gal-1+ve, but not Gal-1-ve GBM cells in vitro. Additionally, these CAR-T cells selectively caused significant release of IL-2, IFN-γ and TNF-α only from Gal-1+ve co-cultures and induced significant Gal-1+ve GBM cell death in an ex vivo model without any general toxicity. CONCLUSION Based on in vitro cell culture and ex vivo APS-brain slice culture results, we conclude that the novel Gal-1 scFv-CD28-4-1BB-CD3ζ CAR-T cell therapy may offer an effective therapeutic option. Further pre-clinical and clinical studies need to be performed to validate this novel approach
TMET-36. INCREASED METHIONINE CYCLE DRIVES PYRIMIDINE METABOLISM IN LETHAL PEDIATRIC EPENDYMOMAS
Authors: Navneesh Yadav, Antony Michealraj Kulandai Manuvel
Journal: Neuro-Oncology (2024)

Abstract Supratentorial ependymomas (ST-EPN) are pediatric brain tumors found in the cerebral hemisphere, driven by the oncogenic fusion of ZFTA with RELA. Other than surgery and radiotherapy, these tumors do not have effective therapeutic options. Recurrent ST-EPN tumors are highly aggressive and hard to treat, which makes these tumors lethal. To understand the disease mechanism and potentially identify or develop therapeutic targets, we established patient-derived models and interrogated the genetic and metabolic dependencies using cutting-edge, near-genome-wide genetic screening and metabolomic tools. Our integrative transcriptomics and metabolic analysis identify that the ZFTA-RELA fusion drives methionine metabolic reprogramming in the cancer stem cells to regulate permissive epigenetic status and pyrimidine nucleotide synthesis to fuel tumor growth. Limiting methionine or inhibiting MAT2A, a rate-limiting enzyme of methionine metabolism in ST-EPN cells, results in profound cell cycle arrest and make the cells vulnerable to pyrimidine inhibitors compared to other pediatric brain tumors. Thus, for treatment, along with radiotherapy, blocking the methionine cycle by using the methionine limited diet or in combination with pyrimidine metabolism inhibitors can be a novel therapeutic strategy against the aggressive paediatric ST-EPN tumors.
SURG-56. TRANSCRIPTION FACTOR CELL LINEAGE DETERMINES AGGRESSIVE BEHAVIOR AMONG NONFUNCTIONAL PITUITARY ADENOMAS
Authors: Alexander Himstead, Gianna Fote, Nischal Acharya, Edward Kuan, Frank Hsu, Ahmed Mohyeldin
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Pituitary neuroendocrine tumors (PitNETs) are the second most common intracranial neoplasm. Silent or non-functional PitNETs represent a common neuro-oncological challenge due to their size and unpredictable invasion of parasellar structures. This makes their complete surgical resection difficult and puts patients at higher risk for recurrence. OBJECTIVE To characterize differences in tumor volume, cavernous sinus invasion, and recurrence in nonfunctional PitNETs. METHODS Out of 615 transsphenoidal surgeries from 2012 to 2024, there were 309 overall PitNETs and 181 nonfunctional PitNETs. Based on new WHO criteria for transcription factor profiling (PIT-1, TPIT, and SF-1), there were 98 silent gonadotroph adenomas (SGA), 31 silent corticotroph adenomas (SCA), 10 silent pleurihormonal tumors (PHT), and 2 null cell adenomas. Tumor volume was calculated using (AxBxC/2). Knosp grade was calculated. Cavernous sinus invasion was defined as Knosp ≥ 3. Residual disease at 3 months postoperative was recorded and surgical intervention for growing residual disease was captured. RESULTS Average tumor volume of PHT (18.08 cm3) was significantly higher than SGA (8.44 cm3, p=0.007) and similar to SCA (10.33 cm3, p=0.11). Percentage of cavernous sinus invasion was significantly different between SCA (31.82%) and SGA (10.20%, p=0.003), but not PHT (33.33%; p&amp;gt;0.05). There was a significantly higher residual rate in SCA compared to SGA (31.71% vs. 11.22%, p=0.006). There were significantly more reoperations in the SCA group compared to SGA and PHT. CONCLUSIONS Despite similar tumor volume between SCA and SGA, there was a significantly higher rate of cavernous sinus invasion and residual disease among SCA. This has important neuro-oncological implications regarding surgical technique, postoperative surveillance, and need for adjuvant therapy to mitigate aggressive recurrent disease.
SURG-54. RECURRENT BRAIN METASTASES (RBM) TREATED WITH SURGICALLY TARGETED RADIATION THERAPY (START): PRELIMINARY SAFETY EVALUATION FROM A MULTI-INSTITUTIONAL PROSPECTIVE REGISTRY
Authors: Rupesh Kotecha, Stuart Lee, Matthew S Peach, Toral Patel, Zabi Wardak, John Floyd, Michael McGinity, Simon Hanft, Adam Robin, Ian Lee, Lindsey Sloan, Colette Shen, Analiz Rodriguez, Kimberly Bojanowski-Hoang, John Wanebo, Kris Smith, Mitesh Shah, Angela Richardson, Roukoz Chamoun, Paul Camarata, Brian Milligan, Lewis Leng, Patricia Seid, Andrea Wasilewski, David Monyak, Adam Nowlan, David McCracken, Erin Dunbar, Tulika Ranjan, Vincent DiNapoli, Huong Pham, Robert Ryan, Catherine Mercado, Nicholas Avgeropoulos, Ondrej Choutka, Akash Patel, Ali Jalali, Devon Haydon, Nimisha Deb, James Zhu, David Piccioni, Mark Hoeprich, Michelle Aizenberg Ansari, David Baskin, Parag Sevak, David Brachman, Michael Garcia, Sita Patel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Resection and intraoperative brachytherapy for operable recurrent brain metastasis allows for pathologic confirmation of recurrent disease, mass effect relief, and immediate initiation of radiotherapy (RT). In this analysis, we report patterns-of-use and treatment-related adverse events (AEs) for rBM patients treated with Cs-131 collagen tiles, an FDA-cleared intracranial brachytherapy device. METHODS Patients with rBM who underwent resection and surgically-targeted radiation therapy (GammaTile, GT Medical Technologies Inc., Tempe, AZ USA) on a prospectively enrolling phase 4 registry study (NCT04427384) were analyzed. AEs were graded per CTCAE v5.0. RESULTS Between 11/2020 and 2/2024, 56 rBM in 51 consecutive patients underwent STaRT at 19 centers, with 5 patients having 2 metastases implanted concurrently. 44 patients (86%) had prior same-site RT (median interval 14.5 mo, range 3-56). Primary tumor histologies were lung (27), melanoma (8), breast (7), renal (4), colon (2), and “other” (3). Median pre-operative maximum diameter was 3.0 cm (range 1.4-5.7); age 63 (range 28-81); 53% females; KPS median 90 (range 40-100); and median implantation time 3 minutes. 26 patients were implanted at a 1st, 15 at a 2nd, and 10 at ≥ 3rd same-site recurrence (range 1-9). At a median follow-up of 6.2 months (range &amp;lt;1-35.1), 6/51 patients (11.8%) experienced ≥Gr 3 AEs at a median of 12 (range 1-69) days postoperatively (POD). No radiation necrosis (RN) events were observed, and no AEs occurred in multi-implant cases or where STaRT was the initial form of RT. CONCLUSIONS In this prospective multi-institutional study, STaRT demonstrated an excellent safety profile in a cohort of larger rBM, even in the setting of multi-recurrent disease. Accrual and follow-up are on-going and will provide data on tumor control and long-term RN rates.
EPCO-39. MULTIOMIC AND CLINICAL ANALYSIS OF MULTIPLY RECURRENT MENINGIOMAS REVEALS RISK FACTORS, UNDERLYING BIOLOGY, AND INSIGHTS INTO EVOLUTION
Authors: Sangami Pugazenthi, Bhuvic Patel, Collin English, Kyle McGeehan, Colin McCornack, David Mok, Markus Anzaldua-Campos, Shervin Hosseingholi Nouri, Hiroko Yano, Tiemo Klisch, Akdes Harmanci, Akash Patel, Albert Kim
Journal: Neuro-Oncology (2024)

Abstract Although meningiomas, the most common primary brain tumor, are often effectively treated with surgery and radiation, an important subset of meningiomas behave aggressively and are characterized by treatment resistance and multiple recurrences. Prior work has yet to specifically study multiply recurrent meningiomas (MRMs), including whether they are molecularly distinct from non-recurrent meningiomas (NRMs) at initial diagnosis and whether the molecular features of MRMs evolve with subsequent recurrences. The objective of this study was to identify clinical and molecular features associated with MRMs and determine if longitudinal molecular changes occur in paired MRM samples. In this dual institution study, clinical parameters were collected for 1,186 meningioma patients. After propensity score matching, 31 MRMs were matched to 84 NRMs. Molecular sequencing including whole exome sequencing (n=44), EPIC bead chip methylation array (n=43), and RNA-sequencing (n=66) were performed. On multivariable binomial logistic regression, MRMs were significantly associated with male sex (P=0.012), subtotal resection (P=0.001), higher number of meningiomas on presentation (P=0.017), and histopathological sheeting (P=0.002). Multiomic analysis of primary meningiomas revealed MRMs exhibit greater global copy number alternations (CNA) (P=0.0113) and increased DNA methylation (P=0.0161). Integrated methylation profiling and RNA-sequencing identified candidate driver genes of MRMs. Among these genes, we demonstrate that knockdown of EDNRB, a locus with higher promoter methylation and decreased gene expression in MRMs, leads to increased meningioma cell proliferation, suggesting a tumor suppressor function. CNAs, subclonal evolution, and methylation profiles of MRMs did not significantly change from primary tumor to recurrence, even after radiation treatment, suggesting MRMs are molecularly aggressive from initial diagnosis. Overall, we identify several novel clinical and molecular risk factors associated with MRMs. MRMs harbor unique molecular features on presentation, which do not appear to change during evolution and after treatments, which has implications for development of biomarkers and therapeutic agents for these aggressive tumors.