tbuckley/cabot-search huggingface dataset:
CTNI-60. SAFETY LEAD-IN RESULTS FOR QBS10072S IN THE INDIVIDUAL SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT) TRIAL, A RANDOMIZED ADAPTIVE PLATFORM TRIAL FOR NEWLY DIAGNOSED MGMT UNMETHYLATED GLIOBLASTOMA
Authors: Rifaquat Rahman, Lorenzo Trippa, Elisa Aquilanti, Eudocia Lee, Isabel Arrillaga-Romany, Jennifer Wiley, Ugonma Chukwueke, Jose McFaline-Figueroa, Kathryn Partridge, Rameen Beroukhim, Lakshmi Nayak, Tracy Batchelor, Christine Lu-Emerson, Jan Drappatz, Andy Lassman, Mary Welch, Manmeet Ahluwalia, Wenya Bi, Omar Arnaout, Daphne Haas-Kogan, Shyam Tanguturi, Ayal Aizer, Lisa Doherty, Geoffrey Fell, Maria Lavallee, Anna Smokovich, Shannon Peabody, Catharina Westergaard, Vasvi Bhutani, Alyssa Russ, Brooke Barlow, Ennio Chiocca, Gordon Ringold, Ron Weitzman, Jaymes Holland, David Reardon, Keith Ligon, Patrick Wen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND QBS10072S, is a L-type amino acid transporter 1 (LAT-1) targeted alkylating agent that utilizes LAT1 as both a transport and targeting mechanism. QBS10072S can cross the blood-brain barrier, exhibits potential for cytotoxicity with a mechanism distinct from temozolomide and has low off-target effects. QBS10072S is being evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial (NCT02977780), a randomized phase 2 adaptive multi-arm platform trial. METHODS Adult patients with newly diagnosed MGMT-unmethylated glioblastoma are eligible for INSIGhT. Since there is no safety data available for QBS10072S in combination with radiotherapy, a safety lead-in evaluation was conducted utilizing a 3 + 3 design. Starting dose for QBS10072S was 12mg/m2 in combination with radiation therapy and adjuvantly as monotherapy in 28 day cycles. Patients were monitored for dose-limiting toxicities (DLTs) to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). RESULTS Nine patients were enrolled December 2022 to October 2023 for safety lead-in testing, and median age was 57 years (41-67) with 6 (66%) males, 6 (66%) patients with gross total resection, and median KPS 90 (range 80-100). Pharmacokinetic studies indicated that drug exposure was lower than prior studies, and three patients received 12mg/m2, 15mg/m2, and 18mg/m2, respectively, per dose escalation protocol. No DLTs nor adverse events leading to study drug discontinuation were reported during the evaluation period. Four patients had possible treatment-related CTCAE grade ≥ 3 toxicity including lymphopenia (n=3) and fatigue (n=1). The RP2D was determined to be 18mg/m2. Seven patients were discontinued from study treatment due to progressive disease and two patients remain on treatment. CONCLUSION QBS10072S, concurrent and adjuvant to radiation therapy, was well-tolerated in patients with newly diagnosed unmethylated MGMT glioblastoma. QBS10072S 18mg/m2 is being evaluated as a treatment arm in phase 2 testing in the ongoing INSIGhT trial.
BIOM-33. INVESTIGATING MIR-21 AS A NON-INVASIVE PROGNOSTIC BIOMARKER IN GLIOMA PATIENTS IN RESOURCE CONSTRAINT SETTINGS
Authors: Altaf Ali Laghari, Sana Naeem, Sufiyan Sufiyan, Wajiha Amin, Sahar Ilyas, Mohammad Hamza Bajwa, Siraj Uddin Qazi, Nouman Mughal, Syed Ather Enam
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioma treatment remains challenging due to high recurrence rates and resistance to treatment. Diagnosis and follow-up in resource-constrained regions often leads to significant patient attrition. Serum microRNA (miRNA) expression profiles are shown to be expressed in tumor tissue and peripheral samples, offering a pathway for non-invasive, repetitive liquid biopsies. miR-21 shows promise in many populations; however, there is a dearth of data from our region. METHODOLOGY we collected 89 intraoperative tumor tissue samples, 42 pre- and post-operative serum samples from glioma patients, and included 10 control tissue samples along with 8 normal serum samples and analyzed for miR-21 expression through qPCR. Serum samples were collected before tumor resection and post-surgery (pre- and post-operative). Correlational analysis with molecular markers IDH, Ki-67, ATRX, p53, and survival curves through the Kaplan-Meier method were calculated in high and low miR-21 expression groups, The hazard ratio was quantitatively determined using Cox regression analysis, considering both univariate associations and multivariate correlations with clinical parameters. RESULTS miR-21 expression in tissue increased with higher grades of glioma (p=0.00064), of patients above 50 years (p=0.0027), and shows a positive correlation with tumor volume (r= 0.22, p=0.081). IDH-wildtype (p=2.06e-03) and high Ki-67 (p=2.50e-03) expression in tumors showed significant upregulation of miR-21 compared to IDH-mutant and low Ki-67. Patients with low miR-21 expression had significantly longer overall survival (OS) than patients with high miR-21 expression (p =0.006). Quantitative hazard analysis indicates that patients in the high expression group have a 2.77 times higher risk of mortality (95% CI: upper - 0.19, lower - 0.92), in comparison to patients in the low expression group (p= 0.008). CONCLUSION Our findings validate the future utility of miR-21 as a serum assay to help diagnose and assess treatment response in different grades of glioma, within our population. Keywords: Glioma, Biomarker, Molecular markers, Liquid biopsy
NIMG-19. DEUTERIUM METABOLIC IMAGING INTERROGATES THE HISTONE H3K27M MUTATION AND PROVIDES AN EARLY READOUT OF RESPONSE TO THERAPY IN DIFFUSE MIDLINE GLIOMAS
Authors: Celine Taglang, Georgios Batsios, Suresh Udutha, Anne Marie Gillespie, Benison Lau, Sunjong Ji, Sabine Mueller, Timothy Phoenix, Sriram Venneti, Carl Koschmann, Pavithra Viswanath
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline gliomas (DMGs) are lethal primary brain tumors in children that are driven by recurrent lysine 27 to methionine mutations in histone H3 (H3K27M). Radiation is standard of care and the imipridones ONC201 and ONC206 have emerged as promising therapies for DMG patients. Although magnetic resonance imaging (MRI) is the mainstay for patient management, it does not reliably assess response to therapy. Therefore, the goal of this study was to identify metabolic alterations induced by H3K27M that can be leveraged for non-invasive metabolic imaging of DMGs. Using patient-derived (BT245, SF8628, SF7761, SU-DIPG-6, DIPG7, SU-DIPG-13) and syngeneic (26-B7, 26-C2) models, we show that the H3K27M mutation upregulates glucose metabolism via glycolysis to lactate. Silencing the H3K27M mutation reduces glycolytic capacity and depletes lactate, an effect that is associated with downregulation of rate-limiting glycolytic enzymes and transporters (SLC2A1, HK2, PFKFB3, PGK1, SLC16A3). Deuterium metabolic imaging (DMI) is a novel, clinical stage method of tracing glucose metabolism in vivo. Our studies show that lactate production from [6,6-2H]-glucose is spatially localized to tumor vs. normal brain in mice bearing intracranial BT245, SF8628 or 26-B7 xenografts at clinical magnetic field strength (3T). Lactate production from [6,6’-2H]-glucose is reduced in patient-derived (BT245, SF8628, SF7761) or syngeneic (26-B7) cells treated with radiation, ONC201 or ONC206. Importantly, lactate production is reduced at an early timepoint (5 days) following treatment with ONC206, when changes cannot be detected by MRI, in mice bearing intracranial BT245 or SF8628 xenografts. Collectively, our studies link the H3K27M mutation with elevated glycolysis and identify [6,6’-2H]-glucose as a safe, orally administered contrast agent for visualizing the metabolically active lesion and for imaging early response to therapy in DMGs in vivo. Clinical translation of our studies will provide physicians with a much-needed tool to determine whether DMG patients are responding to standard and experimental therapies under development.
CNSC-62. DIFFERENTIAL SURVIVAL IMPACT OF TRASTUZUMAB DERUXTECAN IN HER2-POSITIVE VERSUS HER2-LOW BREAST CANCER PATIENTS WITH BRAIN METASTASES
Authors: Tulika Ranjan, Vivek Podder, Mainak Bardhan, Andrea McCracken, Charlie Hurmiz, Reshma L Mahtani, Manmeet Singh Ahluwalia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BM) in breast cancer (BC) present significant treatment challenges, with varying outcomes based on HER2 expression. There is limited real-world evidence of outcomes with the use of trastuzumab deruxtecan (T-DXd) on survival in patients (pts) with HER2-low and HER2-positive (HER2+) MBC with BM. METHODS We conducted a retrospective cohort study using data from seven US-based health systems within the Guardian Research Network (GRN). We included pts treated with T-DXd from December 2019 to December 2023, classified as HER2-low (IHC 1+ or IHC 2+/HER2 FISH non-amplified) or HER2+ (IHC 3+ or HER2+ with FISH amplified). Survival analysis was performed using Kaplan-Meier curves and the log-rank test. RESULTS 125 pts with BCBM treated with T-DXd were included in the final analysis, of which 70 (56%) were HER2+ and 55 (44%) were HER2-low. The median age at BM diagnosis was 60.5 years (range 21.6 to 87.1 years). HER2 low pts had a higher prevalence of ER+ disease than HER2+ pts (81.9% vs. 55.7%, p=0.01). Most of these pts (≥75%) had received multiple prior lines of therapy. HER2+ pts with BM had a median overall survival (mOS) of 9.3 months (95% CI: 6.79-11.88), significantly longer than 4.3 months (95% CI: 1.89-6.82) in HER2-low pts (p &amp;lt; 0.001). At 6 months, OS for HER2+ pts with BM was 40% compared to 25% in HER2-low pts. At 12 months, OS for HER2+ pts was 20% compared to 10% in HER2-low pts. CONCLUSIONS This study represents the largest real-world evidence to date on the effectiveness of T-DXd in treating BM from breast cancer. HER2+ BCBM exhibited longer mOS and 12-month survival rates than pts with HER2-low disease, suggesting HER2 expression is crucial in determining T-DXd’s effectiveness. Future research should explore combination therapies and identify predictive biomarkers to optimize treatment strategies through clinical trials.
PATH-41. PRIMARY BRAIN SARCOMA WITH DROP METASTASES AND LEPTOMENINGEAL DISEASE
Authors: Shama Farooq, Carlos Eduardo Silva Correia
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Primary brain sarcoma is extremely rare and has a very poor prognosis. Sarcomas are a highly diverse group, with over 100 different subtypes identified in the recent WHO classification. Case: In this case, we describe a 51-year-old man diagnosed with primary right frontal poorly differentiated sarcoma. He experienced cognitive changes for weeks. Brain MRI revealed a lobulated mass with peripheral enhancement measuring 67 mm by 61 mm by 52 mm. He underwent gross total resection, and pathology indicated high-grade poorly differentiated sarcomatous lesions. Further analysis at Memorial Sloan Kettering and NIH failed to match any DNA methylation class. Next generation sequence (NGS) testing revealed mutation of NF2, CDKN2A, COL3A1, CD33, and PIK3CA genes, increased PD-L1 mRNA, and PD-L1 expression, greater than 50%. The conclusive diagnosis was a PD-L1 high poorly differentiated sarcoma, not otherwise specified. Since no primary site was found elsewhere, planned to treat it as a primary brain sarcoma. Patient underwent focal radiation therapy with a plan to start immunotherapy combination of anti-CTLA4 and anti-PD1 therapy. In addition, an anti-VEGF therapy with pazopanib because of the efficacy of pazopanib in the setting of soft tissue sarcomas. The patient completed IMRT on 07/13/2023 and presented with a new onset of left leg weakness and urinary incontinence on 07/25/2024, further neuraxis imaging with MRI showed local and distant intracranial recurrence with drop metastasis at C1, C5-C6, and S2. The patient was started on IMRT to address drop metastasis, however further clinical decline led to treatment discontinuation. DISCUSSION There is no consensus on treatment guidelines on primary brain sarcomas given that they are exceedingly rare. DNA methylation and NGS provided very valuable information. We were unable to find any reported cases of primary brain sarcoma with drop metastases and leptomeningeal disease in the literature.
RBIO-03. A SMALL ANIMAL RADIATION RESEARCH PLATFORM (FLASH-SARRP) TO MEASURE IMMUNOLOGICAL EFFECT OF ULTRA HIGH DOSE RATE (FLASH) RADIOTHERAPY
Authors: Khaled Aziz, Daniel Sforza, Ehsan Tajik-Mansoury, Mohammad Rezaee, Lawrence Kleinberg
Journal: Neuro-Oncology (2024)

Abstract Patients who undergo radiation therapy (RT), particularly fractionated courses, often develop lymphopenia. Clinical outcome for various cancer types, including brain tumors, identifies lymphopenia as a negative prognostic factor. The mechanism for RT induced lymphopenia is unclear. Simulated models suggest the volume of blood flowing through a radiation field could play a crucial role in death of radiosensitive lymphocytes. FLASH RT is ultrahigh dose rate administration of RT, &amp;gt;100 times faster dose rate than standard RT that has been observed to improve the therapeutic ratio in preclinical models by preferential normal tissue sparing. Hypothesized mechanisms include chemical reactions depleting oxygen in well oxygenated normal cells creating radioresistance, differing pro-inflammatory signaling impacting tumor and normal tissue, and less impact on circulating immune cells consequent to decreased proportion exposed during a treatment session which may enhance antineoplastic response. We designed the novel FLASH kV x-ray cabinet system for preclinical laboratory research (FLASH-SARRP) to deliver ultra-high dose rates up to 100 Gy/s as well as conventional dose rates of 1.0 Gy/s to facilitate comparative studies. A custom designed docking system was developed to reproducibly position and immobilize mouse for stereotactic radiation of the brain. Dose and dose rate measurements were performed with calibrated Gafchromic EBT3 film in solid water with 0.025 mm additional copper filter. FLASH-SARRP system delivered kV x-rays at an average dose-rate of 79.2±2.1Gy/s corresponding to 10 mm depth in the immobilized mouse brain. For the delivery of 15 Gy, treatment duration was 0.2 seconds for FLASH RT administration whereas it was 244 seconds for conventional dose rate. We successfully designed a high-precision platform to study partial brain x-ray FLASH effects in mice and studies are ongoing to assess differential impact on normal brain tissue, circulating cytokines, and immune cell populations for single dose and fractionated administration of FLASH and standard radiotherapy.
BIOM-66. GENOME-WIDE DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD OF PATIENTS WITH GLIOBLASTOMA ENROLLED ON THE PHASE II VERTU TRIAL
Authors: Eugene Vaios, Courtney Wimberly, Hao-Wen Sim, Liz Barnes, Eng-Siew Koh, Sonia Yip, Merryn Hall, David Ashley, Erik Sulman, Zachary Reitman, Kyle Walsh, Mustafa Khasraw
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND For patients with glioblastoma, the identification of a non-invasive biomarker for longitudinal molecular profiling could improve risk stratification, clinical trial design, and surveillance. In a secondary analysis of the phase II randomized VERTU trial (ACTRN12615000407594) of adult patients with newly diagnosed MGMT-unmethylated glioblastoma, we assessed the feasibility of characterizing peripheral blood genome-wide DNA methylation patterns. METHODS DNA was extracted from whole blood and serum samples at baseline and end-of-treatment (EOT) from patients enrolled on VERTU, which evaluated the PARP inhibitor veliparib combined with radiotherapy and temozolomide. Infinium FFPE QC qPCR and DNA Restoration Kits were used to restore and concentrate fragmented serum DNA. Genomic DNA was plated, bisulfite converted, and profiled for methylation patterns at &amp;gt;935,000 CpG sites using the Infinium MethylationEPIC microarray V2.0. Quality control, pre-processing, leukocyte deconvolution, and calling of MGMT status were completed in R Studio. RESULTS Peripheral blood methylation data were generated and passed quality control for 104/104 baseline and 24/34 EOT samples available for analysis. The median concentration of genomic DNA at baseline and EOT was 104.50 ng/μl (range:1.97-550) and 0.98 ng/μl (range:0.11-19.8). The deconvoluted median leukocyte proportions differed significantly between baseline and EOT for neutrophils (0.64vs0.90,p&amp;lt;0.01), CD4 memory (0.09vs0.00,p&amp;lt;0.01), CD4 naive (0.03vs0.01,p=0.02), CD8 memory (0.04vs0.00,p&amp;lt;0.01), monocyte (0.07vs0.03,p&amp;lt;0.01), natural killer (0.05vs0.00,p&amp;lt;0.01), and T regulatory (0.000vs0.001,p=0.01) cells. There were no differences in baseline leukocyte proportions between patients with (n=6) and without (n=98) biopsy-proven pseudoprogression. 2/104 samples were determined to be MGMT-methylated based on peripheral blood methylation analysis. Unsupervised hierarchical clustering based on the 1,000 most differentially methylated CpG sites generated two patient clusters (n=64, n=40). CONCLUSIONS To our knowledge, this is the first study to demonstrate the feasibility of analyzing peripheral blood methylation patterns from patients with glioblastoma receiving chemoradiation on a randomized clinical trial. Efforts are underway to correlate these blood methylation patterns with previously published tumor tissue methylation patterns and clinical outcomes.
IMMU-72. TYPE I INTERFERON SIGNALING WITHIN GLIOBLASTOMA CELLS PROMOTES T-CELL EXHAUSTION AND RESISTANCE TO CHECKPOINT INHIBITORS
Authors: Joshua Jackson, Peter Fecci
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) remains among the most fatal cancers with few treatment modalities and resistance to modern immunotherapeutic treatment paradigms including immune checkpoint inhibitors (ICI). ICIs neutralize the regulatory signals that disable T cells and have demonstrated remarkable efficacy against a variety of cancers, though not in GBM. The impotence of ICI in GBM has been linked to the tumor’s remarkable capacity to elicit T cell exhaustion, though the mechanism remains poorly understood. Chronic interferon (IFN) cytokine signaling is known to promote immunosuppression and Tex in several cancer types as well as resistance to ICI. However, the role of IFN in GBM has not been investigated despite evidence that IFN signatures exist within clinical samples of GBM. Syngeneic murine GBM cell lines CT2A and SB28 were utilized for in vivo and in vitro studies. Anti-mouse PD-1 and CD8 antibodies or PBS control were injected intraperitoneally. CRISPR editing was used to create validated knockouts (KO) of the type I IFN receptor (IFNAR1) in CT2A. Mice bearing IFNAR1 KO intracranial tumors have improved median survival (p &amp;lt; 0.05) and are exquisitely sensitive to checkpoint anti-PD-1 blockade (p &amp;lt; 0.05) with the majority of mice surviving. Furthermore, surviving mice reject the subsequent intracranial re-challenge with parental CT2A tumors compared to controls (p &amp;lt;0.05) suggesting central memory responses mediating rejection. We conclude that abrogation of Type I IFN signaling is sufficient to extend survival which is further enhanced by ICI. Work is ongoing to further elucidate the precise mechanism that mediates this response and to identify a therapeutic intervention that enables tumor-specific inhibition of the IFN pathway with preliminary work suggesting a CD8 T cell mediated response and reversal of the T cell exhaustion phenotype.
DDEL-06. CONVECTION-ENHANCED DELIVERY OF SEVEN DIFFERENT MOLECULES SHOW LARGE DIFFERENCES IN CONVECTIVE PROPERTIES BETWEEN MOLECULES. INFORMED DECISION MAKING FOR OPTIMIZED CATHETER PLACEMENT AND SUBSEQUENT INFUSION STRATEGIES
Authors: Bo Halle, Max Woolley, Dave Johnson, Julia Williams, Charlotte Kidd, Mikkel Schou Andersen, Frantz Rom Poulsen, Vigga Sand Gammelsrød, Aaraby Yoheswaran Nielsen, Mahsa Amirrashedi, Natan Johannes Willem Straathof, Katharina Ravn, Qing Tang, Christian Glarbo Pedersen, Andrea Tue Ingemann Jensen, Helge Thisgaard
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Glioblastoma (GBM) trials based on convection-enhanced drug delivery (CED) bypassing the blood-brain barrier have failed to prove efficient until now. Many factors influence CED. In this study we evaluated CED of seven different molecules using dynamic PET/MRI during infusion. This enabled in-depth evaluation of drug distribution and concentration gradients providing a more precise understanding of the Vd/Vi ratio and the extent of efficacy level across the Vd zone. Novel surgical catheter placement software algorithms, results in more informed-decision-making for catheter positioning and subsequent infusion planning strategies. METHODS Pigs were implanted with neuroinfuse™ drug delivery systems enabling intermittent drug infusions. Gadolinium, [124I]-UdR, [55Co]Co-DOTA-hEGF, [55Co]Co-DOTA-SP4, [18F]PSMA-1007 and three differently sized [64Cu]-labelled nanocarriers were evaluated in both pigs with and without a brain resection cavity. Gadolinium distribution was followed by MRI. PET imaging was used for the rest. To inform clinical trial design, strategic catheter placement and volumes to be infused, planning was investigated on several historical GBM cases. RESULTS Vd/Vi ratios ranged between 1.00 – 3.77. where large-sized liposomes performed best. Catheters stayed patent during weeks of repeated infusions. In the resected animals no leakage of drugs into the brain resection cavity was observed. Effective 3D modelling of novel catheter infusion planning aids provided visualized representations of tailor-made infusion plumes, capable of being suitably positioned to optimize surgical planning of catheters and transcutaneous reaccess port. CONCLUSION Large differences in convective properties between different molecules were observed. Large-sized liposomes as drug-carrier system showed superior performance to all other molecules. Vd/Vi ratios for promising drugs should be determined before initiating future clinical CED trials. Infusion concentration gradients to facilitate more precise Vd/Vi ratios provided important performance metrics for visualised infusion planning aids of a novel chronic drug delivery system, illustrating informed decision making for optimised catheter placement and subsequent infusion strategies is clinically translatable for GBM indications.