tbuckley/cabot-search huggingface dataset:
EPCO-59. FIRST CASE REPORT OF COMBINED GERMLINE NF1 AND BRCA2 MUTATIONS PRESENTED WITH NEUROFIBROMAS AND LIPOMATOSIS
Authors: Yoon Choi
Journal: Neuro-Oncology (2024)

Abstract Both Neurofibromatosis type 1(NF1) and BRCA2 are common tumor suppressor genes, with mutations in each associated with genetic tumor syndromes. However, it is extremely rare to observe two different germline mutations in one patient. To the author’s knowledge, this is the first case report of a patient with germline mutations in both pathological NF1 and BRCA2 genes. We report a 41-year-old male patient with neurofibromas and lipomatosis. The patient with known family history of NF1, was diagnosed with NF1 after skin biopsy at 28 years old. At 40 years old, he underwent resection of a large intrathoracic neurofibroma. For genetic confirmation, next generation sequencing test was performed on both the intrathoracic neurofibroma tumor sample and saliva sample, revealing unexpected pathological germline mutation in both NF1 and BRCA2 genes. Consequently, the patient underwent resection of multiple lesions in the chest, abdomen, and upper extremities due to concern for potential breast cancers, and pathology of these lesions predominantly showed lipomas and one angiolipoma. Patient has family members with NF1 including a maternal aunt, a maternal cousin, and one son. However, there is no family history of lipomatosis or cancers commonly associated with BRCA2 mutation such as breast, ovarian, pancreatic, or prostate cancer. While lipomas are reported in patients with NF1, it is unusual that patient does not have typical café-au-lait spots or multiple neurofibromas but instead has multiple lipomas. This unusual presentation may be related to his unique genetic condition involving germline mutations in two tumor suppressor genes. Long term follow-up with screening tests for known tumors associated with each genetic mutation will be essential.
EPCO-52. INVESTIGATING EGFR CONTAINING EXTRACHROMOSOMAL DNA DYNAMICS IN GBM
Authors: Bo Zhao, Chae Yun Cho, Lingqun Ye, Kadir Akdemir
Journal: Neuro-Oncology (2024)

Abstract The epidermal growth factor receptor (EGFR) is the most frequently altered gene in GBM, with EGFR amplification occurring in approximately 40% of all glioblastomas, half of which exhibit the EGFRvIII deletion variant. EGFR amplification often occurs through the formation of extrachromosomal DNA (ecDNA), where EGFR typically co-amplifies with upstream enhancers. ecDNA is commonly found in a wide range of cancer types, particularly Glioblastoma (GBM), but is rare in normal cells. The uneven segregation of ecDNAs results in oncogene copy number variations in subclones, producing highly heterogeneous tumor cells and providing a selective advantage to cancer cells in response to changing environmental conditions. Meanwhile, ecDNAs keep evolving through fusion, deletion, or integration of new fragments, resulting in alterations to their structure and sequence. Some ecDNAs can reintegrate into chromosomal DNA, disrupting the integrity of chromosomal genes or rewiring chromosomal gene expression via ecDNA resident enhancers. However, the dynamics of EGFR-containing ecDNA (ecEGFR) have not been thoroughly investigated across primary and recurrent GBM. In this study, we profiled 47 glioblastoma specimens (both primary and recurrent) using a multi-omic approach, including WGS, RNA-seq, and ATAC-seq, identifying ecDNA in 14 samples, 10 of which carried EGFR. EGFR deletions were observed in 4 ecEGFR-positive samples, with 2 being the vIII variant. Interestingly, EGFR deletions predominantly occurred in the primary GBM. These ecEGFR samples exhibited significantly high EGFR copy number, gene expression, and chromatin accessibility. Additionally, there were samples with ecEGFR in the primary tumor but not in the recurrent tumor, or ecEGFR appears only in recurrent tumor. One patient showed an ecEGFR deletion in the primary tumor, while the recurrent tumor exhibited wild type ecEGFR.
DDEL-11. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING OF SPATIAL HETEROGENEITY OF DRUG PENETRATION AND EXPOSURE IN THE HUMAN BRAIN AND BRAIN TUMORS
Authors: Jing Li, Charuka Wickramasinghe, Andrew Wu, Yuanyuan Jiang, Jun Jiang, Artak Tovmasyan, Seongho Kim, Nader Sanai
Journal: Neuro-Oncology (2024)

Abstract BACKGROUD The difficulty in early, reliable prediction of drug penetration and exposure in the human brain and brain tumors makes development of new drugs and use of existing drugs for treating brain cancer a challenging and often unsuccessful task. We developed a physiologically based pharmacokinetic (PBPK) model platform for prediction of spatial pharmacokinetics in the central nervous system (CNS) following systemic drug administration. METHODS A 9-compartment CNS (9-CNS) PBPK model was developed to predict drug concentrations in brain blood, 2 brain parenchyma compartments (brain tissue adjacent to the CSF tract and deep brain parenchyma), 3 CSF compartments (ventricular CSF, cranial and spinal subarachnoid CSF), and 3 tumor compartments (tumor rim, bulk tumor, and tumor core). The pharmacokinetics in the CNS compartments were driven by plasma concentrations and governed by drug properties and CNS pathophysiology. The 9-CNS model was developed and validated with 4 drugs (abemaciclib, ribociclib, ceritinib, and temuterkib). RESULTS When considering tumor heterogeneity and inter-individual plasma pharmacokinetic variability following clinical standard dosing regimens, the model-predicted steady-state unbound drug tumor concentrations varied from 7.1 to 356 nM for abemaciclib, 74 to 4577 nM for ribociclib, 0.66 to 97 nM for ceritinib, and 0.8 to 288 nM for temuterkib, which were consistent with the heterogeneous drug tumor concentrations observed in glioblastoma patients. Drug penetration into the deep brain parenchyma was significantly less than that into tumors and CSF-adjacent brain tissue, particularly for strong ABCB1/ABCG2 substrate drugs. The ventricular and cranial subarachnoid CSF shared similar pharmacokinetics, while the spinal CSF pharmacokinetics was different. CONCLUSION A novel 9-CNS PBPK model was developed and validated for mechanistic prediction of spatial heterogeneity of drug penetration and exposure in the human brain, brain tumors, and CSF. It provides a valuable computational modeling tool to assist development and design of improved drugs or dosing regimens for brain cancer treatment.
CSIG-29. BRAF INHIBITOR THERAPY IN BRAF-MUTATED PRIMARY BRAIN TUMORS: A SINGLE-CENTER EXPERIENCE
Authors: Duru Baykal, Hazal Ser, Jessica White, Bryan Neth, Joon Uhm, Michael Ruff, Jann Sarkaria, Jessica Wilson, Elizabeth Yan, Fredric Meyer, Maria Peris Celda, Ugur Sener
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND BRAF pathway alterations are frequent in glial/neuroepithelial tumors. BRAF-targeted therapy with BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) has proven efficacy in clinical trials, though mainly enrolling pediatric patients. We sought to investigate real-world data for adult patients with BRAF-pathway mutant glial/neuroepithelial neoplasms treated with BRAFi/MEKi. METHODS Adults with BRAF-pathway mutated glial/neuroepithelial neoplasms treated with BRAFi/MEKi were retrospectively reviewed. RESULTS Five patients (n=4 female, median age at diagnosis 36) were identified (tumor types: glioblastoma n=1, high-grade astrocytoma with epithelioid features n=1, low-grade neuroepithelial tumor n=1, pilocytic astrocytoma n=1, pleomorphic xanthoastrocytoma n=1). Four had BRAF V600E and one had NF1 p.S2687Cfs*5 mutant tumors. Prior to targeted therapy initiation, patients underwent a median 2.4 treatments including surgery (n=4), radiation therapy (n=4), chemotherapy (temozolomide n=4; carboplatin/vincristine n=1). BRAF-targeted therapies included dabrafenib/trametinib (n=4), binimetinib/encorafenib (n=2), binimetinib (n=2). One NF1-mutant glioblastoma received binimetinib followed by binimetinib/bevacizumab. Median BRAFi/MEKi treatment was 15.2 months (range: 6-36 months). Toxicities included leukopenia (n=3), peripheral edema (n=1), reduced ejection fraction (n=1), skin rash (n=5), transaminitis (n=1) with all patients requiring dose reductions and 3 cases requiring discontinuation. Among patients where BRAFi/MEKi was discontinued due to toxicity, 2 received other treatments at progression, then switched to a different BRAFi/MEKi combination, which they tolerated (duration 6-10months). Best radiographic response was partial response, noted in 3 patients treated with dabrafenib/trametinib. Four patients remain alive and continue BRAFi/MEKi. CONCLUSIONS In this cohort of heavily-pretreated patients with glial/neuroepithelial neoplasms, BRAF-targeted therapy was associated with durable responses. Interestingly, two patients who were unable to tolerate one combination of BRAFi/MEKi were able to tolerate a different combination with sustained response. Our findings support ongoing use of BRAF targeted therapy for CNS tumors. Optimal timing and duration of treatment requires further prospective evaluation in adult patients.
CTNI-51. A PHASE 0/1 STUDY OF BDTX-1535 IN RECURRENT GLIOBLASTOMA (GBM) PATIENTS WITH EGFR ALTERATIONS OR FUSIONS
Authors: Nader Sanai, Yoshie Umemura, Vahuni Karapetyan, Tigran Margaryan, Dylan Huttenlocher, Jocelyn Harmon, Amy Hong, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Alterations to epidermal growth factor receptor (EGFR) occur frequently in high-grade gliomas (HGG) and are critical to its pathogenesis. This Phase 0/1 study evaluates pharmacokinetic (PK), pharmacodynamic (PD), and clinical response to an ATP-competitive, irreversible EGFR inhibitor, BDTX-1535, in recurrent HGG patients with EGFR alterations and/or fusions. MATERIALS/METHODS Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 at 200 mg/daily (cohort 1) or 400 mg/every other day (cohort 2) prior to planned resection at 2-4 hours following the final dose. In the Phase 0 component of the study, total and unbound drug concentrations were measured in tumor tissue (gadolinium (Gd) enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’ was defined as unbound drug concentration above 1 nM and 4.1 nM in Gd non-enhancing tumor in patients with EGFR mutations and amplification, respectively, determined eligibility for Phase 1 therapeutic dosing. PD response was assessed by quantification of percentage of positive pEGFR, pERK and MIB-1 cells in the surgical tumor tissue compared to baseline pre-treatment tissue. RESULTS Eleven recurrent HGG patients were enrolled (Arm A, n=11; Arm B, n=0). Mean unbound concentrations of BDTX-1535 in non-enhancing tumor regions were 11.9 nM and 18.8 nM in cohorts 1 and 2, respectively. Eight of nine (88.9%) evaluable patients exceeded the PK threshold and qualified for Phase 1. Suppression of pEGFR and MIB1 was observed in 55% and 67% of patients, respectively. No serious adverse events related to BDTX-1535 were observed. At the time of submission, median PFS and OS have not yet been reached. CONCLUSIONS BDTX-1535 is well-tolerated in recurrent HGG patients, achieves pharmacologically relevant concentrations in non-enhancing tumor tissue, and is associated with suppression of EGFR signaling. Efficacy data accompanying this PK/PD response will be reported.
EPID-17. REAL-WORLD OUTCOMES OF BRAIN METASTASES FROM PANCREATIC CANCER: AN ANALYSIS OF 1266 PATIENTS
Authors: Diya Jayram, Shreyas Bellur, Shahzaib Ahmad, Ahmad Ozair, Julia Steger, Samuel Sommer, Numa Frias, Manmeet Ahluwalia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BMs) from pancreatic cancer (PC) are uncommon. This study examined patterns of care and clinical outcomes for PC BMs. METHODS A retrospective analysis was conducted on PC BMs patients in the US National Cancer Database between 2010-2020, following STROBE guidelines. Treatments were categorized into systemic therapy (Sys) alone, stereotactic radiosurgery (SRS)±Sys, whole brain radiation (WBRT)±Sys, and no brain-specific treatment (NoTx). Primary outcome was median overall survival (mOS), with corresponding hazard ratio for death (HR) and 95% confidence intervals. Prognostic factors were determined using multivariable Cox proportional-hazards analysis including age, sex, race/ethnicity, insurance, Charlson-Deyo score (CDS), concurrent metastases (CMs), and treatment type. RESULTS Of 170,071 metastatic PC patients, 1,266 (0.7%) PC BM patients were included. 45.7% were female and 81.3% were White. Median age was 66.0 years (IQR:58.0-74.0). 34.4% had bone CMs, 45.4% had lung CMs, 60.2% had liver CMs. 48.1% of patients received NoTx, 22.6% Sys, 12.4% WBRT+Sys, 9.8% WBRT, 4.6% SRS+Sys, and 2.5% SRS. mOS (95% CI) was 2.4 months (2.2-2.5) in patients with BMs and 3.9 months (3.8-3.9) in those without BMs (P&amp;lt;0.001). Amongst BM patients, SRS+Sys had a significantly higher mOS of 7.8 months (6.1-14.3) followed by WBRT+Sys: 5.2 months (4.2-6.8), Sys: 4.8 months (4.2-5.8), WBRT: 2.0 months (1.6-2.2), SRS: 1.8 months (1.4-3.7), and NoTx: 1.2 months (1.0-1.3) (P&amp;lt;0.001). Patients treated with SRS alone (HR:2.9, 1.8-4.7, P&amp;lt;0.001), WBRT alone (HR:2.9, 2.0-4.0, P&amp;lt;0.001), and Sys alone (HR:1.5, 1.1-2.1, P=0.009) had significantly lower survival than with SRS+Sys. Patients treated in nonacademic facilities (HR:1.3, 1.1-1.4, P&amp;lt;0.001) and those with CMs (HR:1.4, 1.2-1.6, P&amp;lt;0.001) had poorer survival. CONCLUSIONS BMs in PC are rare and associated with lower survival. SRS+Sys was associated with the best prognosis, but &amp;lt;5% received it. 48% of patients receiving NoTx had mOS of 1.2 months. Future studies exploring care variations are warranted.
EPCO-48. RESOLVING INTRATUMORAL TRANSCRIPTIONAL HETEROGENEITY ACROSS THE CORE-EDGE SPATIAL AXIS IN GLIOBLASTOMA
Authors: Adam Luo, Kelly Casella, Ezra Baraban, Calixto-Hope Lucas, Eugene Shenderov
Journal: Neuro-Oncology (2024)

Abstract Intratumoral heterogeneity promotes tumor progression, treatment resistance, and recurrence in glioblastoma (GBM), and the cellular tumor core and infiltrating edge represent transcriptionally distinct cellular ecosystems. In this study, we characterize and validate the molecular differences across the core-edge spatial axis in GBM by applying whole-transcriptome GeoMx Digital Spatial Profiling (DSP) to 5 IDH-wildtype tumors. Three 3-micron tissue cores were extracted from each tumor and arranged into a tissue microarray (TMA). Core and edge regions of interest (ROIs) were chosen through coregistration of H&amp;E and immunofluorescent TMA scans. Following DSP, data for 44 ROIs (30 core and 14 edge) and 8530 RNA targets were bioinformatically analyzed. Single-sample gene set enrichment analysis aligned the DSP core and edge regional signatures to those of publicly annotated datasets, substantiating our profiling methodology. Unsupervised analyses revealed ROI clusters unique to each tumor specimen for both pre- and post-normalized data. To mitigate a potential patient-level effect in subsequent differential gene expression and pathway analyses, we leveraged a linear mixed-effect model using core versus edge as a fixed effect and tumor specimen as a random effect. Our analyses showed upregulation of epigenomic markers in core ROIs and neuronal markers in edge ROIs. Further, core and edge signatures were incongruent with the canonical GBM subtypes (Mesenchymal, Classical, Proneural) and malignant cell states (OPC-like, NPC-like, AC-like, MES-like). Cellular deconvolution analysis highlighted differential enrichment of neoplastic cells in core ROIs and neuroglia (astrocytes and oligodendrocytes) in edge ROIs. In summary, we leverage spatial profiling to further validate the geographic molecular heterogeneity of GBM, which is characterized by divergent neuronal programs within the infiltrating edge.
TMIC-33. MICROENVIRONMENT-DRIVEN CHANGES IN GLIOBLASTOMA CELL STATE SIGNATURES EXAMINED USING REGION-SPECIFIC HUMAN BRAIN ORGANOIDS
Authors: Tarun Bhatia, Saisrinidhi Ganta, Anson Sing, Alexia King, Caitlin Sojka, Kimberly Hoang, Edjah Nduom, Renee Read, Jeffrey Olson, Steven Sloan
Journal: Neuro-Oncology (2024)

Abstract Cell state plasticity is retained by all stem-like and differentiated cells within glioblastoma (GBM) tumors. GBM cells can exploit these state-shifting capacities to evade and resist therapeutics. Thus, there is a need to identify and target the regulators of GBM cell state transitions. To address this question, we use a fully human platform where hiSPC-derived organoids serve as a recipient environment to host cells engrafted directly from surgically resected GBMs. This allows us to precisely examine how microenvironmental variables impact the molecular signatures of GBM cells. We acutely isolate GBM cells from surgical resections, label cells with a GFP-lentivirus for 4 hours, and then engraft these tumor cells into parallelly patterned region-specific organoids that mimic dorsal forebrain, ventral forebrain, midbrain, and hindbrain identities. These regions were chosen as they capture derivatives of the three primary brain vesicles and because these regions contain unique cell types and signaling molecules. We performed paired single-cell RNA sequencing on tumor cells pre-engraftment and 14 days post-engraftment. Universal to all regional organoids, we find that GBM cells shift towards a neural progenitor-like and neuron-like signature within organoids, regardless of the cell state of the parent tumor prior to engraftment. To support our findings, we also observed that patient-derived glioma cell lines converge on a neural progenitor-like state within organoids. Thus, the dominance of this shared GBM cell state within organoids implies the existence of shared extrinsic factors in these immature (neurogenic) organoids that favor a progenitor-like or neuron-like identity across all four regions. We are now asking whether this bias towards neuronal and/or neural progenitor identity is a result of engrafting into young neurogenic organoids, or if the same phenomenon could be true in late-stage (post-gliogenic) mature organoids. We are also using this valuable platform and data to identify the extrinsic signals that GBM cells rely on to fulfill their plastic potential, adapt to the microenvironment, and resist therapeutics.
CSIG-13. TARGETING GENETIC DEPENDENCIES EXPOSES DIFFUSE MIDLINE GLIOMA CELL OF ORIGIN VULNERABILITIES
Authors: Matthew D Dun, Evangeline Jackson, Tuan Vo, Clara Savary, Madisen Riley, Alicia Douglas, Izac Findlay, Zacary Germon, Abdul Mannan, Bryce Thomas, Ryan Duchatel, Ranjith Jayaraman
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), are uniformly fatal brain cancers affecting children, adolescents, and young adults. These tumors are characterized by ‘oncohistone’ mutations in histone H3 genes (H3F3A, HIST1H3B, HIST1H3C), resulting in the substitution of lysine 27 to methionine (H3K27M), resulting in dominant negative hypomethylation at lysine 27 (H3K27) and a global loss of gene silencing. CRISPR-Cas9 loss-of-function gene deletion screens identified mutation-independent dependencies on PIK3CA and MTOR genes for tumor growth and proliferation, highlighting a targetable molecular dependency across DMG patient-derived models (n=38). However, systemic PI3K/mTOR inhibition increased blood glucose and insulin levels, promoting hyperinsulinemia/hyperglycemia and reduced efficacy in vivo. To exploit genetic dependencies while maintaining compliance and therapeutic benefit, we optimized combinations of clinically relevant PI3K inhibitors (paxalisib, GCT007, everolimus) with the antiglycemic drug metformin to restore glucose homeostasis and decrease DMG insulin receptor activity in vivo, extending the survival of DIPG xenograft models. Phosphoproteomic profiling of DIPG models treated with PI3K/mTOR inhibitors promoted calcium-activated PKC signaling. The brain-penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of DIPG xenograft models, including those mimicking disease progression, with further benefits potentiated using metformin in a multimodality approach. Combined PI3K-PKC inhibition in vivo promoted differentiation of OPC-like DMG to more OC-like cells, enhancing PDGFRA-JAK/STAT proinflammatory signaling, showing features of demyelination and MHC-II+ antigen expression, including PD1/PDL1. In parallel, combined PI3K/mTOR and PDGFRA inhibition using paxalisib and avapritinib synergistically extended the survival of patient-derived xenograft models, showing the preclinical relevance of simultaneously targeting these vulnerabilities. Together, we reveal that therapeutic inhibition of PI3K/mTOR and compensatory PKC signaling, while mitigating side effects with metformin, altered the chromatin architecture, leading to cellular differentiation and opening the door for clinically relevant checkpoint inhibitors. This combination strategy addresses DMG genetic dependencies, cellular and systemic responses to precision therapies, while harnessing the immune system for potential clinical translation.
BIOM-55. SENSITIVITY OF IMMUNOHISTOCHEMISTRY WITH BRAF VE1 ANTIBODY FOR BRAF V600E IN PRIMARY CENTRAL NERVOUS SYSTEM TUMORS
Authors: Juan Blaquier, Sophie Egea, Sakir Gultekin, Fulvio D’Angelo, Antonio Iavarone, Macarena de la Fuente
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND BRAF gene encodes for a key protein of the RAS-RAF-MEK-ERK pathway. BRAF alterations are found in a variety of primary central nervous system (CNS) tumors ranging from 3% of glioblastomas to 60% of pleomorphic xanthoastrocytomas. BRAF V600E mutation is the most common BRAF alteration found in CNS malignancies, and it has been successfully targeted with BRAF/MEK inhibitors. Novel BRAF inhibitors, still in development, have shown promising antitumor activity. Next-generation sequencing (NGS) has become a standard test in the era of histo-molecular diagnosis, but it can be unavailable or inaccessible, and results usually take longer. Immunohistochemistry (ICH) with VE1 antibody for BRAF V600E protein has shown high discordant results with sequencing in other tumor types. We aimed to establish the concordance of BRAF VE1 and NGS sequencing in CNS tumors. METHODS Single-center retrospective analysis of patients with BRAF V600E mutant CNS tumors by NGS testing. RESULTS 30 patients with BRAF V600E mutant primary CNS tumors by NGS were included, 18 were male. 15 were classified as IDH-wildtype gliomas, 4 low grade neuroepithelial gliomas, 8 pleomorphic xanthoastrocytoma, 2 pilocytic astrocytomas and 1 papillary craniopharyngioma. IHC testing with BRAF VE1 antibody was done at the initial pathological classification in 23 of the cases being positive in 15 and negative in 8 cases. In 7 cases IHC was not done but has been requested for retrospective analysis and results are pending. Sensitivity for BRAF VE1 IHC was 65%. CONCLUSION When compared to NGS testing, ICH with BRAF VE1 antibody for BRAF V600E in CNS tumors shows modest sensitivity, being a limited tool when results are needed promptly or NGS is inaccessible. Determining specificity of the test will be crucial to establish its reliability for patient selection. Sequencing should be obtained when possible and remains the more reliable method for detecting V600E.