tbuckley/cabot-search huggingface dataset:
P18.46.B THE INVERSE PARADIGM OF IDH-WILDTYPE GLIOBLASTOMA EXPLAINS THE TWO DISTINCT MODALITIES OF MICRO-INFILTRATION AND PINPOINTS THE ANCESTRAL FOUNDER CELL AS THE KEY THERAPEUTIC TARGET
Authors: E Brognaro
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The IDH-wildtype glioblastoma is the only brain tumor that originates from the ribbon layer of the SVZ and can spread quiescently across the supratentorial brain parenchyma before starting to grow. Moreover, due to indirect and direct experimental evidence, it is finally unquestionably clear that two diffuse micro-infiltrations occur in IDH-wildtype glioblastoma, the first long before the primary bulk growth (the only one able to originate the primary bulk and distant relapses) and the second during bulk growth and evolution. The recognition that the latter is ineffective in giving rise to distant recurrences is a fundamental and very recent breakthrough. As a crucial consequence, there are two causes of therapeutic resistance, and the second one has yet to be identified and challenged therapeutically. MATERIAL AND METHODS By collecting multiple spatially separate samples in the tumor mass, we can reconstruct the phylogenetic tree of the primary tumor bulk. However, the therapeutic solution cannot be found in the tumor bulk (where the primordial cells are invariably extinct) but instead in the micro-infiltrated brain, where the ancestral founder CSCs lie quiescently in the perivascular niches. The codified ethical methods (as part of normal glioblastoma surgery) to sample the micro-infiltrated brain parenchyma are enabling us (and our research group is close to achieving this result) to isolate, identify and reproduce the dormant ancestral founder CSCs. RESULTS In the bulk, we can infer and reconstruct the phylogenetic tree of the tumor as well as driver and passenger events and the multitude of CSC variants by using multiple separated samples. The ethical methods for sampling micro-infiltrated brain parenchyma are now enabling us to identify and characterize the ancestral founder CSCs, which hibernate in the perivascular parenchymal niches of the supratentorial brain (their activation being the only cause of distant recurrences). CONCLUSION The first cause of therapeutic resistance is due to intratumor heterogeneity, while the second cause is the silent presence in the entire supratentorial brain of dormant ancestral founder CSCs from the pre-growth micro-infiltration. Only the identification and characterization of the ancestral founder CSC will enable us to simultaneously overcome both causes of resistance and provide an innovative therapeutic solution. Precisely, the ancestral founder CSC is identical to the premalignant progenitor of the SVZ and to the cell that activated in a single or multiple brain location, gave rise to the primary tumor bulk(s), and transmitted the ancestral driver genomic alterations to all subsequent evolutionary CSC variants.
P08.01.A ANGIOGENESIS IN CHEMOTHERAPY INDUCED PERIPHERAL NEUROPATHY (CIPN): EXPLORING CIRCULATING VEGF AS BIOMARKER OF CIPN DEVELOPMENT AND RECOVERY
Authors: R Velasco, P Andrés-Benito, C Marco, S Roca-Pereira, A Pros-Marsal, Y López-Sampere, D Eva, C Santos, A Stradella, J Bruna
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Chemotherapy induced peripheral neuropathy may result from an antiangiogenic effect of these drugs, resulting in destruction of the vasa nervorum. Vascular integrity alterations may contribute to neuropathic pain pathogenesis. Vascular endothelial growth factor A (VEGF-A) is an angiogenic factor that enhances nerve blood flow and oxygen supply by inducing angiogenesis, in response to the nerve ischemia and hypoxia caused by these drugs. Besides, microvascular damage has been suggested as the basis for neuropathic pain due to chemotherapy. Whether VEGF-A plays a role in the pathogenesis and repairment of CIPN is unknown. The aim of this study was to (1) explore the evolution of plasma VEGF during and after chemotherapy treatment and its association with development and recovery of CIPN; (2) compare the VEGF among different neurotoxic chemotherapy agents; (3) investigate the potential role of VEGF as biomarker of CIPN severity and prognosis. MATERIAL AND METHODS This is a single-center prospective observational longitudinal study including three cohorts of patients with breast, lymphoma or colorectal cancer treated with paclitaxel, brentuximab and oxaliplatin, respectively. All patients were assessed using the Total Neuropathy Score- clinical, Common Terminology Criteria for Adverse Events, EORTC QLQ-CIPN20 and nerve conduction studies (NCS) before, and periodically up to 12 months after finishing treatment. Serial VEGF and light chain Neurofilaments (NfL), a biomarker of nerve axon damage, were collected at the same timepoints and quantified using ELISA and SIMOA techniques, respectively. The changes in VEGF identified will be compared between groups of agents (platinum or microtubule disruptors) alone or in combination, and correlated with clinical, NfL and NCS data, depending on the degree of neuropathy and the presence of neuropathic pain. RESULTS One-hundred patients are included, mostly women (60%). At baseline, mean VEGF plasma levels were for males (215,70 +/- 204,06 pg/mL) and females (204,60 +/- 224,97 pg/mL), with no differences according to type of chemotherapy agent received (p=0.148). No correlation between VEGF and NfL at baseline was identified (p=0.9). One-third of the whole patients developed clinically relevant (&amp;gt; grade 2) CIPN) or painful CIPN. Analysis of VEGF is ongoing and will be reported as part of this abstract. CONCLUSION Mechanisms of CIPN are not fully elucidated and differences among agents must be investigated. Whether CIPN development and/or recovery is associated with a significant modulation of angiogenesis identified by changes in the levels of VEGF will be reported.
P14.11.B DISTINGUISHING RESPONDERS FROM NON-RESPONDERS IN PATIENTS WITH GLIOBLASTOMA AFTER FIRST LINE THERAPY USING GRASP DCE-MRI
Authors: B Vankan, N Rommers, M N Psychogios, R A Todea
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND After completion of radiochemotherapy distinguishing responders from non-responders in glioblastoma patients with conventional sequences is still challenging. The purpose of this study is to investigate whether Golden Angle Radial Sparse Parallel Dynamic Contrast-Enhanced (GRASP DCE) MRI can aid in making this differentiation. METHODS In total, 66 patients with glioblastoma, diagnosed between 01/2017-12/2021 who had undergone first line therapy and developed new or enlarging contrast-enhancing lesions suspicious of tumor progression and had GRASP DCE-MRI, were analyzed. Using MRI follow-up, PET CT, histology as gold standard the scans were classified into two groups: responders and non-responders to first line therapy. The scans were then analyzed based on the time window after the completion of radiochemotherapy during which they had been completed (1-2, 3-4, 5-6, &amp;gt;6 months) and then all together independent of the time window. To evaluate the accuracy of the DCE-MRI kinetics parameters in differentiating responders from non-responders, a descriptive analysis and a diagnostic accuracy analysis were performed using the area under the receiver operating characteristic curve. RESULTS In total, 138 GRASP DCE-MRI scans were analyzed. The peak enhancement (PE%) and the initial area under the curve for 30 seconds (IAUC 30) 60 seconds (IAUC 60), were consistently lower in the responders (n=63) than in the non-responders (n=75). Considering the scans independent of their time window, the PE% for responders vs non-responders was 29% IQR [26, 35] vs. 53% IQR [45, 69] respectively. The best threshold to differentiate the responders from non-responders was 41% (Sensitivity 89% (95% CI [83, 96]), Specificity 87% (95% CI [78, 95]), AUC 0.94 (95% CI [0.89, 0.98])). The IAUC 30 for responders vs. non-responders was 949 IQR [756, 1196] vs. 1627 IQR [1358, 2058] respectively. The best threshold to differentiate the responders from non-responders was 1079 (Sensitivity 93% (95% CI [87, 99]), Specificity 68% (95% CI [57, 79]), AUC 0.90 (95% CI [0.85, 0.94])). The IAUC 60 for responders vs. non-responders was 1847 IQR [1439, 2386] vs. 3337 IQR [2670, 3965] respectively. The best threshold to differentiate the responders from non-responders was 2614 (Sensitivity 79% (95% CI [69, 88]), Specificity 83% (95% CI [75, 92]), AUC 0.89 (95% CI [0.84, 0.94])). CONCLUSION The peak enhancement and the initial area under the curve (30 seconds), extracted from GRASP DCE MRI, considering all scans independent of their time window, had the best diagnostic accuracy to differentiate responders from non-responders in glioblastoma patients with a threshold of 41% vs 1079 respectively.
P08.03.A CSF-BASED PROTEOMIC BIOMARKERS OF RESPONSE TO MULTI-AGENT INTRAVENTRICULAR CHEMOTHERAPY IN CNS LYMPHOMA
Authors: A Mansouri, A Aastha, H Wilding, N Mikoljewicz, L de Macedo Filho, M Glantz, T Kislinger
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite promising responses to initial therapy for central nervous system lymphoma (CNSL), relapse is common and overall responses are disappointing compared to other non-CNS diffuse large B-cell lymphomas. Literature reports 1- and 3-year survival rates of 50% and 30-40% respectively, with standard treatment. Incorporation of multi-agent intrathecal chemotherapy (MAITC) alongside systemic therapy is novel but not widely adopted. Biomarkers predictive of response could help select patients most likely to benefit. Our retrospective analysis of CNSL patients treated with MAITC between 2015-2021 indicates a significant overall survival advantage. Cerebrospinal fluid (CSF) is a less invasive alternative for diagnosis and management of CNSL compared to traditional biopsies, while also reducing sampling bias. The objective of this study is to identify CSF-based proteomic biomarkers that can serve as reliable indicators of MAITC treatment response and guide CNSL management. MATERIAL AND METHODS Patient-matched CSF samples were banked at pre- and post-therapeutic endpoint in 22 primary and 36 secondary CNSL patients. The samples were profiled using high-throughput fluid sample protocol coupled with mass-spectrometry that only requires 30 microliters of CSF. Clinically, patients were categorized as “early responders” (objective imaging response and cytology clearance by cycle 6, both maintained until cycle 12) vs. “non responders”. Tumor burden (based on MRI and cytology) was correlated with proteomic markers to identify potential correlative markers. RESULTS SGCE, LCP1 and AGRN were found to reliably (AUROC 0.95, 95% CI 0.81-0.98, Sensitivity: 0.62, Specificity: 0.76) stratify patients based on MAITC response (responder vs. non-responder). Through analysis of matched pre- and post-treatment samples (&amp;gt;3 cycles) from the same patient cohort and correlation with brain MRI and CSF cytology, we identified H3F3A, YWHAE, LCP1, CA1 and GAPDH as candidate tumor burden biomarkers (AUROC 0.9, 95% CI 0.79-1.0). Conclusion: Our low input proteomic analyses of CSF has identified candidates potentially predictive of response to MAITC along with potential tumor burden markers. Validation studies with a larger cohort and additional timepoints are currently underway.
P01.03.A DECIPHERING THE TUMOUR ECOSYSTEM IN GLIOMAS USING SPATIAL TRANSCRIPTOMICS
Authors: Z Seferbekova, D Calafato, G Rukhovich, A Patel, M Ritter, F Ippen, A Suwala, F Sahm, M Gerstung
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumours are complex ecosystems comprised of tumour cells and various normal cell types. The interactions among these cells with diverse molecular characteristics lead to intratumoral heterogeneity and cancer evolution. However, little is known about the spatial organisation of the glioma tumour ecosystem, the cellular interactions therein, and their influence on patient outcomes. Spatially resolved transcriptomics, which measures the activity of hundreds of genes in situ, offers new avenues to address these long-standing questions. MATERIAL AND METHODS We assembled a clinically annotated cohort of glioma patients spanning 278 specimens from low- and high-grade IDH-mutant astrocytoma, IDH-mutant and 1p/19q co-deleted oligodendroglioma, ependymoma, and glioblastoma. Using tissue microarrays from archival FFPE, we performed spatial transcriptomics profiling with the 10x Xenium platform. A custom panel of 344 genes, selected based on publicly available single-cell RNA sequencing datasets of gliomas, was interrogated. RESULTS The spatial transcriptomics data enabled annotation and spatial mapping of more than 20 tumour microenvironment (TME) cell types and various tumour cell types present across the 5 glioma entities. We observed broadly conserved transcriptional profiles of TME cell types across gliomas, but TME cell type composition and spatial organisation varied depending on tumour entity. In particular, lower amounts of macrophages and microglia as well as oligodendrocytes and oligodendrocyte progenitor cells were observed in oligodendroglioma tumours compared to other entities. High-grade astrocytoma samples contained more myeloid dendritic cells and monocytes in comparison to low-grade astrocytomas. A lower proportion of vascular cells correlated with better overall survival for glioblastomas and low- and high-grade astrocytomas. Tumour cells exhibited mostly entity-specific gene expression, but also distinct tumour cell states including AC-, OPC-, NPC-, and MES-like cell states. CONCLUSION Our work demonstrates the utility of the 10x Xenium platform for high-resolution spatial profiling of expression in archival FFPE samples. Preliminary mapping of the TME and tumour cell types unravelled a complex spatial architecture of the glioma ecosystems. Distinct compositions of the TME were found in each glioma subtype, which may help understand different mechanisms of malignancy. Associations between cellular spatial patterns and clinical data available for FFPE samples have the potential to provide better insights for improved patient stratification and treatment.
P02.19.B NEW MURINE MODEL OF GLIOBLASTOMA SHOWS SUPPRESSIVE IMMUNE INFILTRATION
Authors: D R Forsythe, O K Burn, S J Small, I F Hermans, M J McConnell
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) research urgently requires a new murine model for preclinical research. The highly used cell line, GL261, reliably forms glioma-like tumours when transplanted intracranially, yet these tumours do not recapitulate human GBM, particularly when applied as a model for immune therapy. The tumour immune microenvironment (TIME) of a GL261 tumour consistently responds to immune checkpoint inhibitors, such as αPD-1 and αCTLA-4, which have shown no significance in multiple clinical trials. MATERIAL AND METHODS We have developed a novel murine model of GBM which has been designed to address the shortcomings of GL261. Into an immortalised eGFP astrocyte C57BL/6 cell line mutations were introduced to create genetic profile similar to human GBM cells. One version of these astrocytes models a classical GBM cell, with a Pten knockdown and RAS V12 stable transfection. Pten/RAS V12 and GL261 cells were separately transplanted intracranially into C57BL/6 mice and developed for either two weeks (spectral flowcytometry) or until ethical endpoint (survival and histological analysis). RESULTS Intracranial tumours reliably formed in both GL261 and Pten/RAS V12 models, with median survivals of 19.50 and 20.00 days, respectively. However, key histological differences were seen in H&amp;E sections. The GL261 tumours were highly vascularised and showed clear borders with the healthy tissue. The Pten/RAS V12 tumours had very densely packed cell mass with more invasion into the surrounding tissue. Spectral flow cytometry indicated that macrophages and monocytes contributed predominately to the tumour immune infiltration of both models. Despite similar abundance of these cells, key inflammatory markers showed significant differences. The GL261 tumours myeloid compartment was largely comprised of classical monocytes (cMo). While the populations were heterogeneous, these cMo cells were characterised by high expression of Ly6C and MHCII, both markers associated with a proinflammatory, anti-tumour responses. Conversely, Pten/RAS V12 tumours showed significantly less of Ly6C+ MHCII+ cells, indicative of an immune suppressive environment comprised of anti-inflammatory TAMs and non-classical monocytes (ncMo). Additionally, GL261 tumours contained higher numbers of dendritic cells suggesting increased antigen presentation and greater potential for anti-tumour immune responses. Higher PDL1 expression was seen on infiltrating leukocytes in GL261 tumours, consistent with literature on GL261 demonstrating response to PD1 inhibitors. However, Pten/RAS V12 tumours showed minimal expression of PDL1, consistent with poor responses in GBM patients to immune checkpoint inhibitors. CONCLUSION Together, these data indicate that this novel model will be a more appropriate tool for GBM research to help understand how to better implement immune therapy.
P08.04.B DECREASED PERIPHERAL BLOOD SEROTONIN AND KYNURENINE LEVELS ARE ASSOCIATED WITH POOR ONCOLOGICAL OUTCOMES IN GLIOBLASTOMA IDH-WT PATIENTS
Authors: P De Domenico, S Snider, S Comai, A Bertazzo, S Nasini, F Roncelli, P Mortini, F Gagliardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The contribution of tryptophan (TRP) metabolism via the kynurenine (KP) and serotonin (SP) pathways in GBM biology has recently seen a growing interest. This study aims to address the association between pre-operative peripheral blood levels of TRP, kynurenine (KYN), 5-hydroxy-tryptophan (5-HTP), and serotonin (5-HT) and relevant oncological outcomes in GBM IDH-wt patients. MATERIAL AND METHODS A total of 62 adult patients undergoing maximal safe resection of newly diagnosed glioblastoma WHO grade 4 IDH-wt (GBM) were included. The variables were dichotomized and analyzed to explore their single contributions in building a predictive model of overall survival (OS) and progression-free survival (PFS) in GBM patients. RESULTS The mean baseline serum levels of 5-HT, KYN, 5-HTP, and 5-HT/TRP were significantly lower (-76%, -87%, -76%, -75%, p&amp;lt;0.001 respectively) in GBM patients when compared to n=27 healthy individuals. The median OS in the whole cohort of GBM patients was 16.3 months (95% CI:13.4-21.7). Patients with 5-HT &amp;lt; 78 ng/mL had a median OS of 14.4 months (95% CI: 11.4-17.6) compared to 22.5 (95% CI:17.7-27) in patients with 5-HT &amp;gt; 78 ng/mL (p = 0.01). Shorter OS was recorded in patients with KYN &amp;lt; 18 ng/mL (9.8, 95% CI:11.4-17.6 vs 17.5 months, 95% CI:14.4-22.5, p=0.002), KYN/TRP &amp;lt; 2.55 (13.4, 95% CI:11.4-15.6 vs 19.1 months, 95% CI:14.0-28.6, p=0.002), 5-HTP/TRP &amp;lt; 0.89 (11.5, 95% CI:10.9-20.6 vs 17.6 months 95% CI:14.4-32.4, p=0.02), and 5-HT/TRP &amp;lt; 5.78 (13.4, 95% CI: 11.4-15.6 vs 19.1 months, 95% CI: 14.0-28.6, p=0.002)The median PFS was 9.27 months (95% CI:7.77-13.9). Significantly shorter PFS was observed in patients with 5-HT &amp;lt; 78 ng/mL (p=0.04), KYN &amp;lt; 18 ng/mL (p=0.02), 5-HT/TRP &amp;lt; 5.78 (p=0.001), KYN/TRP &amp;lt; 2.55 (p=0.005). Multivariate Cox analysis (R2=67%) confirmed an independent predictive role for poor OS of decreased KYN (p=0.001), 5-HTP (p&amp;lt;0.001) and 5-HT (p&amp;lt;0.001). Similarly, decreased 5-HT (p=0.004), and decreased 5-HTP (p=0.01) were predictive of poorer PFS. CONCLUSION This study highlights an intriguing association between enhanced degradation of TRP into KYN at the expense of the amount of the amino acid for the SP and median survival times in GBM. Decreased levels of KYN, 5-HTP, and 5-HT were associated with shorter OS.
OS06.9.A A PHASE 0/1 ‘TRIGGER’ TRIAL OF BDTX-1535 IN RECURRENT HIGH-GRADE GLIOMA (HGG) PATIENTS WITH EGFR ALTERATIONS OR FUSIONS
Authors: N Sanai, Y Umemura, V Karapetyan, T Margaryan, D Huttenlocher, J Harmon, A Hong, W Yoo, A Tien, A Tovmasyan, S 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’, 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 glioblastoma (GBM) patients were enrolled (Arm A, n=11; Arm B, n=0) and two were excluded from PK/PD analysis due to pseudoprogression. The mean unbound concentrations of BDTX-1535 in Gd 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. Median progression-free and overall survival have not yet been reached. CONCLUSIONS BDTX-1535 is well-tolerated in recurrent GBM patients, achieves pharmacologically relevant concentrations in Gd non-enhancing tumor tissue and is associated with suppression of EGFR signaling. Clinical efficacy data accompanying this PK/PD response is maturing.