bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–01–12
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. A Bi-Specific T Cell-Engaging Antibody Shows Potent Activity, Specificity, and Tumor Microenvironment Remodeling in Experimental Syngeneic and Genetically Engineered Models of GBM.
  2. Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity.
  3. KL-50: A Novel Therapeutic Agent Targeting MGMT-Deficient Glioblastoma.
  4. Switching Drivers: Epigenetic Rewiring to Genetic Progression in Glioma.
  5. Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma.
  6. Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.
  7. Genome-wide CRISPR-Cas 9 screens identify BCL family members as modulators of response to regorafenib in experimental glioma.
  8. A field resource for the glioma cerebrospinal fluid proteome: impacts of resection and location on biomarker discovery.
  9. Inhibition of the extracellular matrix protein fibulin-3 reduces immunosuppressive signaling in tumor stem cells and increases macrophage activation against glioblastoma.
  10. Mapping the developmental trajectory of human astrocytes reveals divergence in glioblastoma.
  11. Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial.
  12. A Hitchhiker's Guide Toward CSF Biomarkers for Neuro-Oncology.
  13. Heating Up IDH-Mutant Gliomas.
  1. bioRxiv. 2024 Dec 21. pii: 2024.12.18.628714. [Epub ahead of print]
    A Bi-Specific T Cell-Engaging Antibody Shows Potent Activity, Specificity, and Tumor Microenvironment Remodeling in Experimental Syngeneic and Genetically Engineered Models of GBM.
    Markella Zannikou, Joseph T Duffy, Daniele Procissi, Rebecca N Levine, Dolores Hambardzumyan, Catalina Lee-Chang, Lara Leoni, Bin Zhang, Jason M Miska, Irina V Balyasnikova.
       Background: Bispecific T cell-engagers (BTEs) are engineered antibodies that redirect T cells to target antigen-expressing tumors. BTEs targeting various tumor-specific antigens, like interleukin 13 receptor alpha 2 (IL13RA2) and EGFRvIII, have been developed for glioblastoma (GBM). However, limited knowledge of BTE actions derived from studies conducted in immunocompromised animal models impedes progress in the field. To close this gap, we investigated how BTE functions, engaging hosts' immune systems in the context of the immunosuppressive tumor microenvironment (TME) of the orthotopic and genetically engineered pre-clinical models of GBM.
    Methods: We developed a BTE protein that bridges CD3 epsilon on murine T cells to IL13RA2-positive GBM cells. We then investigated the BTE therapeutic mechanism to promote anti-glioma activity in immunocompetent mouse models of GBM. To do so, we paired survival studies with multi-color flow cytometry, multiparametric magnetic resonance imaging (MRI), and single-cell RNA sequencing (RNA-Seq) in several orthotopic and genetically engineered mouse (GEM) models of GBM.
    Results: BTE-mediated interaction of murine T cells and GBM cells potently activated T cells, resulting in antigen-dependent killing of GBM cells. BTE treatment significantly extended the survival of mice bearing IL13RA2-expressing orthotopic glioma and de novo formed GBM in the GEM model. The quantification parametric MR imaging validated the survival data, showing a reduction in tumor volume and decreased tumor viability. Flow cytometric and scRNA-seq analyses of the tumor microenvironment (TME) revealed robust increases in activated and memory T cells and decreases in immunosuppressive myeloid cells in the brains of mice following BTE treatment.
    Conclusions: Our data demonstrate that BTE's survival benefits in GBM are due to its ability to engage the host immune system in direct killing, boost immunological memory, and modulate the TME. These findings provide a deeper insight into the mechanism of BTE actions in GBM.
    DOI:  https://doi.org/10.1101/2024.12.18.628714
  2. Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2403862122
    Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity.
    Noa Furth, Niv Cohen, Avishay Spitzer, Tomer-Meir Salame, Bareket Dassa, Tevie Mehlman, Alexander Brandis, Arieh Moussaieff, Dinorah Friedmann-Morvinski, Maria G Castro, Jerome Fortin, Mario L Suvà, Itay Tirosh, Ayelet Erez, Guy Ron, Efrat Shema.
      Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2mut) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDHmut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single-cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2-HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.
    Keywords:  CyTOF; chromatin; epigenetics; mutant-IDH1; oncometabolite
    DOI:  https://doi.org/10.1073/pnas.2403862122
  3. Neuro Oncol. 2025 Jan 08. pii: noaf001. [Epub ahead of print]
    KL-50: A Novel Therapeutic Agent Targeting MGMT-Deficient Glioblastoma.
    Kenan Zhang, Mehdi Touat, Mustafa Khasraw.
      
    Keywords:   MGMT-deficient glioblastoma; KL-50; mismatch repair deficiency; temozolomide resistance
    DOI:  https://doi.org/10.1093/neuonc/noaf001
  4. Cancer Res. 2024 Dec 30.
    Switching Drivers: Epigenetic Rewiring to Genetic Progression in Glioma.
    Kristen L Drucker, Robert B Jenkins, Daniel Schramek.
      IDH-mutant low-grade gliomas (LGGs) are slow-growing brain tumors that frequently progress to aggressive high-grade gliomas that have dismal outcomes. In a recent study, Wu and colleagues provide critical insights into the mechanisms underlying malignant progression by analyzing single-cell gene expression and chromatin accessibility across different tumor grades. Their findings support a two-phase model: in early stages, tumors are primarily driven by oligodendrocyte precursor-like cells and epigenetic alterations that silence tumor suppressors like CDKN2A and activate oncogenes such as PDGFRA. As the disease advances, the tumors become sustained by more proliferative neural precursor-like cells, where genetic alterations, including PDGFRA, MYCN, and CDK4 amplifications and CDKN2A/B deletion, drive tumor progression. The study further highlights a dynamic regulation of interferon (IFN) signaling during progression. In low-grade IDH-mutant gliomas, IFN responses are suppressed through epigenetic hypermethylation, which can be reversed with DNMT1 inhibitors or IDH inhibitors, leading to reactivation of the IFN pathway. In contrast, higher-grade gliomas evade IFN signaling through genetic deletions of IFN gene clusters. These findings emphasize a broader epigenetic-to-genetic shift in oncogenic regulation that drives glioma progression, provides a valuable framework for understanding the transition from indolent tumors to lethal malignancies, and has implications for therapy and clinical management.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4907
  5. Nat Commun. 2025 Jan 07. 16(1): 471
    Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma.
    Soniya Bastola, Marat S Pavlyukov, Neel Sharma, Yasmin Ghochani, Mayu A Nakano, Sree Deepthi Muthukrishnan, Sang Yul Yu, Min Soo Kim, Alireza Sohrabi, Natalia P Biscola, Daisuke Yamashita, Ksenia S Anufrieva, Tatyana F Kovalenko, Grace Jung, Tomas Ganz, Beatrice O'Brien, Riki Kawaguchi, Yue Qin, Stephanie K Seidlits, Alma L Burlingame, Juan A Oses-Prieto, Leif A Havton, Steven A Goldman, Anita B Hjelmeland, Ichiro Nakano, Harley I Kornblum.
      Extensive neovascularization is a hallmark of glioblastoma (GBM). In addition to supplying oxygen and nutrients, vascular endothelial cells provide trophic support to GBM cells via paracrine signaling. Here we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing stable phenotypic changes in GBM cells. Furthermore, Endocan confers radioprotection on GBM cells in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue GBM recurrence and highlight the importance of vascular-tumor interactions for GBM development.
    DOI:  https://doi.org/10.1038/s41467-024-55487-1
  6. Front Immunol. 2024 ;15 1431112
    Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.
    Nora Essakhi, Alexandre Bertucci, Nathalie Baeza-Kallee, Carole Colin, Rosario Lavignolle-Heguy, Paulina Garcia-Gonzalez, Rafael J Argüello, Aurélie Tchoghandjian, Emeline Tabouret.
      In recent decades, immunometabolism in cancers has emerged as an interesting target for treatment development. Indeed, the tumor microenvironment (TME) unique characteristics such as hypoxia and limitation of nutrients availability lead to a switch in metabolic pathways in both tumor and TME cells in order to support their adaptation and grow. Glioblastoma (GBM), the most frequent and aggressive primary brain tumor in adults, has been extensively studied in multiple aspects regarding its immune population, but research focused on immunometabolism remains limited. Here, we provide an overview of immunometabolism adaptation of myeloid cells in cancers with a specific focus on GBM and other brain tumors, before describing current therapeutic strategies targeting metabolic pathways. The main myeloid cells composing the GBM TME include tumor-associated macrophages (TAMs), which comprise both peripheral macrophages and local microglia, as well as myeloid-derived suppressor cells. The metabolic pathways involved in myeloid cell remodeling encompass the tricarboxylic acid cycle (TCA cycle), the lipid, glucose and amino acid metabolism and hypoxia. Developing treatments that target these metabolic pathways in tumor growth and its TME is a promising and increasing field. It includes both drug-repurposing and the development of innovative metabolic therapies. We finally provide an overview of all clinical trials in neuro-oncology involving treatments modifying cell metabolism and provide the preclinical rationale for both drugs already evaluated within clinical trials and potential candidates for future trials.
    Keywords:  TCA cycle; glioblastoma; glycolysis; lipid metabolism; metabolism; myeloid cells
    DOI:  https://doi.org/10.3389/fimmu.2024.1431112
  7. Neuro Oncol. 2025 Jan 04. pii: noae278. [Epub ahead of print]
    Genome-wide CRISPR-Cas 9 screens identify BCL family members as modulators of response to regorafenib in experimental glioma.
    Lara Annina Haeusser, Hannes Becker, Laurence Kuhlburger, Marcello Zago, Bianca Walter, Foteini Tsiami, Sarah Erdmann, Jil Trampert, Surender Surender, Aaron Stahl, Markus Templin, Eileen Wegner, Tobias Schmidt, Christian Schmees, Nicolas Casadei, Lisa Sevenich, Manfred Claassen, Sven Nahnsen, Susanne Beck, Daniel Josef Merk, Ghazaleh Tabatabai.
       BACKGROUND: Registered systemic treatment options for glioblastoma patients are limited. The phase II REGOMA trial suggested an improvement of median overall survival in progressive glioblastoma by the multi-tyrosine kinase inhibitor regorafenib. This has not been confirmed by GBM AGILE. So far, regorafenib has been administered as monotherapy or as an addition to standard of care in newly diagnosed glioblastoma. Rational combination therapies involving regorafenib might be a reasonable strategy. Here, we aimed at identifying functionally-instructed combination therapies involving regorafenib.
    METHODS: We applied a genome-wide CRISPR-Cas9-based functional genomics target discovery approach using activation and knockout screens followed by genetic, pharmacological, functional validations. Regorafenib-induced molecular alterations were assessed by RNAsequencing and DigiWest. We investigated selected functionally-instructed combination therapies in three orthotopic glioma mouse models in vivo (syngeneic SMA560/VM/Dk model and two xenograft models) and performed immunohistochemistry of post-treatment brains.
    RESULTS: We identified potential modifiers of regorafenib response including BCL2, BCL2L1, ITGB3, FOXC1, SERAC1, ARAF, and PLCE1. The combination of regorafenib with Bcl-2/Bcl-xL inhibition was superior to both monotherapies alone in vitro, ex vivo and in vivo. We identified regorafenib-induced regulations of the Bcl-2 downstream target chemokine receptor 1 (CCR1) as one potential underlying molecular mediator. Furthermore, regorafenib led to changes in the myeloid compartment of the glioma-associated microenvironment.
    CONCLUSION: This preclinical study uses a functional genomics-based target discovery approach with subsequent validations involving regorafenib. It serves as a biological rationale for clinical translation. Particularly, an investigation of the combination of regorafenib plus navitoclax within a clinical trial is warranted.
    Keywords:  Bcl-2; Bcl-xL; Functional genomics; experimental glioma; synergy
    DOI:  https://doi.org/10.1093/neuonc/noae278
  8. Neuro Oncol. 2024 Dec 30. pii: noae277. [Epub ahead of print]
    A field resource for the glioma cerebrospinal fluid proteome: impacts of resection and location on biomarker discovery.
    Cecile Riviere-Cazaux, Christopher J Graser, Arthur E Warrington, Matthew D Hoplin, Katherine M Andersen, Noor Malik, Elizabeth A Palmer, Lucas P Carlstrom, Surendra Dasari, Amanda Munoz-Casabella, Samar Ikram, Keyvan Ghadimi, Benjamin T Himes, Ignacio Jusue-Torres, Jann N Sarkaria, Fredric B Meyer, Jamie J Van Gompel, Sani H Kizilbash, Ugur Sener, Franziska Michor, Jian L Campian, Ian F Parney, Terry C Burns.
       BACKGROUND: While serial sampling of glioma tissue is rarely performed prior to recurrence, cerebrospinal fluid (CSF) is an underutilized longitudinal source of candidate glioma biomarkers for understanding therapeutic impacts. However, the impact of key variables to consider in longitudinal CSF samples for monitoring biomarker discovery, including anatomical location and post-surgical changes, remains unknown.
    METHODS: Aptamer-based proteomics was performed on 147 CSF samples from 74 patients, 71 of whom had grade 2-4 astrocytomas or grade 2-3 oligodendrogliomas. This included pre- versus post-resection intracranial CSF samples obtained at early (1-16 days; n=20 patients) or delayed (86-153 days; n=11 patients) timepoints for patients with glioma. Paired lumbar-versus-intracranial glioma CSF samples were also obtained (n=14 patients).
    RESULTS: Significant differences were identified in the CSF proteome between lumbar, subarachnoid, and ventricular CSF from patients with gliomas. Importantly, we found that resection had a significant, evolving longitudinal impact on the CSF proteome, with distinct sets of proteins present at different timepoints since resection. Our analysis of serial intracranial CSF samples suggests the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies, such as bevacizumab and immunotherapies.
    CONCLUSIONS: The intracranial glioma CSF proteome serves as a rich and dynamic reservoir of potential biomarkers that can be used to evaluate the effects of resection and other therapies over time. All data within this study, including detailed individual clinical annotations, are shared as a resource for the neuro-oncology community to collectively address these unanswered questions and further understand glioma biology through CSF proteomics.
    Keywords:  biomarker; cerebrospinal fluid; glioma; monitoring; proteomics
    DOI:  https://doi.org/10.1093/neuonc/noae277
  9. bioRxiv. 2024 Dec 29. pii: 2024.12.28.628031. [Epub ahead of print]
    Inhibition of the extracellular matrix protein fibulin-3 reduces immunosuppressive signaling in tumor stem cells and increases macrophage activation against glioblastoma.
    Somanath Kundu, Soham Mitra, Arivazhagan Roshini, John A Longo, Sharon L Longo, Abigail Venskus, Harish Babu, Mariano S Viapiano.
      Glioblastoma tumors remain a formidable challenge for immune-based treatments because of their molecular heterogeneity, poor immunogenicity, and growth in the largely isolated and immunosuppressive neural environment. As the tumor grows, GBM cells change the composition and architecture of the neural extracellular matrix (ECM), affecting the mobility, survival, and function of immune cells such as tumor-associated microglia and infiltrated macrophages (TAMs). We have previously described the unique expression of the ECM protein EFEMP1/fibulin-3 in GBM compared to normal brain and demonstrated that this secreted protein promotes the growth of the GBM stem cell (GSC) population. Here, we describe a novel immunomodulatory role of fibulin-3 and the immuno-boosting effects of targeting this ECM protein. Mice carrying fibulin-3-deficient intracranial tumors showed increased myeloid infiltration and reduced expression of TAM pro-tumoral markers (Arginase, CD206) compared to controls. The opposite was observed in orthotopic tumors overexpressing fibulin-3. In silico dataset analysis of clinical datasets revealed positive correlation of fibulin-3 with an immunosuppressive signature, which was validated in GSCs and in vivo . We further demonstrated that fibulin-3 regulates the expression of immunosuppressive signals (CSF-1, TGFβ) and the innate immune checkpoint CD47 in GSCs via autocrine activation of NF-κB signaling. Accordingly, immunosuppressive signals were downregulated in GSCs by knockdown of fibulin-3 or inhibition of this protein with an anti-fibulin-3 antibody. Co-culture of GBM cells with syngeneic macrophage lines or primary macrophages in presence of anti-fibulin-3 antibody increased macrophage phagocytosis and antibody-dependent killing of the tumor cells, Furthermore, locoregional delivery of anti-fibulin-3 antibody in mice carrying intracranial GBM increased the infiltration of TAMs expressing pro-inflammatory markers, reducing tumor viability. Our findings show that anti-fibulin-3 approaches, which impact the pericellular ECM surrounding tumor cells and TAMs, can diminish immunosuppression in GBM and boost innate immune responses against the tumor.
    DOI:  https://doi.org/10.1101/2024.12.28.628031
  10. Nat Cell Biol. 2025 Jan 08.
    Mapping the developmental trajectory of human astrocytes reveals divergence in glioblastoma.
    Caitlin Sojka, Hsiao-Lin V Wang, Tarun N Bhatia, Yangping Li, Pankaj Chopra, Anson Sing, Anna Voss, Alexia King, Feng Wang, Kevin Joseph, Vidhya M Ravi, Jeffrey Olson, Kimberly Hoang, Edjah Nduom, Victor G Corces, Bing Yao, Steven A Sloan.
      Glioblastoma (GBM) is defined by heterogeneous and resilient cell populations that closely reflect neurodevelopmental cell types. Although it is clear that GBM echoes early and immature cell states, identifying the specific developmental programmes disrupted in these tumours has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly 2 years. Through this approach, we chronicled a multiphase developmental process. Our time course of human astrocyte maturation includes a molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wild-type neoplastic astrocyte-lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumour astrocyte-lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D-2-hydroxyglutarate oncometabolite exposure. We propose that this defiance is a consequence of IDH1-mutant-associated epigenetic dysregulation, and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a distinct cellular state aberration in GBM astrocyte-lineage cells and presents developmental targets for experimental and therapeutic exploration.
    DOI:  https://doi.org/10.1038/s41556-024-01583-9
  11. Nat Med. 2025 Jan 07.
    Intracerebroventricular B7-H3-targeting CAR T cells for diffuse intrinsic pontine glioma: a phase 1 trial.
    Nicholas A Vitanza, Rebecca Ronsley, Michelle Choe, Kristy Seidel, Wenjun Huang, Stephanie D Rawlings-Rhea, Madison Beam, Leonel Steinmetzer, Ashley L Wilson, Christopher Brown, Adam Beebe, Catherine Lindgren, Joshua A Gustafson, Amy Wein, Susan Holtzclaw, Corrine Hoeppner, Hannah E Goldstein, Samuel R Browd, Jason S Hauptman, Amy Lee, Jeffrey G Ojemann, Erin E Crotty, Sarah E S Leary, Francisco A Perez, Jason N Wright, Marta M Alonso, Matthew D Dun, Jessica B Foster, Diana Hurst, Ada Kong, Alison Thomsen, Rimas J Orentas, Catherine M Albert, Navin Pinto, Colleen Annesley, Rebecca A Gardner, On Ho, Sowmya Pattabhi, Juliane Gust, Jason P Wendler, Julie R Park, Michael C Jensen.
      Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG. The primary objectives were to assess feasibility and tolerability, which were both met. Secondary objectives included assessments of CAR T cell distribution and survival. A total of 23 patients with DIPG enrolled, and 21 were treated with repeated doses of ICV B7-H3 CAR T cells using intra-patient dose-escalation regimens without previous lymphodepletion. Concurrent tumor-directed therapy, including re-irradiation, was not allowed while on protocol therapy. We delivered a total of 253 ICV doses and established the highest planned dose regimen, DR4, which escalated up to 10 × 107 cells per dose, as the maximally tolerated dose regimen. Common adverse events included headache, fatigue and fever. There was one dose-limiting toxicity (intratumoral hemorrhage) during DR2. For all treated patients (n = 21), the median survival from their initial CAR T cell infusion was 10.7 months and the median survival from diagnosis was 19.8 months with 3 patients still alive at 44, 45 and 52 months from diagnosis. Ultimately, this completed first-in-human trial shows that repetitive ICV dosing of B7-H3 CAR T cells in pediatric and young adult patients with DIPG is tolerable, including multiyear repeated dosing, and may have clinical efficacy that warrants further investigation on a multisite phase 2 trial. ClinicalTrials.gov registration: NCT04185038 .
    DOI:  https://doi.org/10.1038/s41591-024-03451-3
  12. Neuro Oncol. 2024 Dec 30. pii: noae276. [Epub ahead of print]
    A Hitchhiker's Guide Toward CSF Biomarkers for Neuro-Oncology.
    Cecile Riviere-Cazaux, Michael B Keough, Jeffrey A Zuccato, Rahul Kumar, Sebastian Schulz, Arthur E Warrington, Michael W Ruff, Benjamin M Ellingson, Nader Sanai, Jian L Campian, Sani H Kizilbash, Ian F Parney, Gelareh Zadeh, Mustafa Khasraw, Tobias Kessler, Ugur Sener, Daniel P Cahill, Alireza Mansouri, Terry C Burns.
      Cerebrospinal fluid (CSF) has emerged as a valuable liquid biopsy source for glioma biomarker discovery and validation. CSF produced within the ventricles circulates through the subarachnoid space, where the composition of glioma-derived analytes is influenced by the proximity and anatomical location of sampling relative to tumor, in addition to underlying tumor biology. The substantial gradients observed between lumbar and intracranial CSF compartments for tumor-derived analytes underscore the importance of sampling site selection. Moreover, radiographic features, such as tumor-CSF contact and blood-brain barrier (BBB) disruption, are critical covariates that may affect biomarker detectability and the abundance of plasma-derived analytes in CSF, respectively. Longitudinal intracranial CSF sampling, enabled by access devices like Ommaya reservoirs, may offer a window into treatment response and disease progression, though variability in analyte yield, sample volumes, and the dynamic effects of surgical resection pose challenges. This review critically evaluates the anatomic, radiographic, and longitudinal factors that impact glioma CSF biomarker abundance. Practical considerations for longitudinal CSF biobanking, including access device placement and collection, are also reviewed. Key takeaways and recommendations for CSF glioma biomarker discovery and validation are provided based on our collective experience, along with resources for investigators aiming to develop CSF biobanking at their institutions.
    Keywords:  biomarker; cerebrospinal fluid; glioma; monitoring; neuro-oncology
    DOI:  https://doi.org/10.1093/neuonc/noae276
  13. N Engl J Med. 2024 Dec 05. 391(22): 2170-2172
    Heating Up IDH-Mutant Gliomas.
    Michael Platten, Lukas Bunse.
      
    DOI:  https://doi.org/10.1056/NEJMcibr2410562
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