bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023‒03‒19
thirteen papers selected by
Oltea Sampetrean
Keio University
  1. Nucleolin promotes angiogenesis and endothelial metabolism along the onco-fetal axis in the human brain vasculature.
  2. Anti-PD-1 and extended half-life-IL-2 synergize for treatment of murine glioblastoma independent of host MHC Class I expression.
  3. Single-cell heterogeneity of EGFR and CDK4 co-amplification is linked to immune infiltration in glioblastoma.
  4. Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis.
  5. Generation of 3D ex vivo mouse- and patient-derived glioma explant slice model for integration of confocal time-lapse imaging and spatial analysis.
  6. Metformin and simvastatin exert additive antitumour effects in glioblastoma via senescence-state: clinical and translational evidence.
  7. Primitive Oligodendrocyte Precursor Cells Are Highly Susceptible to Gliomagenic Transformation.
  8. Gut microbiota mediated the individualized efficacy of Temozolomide via immunomodulation in glioma.
  9. From Cells to Organoids: The Evolution of Blood-Brain Barrier Technology for Modelling Drug Delivery in Brain Cancer.
  10. Integrated response analysis of pediatric low-grade gliomas during and after targeted therapy treatment.
  11. Visualizing genomic characteristics across an RNA-Seq based reference landscape of normal and neoplastic brain.
  12. Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology.
  13. Clinical outcome of biomarker-guided therapies in adult patients with tumors of the nervous system.
  1. JCI Insight. 2023 Mar 14. pii: e143071. [Epub ahead of print]
    Nucleolin promotes angiogenesis and endothelial metabolism along the onco-fetal axis in the human brain vasculature.
    Marc Schwab, Ignazio de Trizio, Moheb Ghobrial, Jau-Ye Shiu, Oguzkan Sürücü, Francesco Girolamo, Mariella Errede, Murat Yilmaz, Johannes Haybaeck, Alessandro Moiraghi, Philippe P Monnier, Sean E Lawler, Jeffrey P Greenfield, Ivan Radovanovic, Karl Frei, Ralph Schlapbach, Viola Vogel, Daniela Virgintino, Katrien De Bock, Thomas Wälchli.
      Glioblastoma is amongst the deadliest human cancers and is highly vascularized. Angiogenesis is very dynamic during brain development, almost quiescent in the adult brain but reactivated in vascular-dependent CNS pathologies including brain tumors. The onco-fetal axis describes the reactivation of fetal programs in tumors, but its relevance in endothelial- and perivascular cells of the human brain vasculature in glial brain tumors is unexplored. Nucleolin is a regulator of cell proliferation and angiogenesis, but its roles in the brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit in human fetal brains, adult brains and human gliomas in vivo and its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial- and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression correlated with glioma malignancy in vivo. In culture, siRNA-mediated Nucleolin knock-down reduced human brain endothelial cell (HCMEC) and human umbilical vein endothelial cell (HUVEC) sprouting angiogenesis, proliferation, filopodia extension, and glucose metabolism. Furthermore, inhibition of Nucleolin with the aptamer AS1411 decreased brain endothelial cell proliferation in vitro. Mechanistically, Nucleolin knock-down in HCMECs and HUVECs uncovered regulation of angiogenesis involving VEGFR2 and of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that promotes sprouting angiogenesis and endothelial metabolism, characterizing Nucleolin as an onco-fetal protein. Our findings have potential implications in the therapeutic targeting of glioma.
    Keywords:  Angiogenesis; Brain cancer; Glucose metabolism; Neurodevelopment; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.143071
  2. Cancer Immunol Res. 2023 Mar 15. pii: CIR-22-0570. [Epub ahead of print]
    Anti-PD-1 and extended half-life-IL-2 synergize for treatment of murine glioblastoma independent of host MHC Class I expression.
    Zachariah P Tritz, Katayoun Ayasoufi, Delaney M Wolf, Carley A Owens, Courtney S Malo, Benjamin T Himes, Cori E Fain, Emma N Goddery, Lila T Yokanovich, Fang Jin, Michael J Hansen, Ian F Parney, Chensu Wang, Kelly D Moynihan, Darrell J Irvine, K Dane Wittrup, Rosa M Diaz Marcano, Richard G Vile, Aaron J Johnson.
      Glioblastoma (GBM) is the most common malignant brain tumor in adults, responsible for approximately 225,000 deaths per year. Despite pre-clinical successes, most interventions have failed to extend patient survival by more than a few months. Treatment with anti-PD-1 immune checkpoint blockade (ICB) monotherapy has been beneficial for malignant tumors such as melanoma and lung cancers but has yet to be effectively employed in GBM. This study aimed to determine whether supplementing anti-PD-1 ICB with engineered extended half-life IL-2, a potent lymphoproliferative cytokine, could improve outcomes. This combination therapy, subsequently referred to as enhanced checkpoint blockade (ECB), delivered intraperitoneally, reliably cures approximately 50% of C57BL/6 mice bearing orthotopic GL261 gliomas and extends median survival of the treated cohort. In the CT2A model, characterized as being resistant to CBI, ECB caused a decrease in CT2A tumor volume in half of measured animals similar to what was observed in GL261-bearing mice, promoting a trending survival increase. ECB generates robust immunologic responses, features of which include secondary lymphoid organ enlargement and increased activation status of both CD4 and CD8 T cells. This immunity is durable, with long-term ECB survivors able to resist GL261 rechallenge. Through employment of depletion strategies, ECB's efficacy was shown to be independent of host MHC class I restricted antigen presentation but reliant on CD4 T cells. These results demonstrate ECB is efficacious against the GL261 glioma model through an MHC class I-independent mechanism and supporting further investigation into IL-2-supplemented ICB therapies for tumors of the central nervous system.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0570
  3. Cell Rep. 2023 Mar 13. pii: S2211-1247(23)00246-2. [Epub ahead of print]42(3): 112235
    Single-cell heterogeneity of EGFR and CDK4 co-amplification is linked to immune infiltration in glioblastoma.
    Kacper A Walentynowicz, Dalit Engelhardt, Simona Cristea, Shreya Yadav, Ugoma Onubogu, Roberto Salatino, Melanie Maerken, Cristina Vincentelli, Aashna Jhaveri, Jacob Geisberg, Thomas O McDonald, Franziska Michor, Michalina Janiszewska.
      Glioblastoma (GBM) is the most aggressive brain tumor, with a median survival of ∼15 months. Targeted approaches have not been successful in this tumor type due to the large extent of intratumor heterogeneity. Mosaic amplification of oncogenes suggests that multiple genetically distinct clones are present in each tumor. To uncover the relationships between genetically diverse subpopulations of GBM cells and their native tumor microenvironment, we employ highly multiplexed spatial protein profiling coupled with single-cell spatial mapping of fluorescence in situ hybridization (FISH) for EGFR, CDK4, and PDGFRA. Single-cell FISH analysis of a total of 35,843 single nuclei reveals that tumors in which amplifications of EGFR and CDK4 more frequently co-occur in the same cell exhibit higher infiltration of CD163+ immunosuppressive macrophages. Our results suggest that high-throughput assessment of genomic alterations at the single-cell level could provide a measure for predicting the immune state of GBM.
    Keywords:  CDK4; CP: Cancer; EGFR; genetic heterogeneity; glioblastoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2023.112235
  4. Nat Commun. 2023 Mar 16. 14(1): 1459
    Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis.
    Pravin Kesarwani, Shiva Kant, Yi Zhao, Antony Prabhu, Katie L Buelow, C Ryan Miller, Prakash Chinnaiyan.
      There has been considerable scientific effort dedicated to understanding the biologic consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. A majority of this work has focused on the upstream metabolism of tryptophan; however, this has resulted in limited clinical application. Using global metabolomic profiling of patient-derived brain tumors, we identify the downstream metabolism of tryptophan and accumulation of quinolinate (QA) as a metabolic node in glioblastoma and demonstrate its critical role in promoting immune tolerance. QA acts as a metabolic checkpoint in glioblastoma by inducing NMDA receptor activation and Foxo1/PPARγ signaling in macrophages, resulting in a tumor supportive phenotype. Using a genetically-engineered mouse model designed to inhibit production of QA, we identify kynureninase as a promising therapeutic target to revert the potent immune suppressive microenvironment in glioblastoma. These findings offer an opportunity to revisit the biologic consequence of this pathway as it relates to oncogenesis and neurodegenerative disease and a framework for developing immune modulatory agents to further clinical gains in these otherwise incurable diseases.
    DOI:  https://doi.org/10.1038/s41467-023-37170-z
  5. STAR Protoc. 2023 Mar 16. pii: S2666-1667(23)00132-6. [Epub ahead of print]4(2): 102174
    Generation of 3D ex vivo mouse- and patient-derived glioma explant slice model for integration of confocal time-lapse imaging and spatial analysis.
    Andrea Comba, Maria Luisa Varela, Syed M Faisal, Clifford C Abel, Anna E Argento, Wajd N Al-Holou, Todd C Hollon, Jacqueline D Perelman, Patrick J Dunn, Sebastien Motsch, Maria G Castro, Pedro R Lowenstein.
      Development of spatial-integrative pre-clinical models is needed for glioblastoma, which are heterogenous tumors with poor prognosis. Here, we present an optimized protocol to generate three-dimensional ex vivo explant slice glioma model from orthotopic tumors, genetically engineered mouse models, and fresh patient-derived specimens. We describe a step-by-step workflow for tissue acquisition, dissection, and sectioning of 300-μm tumor slices maintaining cell viability. The explant slice model allows the integration of confocal time-lapse imaging with spatial analysis for studying migration, invasion, and tumor microenvironment, making it a valuable platform for testing effective treatment modalities. For complete details on the use and execution of this protocol, please refer to Comba et al. (2022).1.
    Keywords:  Biotechnology and Bioengineering; Cancer; Cell Biology; Cell-based Assays; Health Sciences; Microscopy; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2023.102174
  6. EBioMedicine. 2023 Mar 10. pii: S2352-3964(23)00049-X. [Epub ahead of print]90 104484
    Metformin and simvastatin exert additive antitumour effects in glioblastoma via senescence-state: clinical and translational evidence.
    Antonio C Fuentes-Fayos, Miguel E G-García, Jesús M Pérez-Gómez, Antonio J Montero-Hidalgo, Julia Martín-Colom, Carlos Doval-Rosa, Cristóbal Blanco-Acevedo, Encarnación Torres, Álvaro Toledano-Delgado, Rafael Sánchez-Sánchez, Esther Peralbo-Santaella, Rosa M Ortega-Salas, Juan M Jiménez-Vacas, Manuel Tena-Sempere, Miguel López, Justo P Castaño, Manuel D Gahete, Juan Solivera, Raúl M Luque.
      BACKGROUND: Glioblastoma is one of the most devastating and incurable cancers due to its aggressive behaviour and lack of available therapies, being its overall-survival from diagnosis ∼14-months. Thus, identification of new therapeutic tools is urgently needed. Interestingly, metabolism-related drugs (e.g., metformin/statins) are emerging as efficient antitumour agents for several cancers. Herein, we evaluated the in vitro/in vivo effects of metformin and/or statins on key clinical/functional/molecular/signalling parameters in glioblastoma patients/cells.METHODS: An exploratory-observational-randomized retrospective glioblastoma patient cohort (n = 85), human glioblastoma/non-tumour brain human cells (cell lines/patient-derived cell cultures), mouse astrocytes progenitor cell cultures, and a preclinical xenograft glioblastoma mouse model were used to measure key functional parameters, signalling-pathways and/or antitumour progression in response to metformin and/or simvastatin.
    FINDINGS: Metformin and simvastatin exerted strong antitumour actions in glioblastoma cell cultures (i.e., proliferation/migration/tumoursphere/colony-formation/VEGF-secretion inhibition and apoptosis/senescence induction). Notably, their combination additively altered these functional parameters vs. individual treatments. These actions were mediated by the modulation of key oncogenic signalling-pathways (i.e., AKT/JAK-STAT/NF-κB/TGFβ-pathways). Interestingly, an enrichment analysis uncovered a TGFβ-pathway activation, together with AKT inactivation, in response to metformin + simvastatin combination, which might be linked to an induction of the senescence-state, the associated secretory-phenotype, and to the dysregulation of spliceosome components. Remarkably, the antitumour actions of metformin + simvastatin combination were also observed in vivo [i.e., association with longer overall-survival in human, and reduction in tumour-progression in a mouse model (reduced tumour-size/weight/mitosis-number, and increased apoptosis)].
    INTERPRETATION: Altogether, metformin and simvastatin reduce aggressiveness features in glioblastomas, being this effect significantly more effective (in vitro/in vivo) when both drugs are combined, offering a clinically relevant opportunity that should be tested for their use in humans.
    FUNDING: Spanish Ministry of Science, Innovation and Universities; Junta de Andalucía; CIBERobn (CIBER is an initiative of Instituto de Salud Carlos III, Spanish Ministry of Health, Social Services and Equality).
    Keywords:  Glioblastoma; Metformin; Senescence; Simvastatin; Splicing; Telomere
    DOI:  https://doi.org/10.1016/j.ebiom.2023.104484
  7. Cancer Res. 2023 Mar 15. 83(6): 807-808
    Primitive Oligodendrocyte Precursor Cells Are Highly Susceptible to Gliomagenic Transformation.
    Daniel B Zamler, Jian Hu.
      Glioblastoma is the most deadly and common primary tumor of the central nervous system. Heterogeneity in the disease causes complications from diagnosis to treatment. It has long been suggested that a stem cell and/or progenitor population may be the origin of this disease and provide the underlying heterogeneity. However, which population precisely is the cell of origin, or whether there is only one cell of origin, has remained elusive. Previous studies have shown that, with proper combinations of oncogene expression and tumor suppressor loss, three cell types have the potential to transform into glioma-neural stem cells (NSC), oligodendrocyte precursor cells (OPC), and astrocytes. In a newly published article in Cancer Research, Verma and colleagues make a convincing argument through elegant animal work that an intermediate progenitor cell population, primitive OPCs, has higher tumorigenic potential than the NSCs or OPCs. This study helps rectify the controversy around which cell populations are the most sensitive to transformation in gliomagenesis. See related article by Verma et al., p. 890.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0024
  8. J Transl Med. 2023 Mar 16. 21(1): 198
    Gut microbiota mediated the individualized efficacy of Temozolomide via immunomodulation in glioma.
    Xiaoying Hou, Hongzhi Du, Yufei Deng, Haiping Wang, Jinmi Liu, Jialu Qiao, Wei Liu, Xiji Shu, Binlian Sun, Yuchen Liu.
      BACKGROUND: Temozolomide (TMZ) is the preferred chemotherapy strategy for glioma therapy. As a second-generation alkylating agent, TMZ provides superior oral bio-availability. However, limited response rate (less than 50%) and high incidence of drug resistance seriously restricts TMZ's application, there still lack of strategies to increase the chemotherapy sensitivity.METHODS: Luci-GL261 glioma orthotopic xenograft model combined bioluminescence imaging was utilized to evaluate the anti-tumor effect of TMZ and differentiate TMZ sensitive (S)/non-sensitive (NS) individuals. Integrated microbiomics and metabolomics analysis was applied to disentangle the involvement of gut bacteria in TMZ sensitivity. Spearman's correlation analysis was applied to test the association between fecal bacteria levels and pharmacodynamics indices. Antibiotics treatment combined TMZ treatment was used to confirm the involvement of gut microbiota in TMZ response. Flow cytometry analysis, ELISA and histopathology were used to explore the potential role of immunoregulation in gut microbiota mediated TMZ response.
    RESULTS: Firstly, gut bacteria composition was significantly altered during glioma development and TMZ treatment. Meanwhile, in vivo anti-cancer evaluation suggested a remarkable difference in chemotherapy efficacy after TMZ administration. Moreover, 16s rRNA gene sequencing and non-targeted metabolomics analysis revealed distinct different gut microbiota and immune infiltrating state between TMZ sensitive and non-sensitive mice, while abundance of differential gut bacteria and related metabolites was significantly correlated with TMZ pharmacodynamics indices. Further verification suggested that gut microbiota deletion by antibiotics treatment could accelerate glioma development, attenuate TMZ efficacy and inhibit immune cells (macrophage and CD8α+ T cell) recruitment.
    CONCLUSIONS: The current study confirmed the involvement of gut microbiota in glioma development and individualized TMZ efficacy via immunomodulation, hence gut bacteria may serve as a predictive biomarker as well as a therapeutic target for clinical TMZ application.
    Keywords:  Fecal microbiome; Functional Metabolomics; Glioma; Individualized efficacy; Temozolomide
    DOI:  https://doi.org/10.1186/s12967-023-04042-5
  9. Adv Drug Deliv Rev. 2023 Mar 15. pii: S0169-409X(23)00092-3. [Epub ahead of print] 114777
    From Cells to Organoids: The Evolution of Blood-Brain Barrier Technology for Modelling Drug Delivery in Brain Cancer.
    Gonzales-Aloy E, Ahmed-Cox A, Tsoli M, Ziegler D, Kavallaris M.
      Brain cancer remains the deadliest cancer. The blood-brain barrier (BBB) is impenetrable to most drugs and is a complex 3D network of multiple cell types including endothelial cells, astrocytes, and pericytes. In brain cancers, the BBB becomes disrupted during tumor progression and forms the blood-brain tumor barrier (BBTB). To advance therapeutic development, there is a critical need for physiologically relevant BBB in vitro models. 3D cell systems are emerging as valuable preclinical models to accelerate discoveries for diseases. Given the versatility and capability of 3D cell models, their potential for modelling the BBB and BBTB is reviewed. Technological advances of BBB models and challenges of in vitro modelling the BBTB, and application of these models as tools for assessing therapeutics and nano drug delivery, are discussed. Quantitative, in vitro BBB models that are predictive of effective brain cancer therapies will be invaluable for accelerating advancing new treatments to the clinic.
    Keywords:  Glioblastoma; Transwell; blood-brain tumor barrier; drug delivery; drug screening; microfluidics; nanoparticles; organoid; spheroid
    DOI:  https://doi.org/10.1016/j.addr.2023.114777
  10. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdac182
    Integrated response analysis of pediatric low-grade gliomas during and after targeted therapy treatment.
    Jessica W Tsai, Jungwhan John Choi, Hakim Ouaalam, Efrain Aguilar Murillo, Kee Kiat Yeo, Jayne Vogelzang, Cecilia Sousa, Jared K Woods, Keith L Ligon, Simon K Warfield, Pratiti Bandopadhayay, Tabitha M Cooney.
      Background: Pediatric low-grade gliomas (pLGGs) are the most common central nervous system tumor in children, characterized by RAS/MAPK pathway driver alterations. Genomic advances have facilitated the use of molecular targeted therapies, however, their long-term impact on tumor behavior remains critically unanswered.Methods: We performed an IRB-approved, retrospective chart and imaging review of pLGGs treated with off-label targeted therapy at Dana-Farber/Boston Children's from 2010 to 2020. Response analysis was performed for BRAFV600E and BRAF fusion/duplication-driven pLGG subsets.
    Results: Fifty-five patients were identified (dabrafenib n = 15, everolimus n = 26, trametinib n = 11, and vemurafenib n = 3). Median duration of targeted therapy was 9.48 months (0.12-58.44). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation were 62.1%, 38.2%, and 31.8%, respectively. Mean volumetric change for BRAFV600E mutated pLGG on BRAF inhibitors was -54.11%; median time to best volumetric response was 8.28 months with 9 of 12 (75%) objective RAPNO responses. Median time to largest volume post-treatment was 2.86 months (+13.49%); mean volume by the last follow-up was -14.02%. Mean volumetric change for BRAF fusion/duplication pLGG on trametinib was +7.34%; median time to best volumetric response was 6.71 months with 3 of 7 (43%) objective RAPNO responses. Median time to largest volume post-treatment was 2.38 months (+71.86%); mean volume by the last follow-up was +39.41%.
    Conclusions: Our integrated analysis suggests variability in response by pLGG molecular subgroup and targeted therapy, as well as the transience of some tumor growth following targeted therapy cessation.
    Keywords:  low-grade glioma; pediatrics; targeted therapy; volumetric
    DOI:  https://doi.org/10.1093/noajnl/vdac182
  11. Sci Rep. 2023 Mar 14. 13(1): 4228
    Visualizing genomic characteristics across an RNA-Seq based reference landscape of normal and neoplastic brain.
    Sonali Arora, Frank Szulzewsky, Matt Jensen, Nicholas Nuechterlein, Siobhan S Pattwell, Eric C Holland.
      In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-Seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA-Seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.
    DOI:  https://doi.org/10.1038/s41598-023-31180-z
  12. Nat Med. 2023 Mar 16.
    Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology.
    Dominik Sturm, David Capper, Felipe Andreiuolo, Marco Gessi, Christian Kölsche, Annekathrin Reinhardt, Philipp Sievers, Annika K Wefers, Azadeh Ebrahimi, Abigail K Suwala, Gerrit H Gielen, Martin Sill, Daniel Schrimpf, Damian Stichel, Volker Hovestadt, Bjarne Daenekas, Agata Rode, Stefan Hamelmann, Christopher Previti, Natalie Jäger, Ivo Buchhalter, Mirjam Blattner-Johnson, Barbara C Jones, Monika Warmuth-Metz, Brigitte Bison, Kerstin Grund, Christian Sutter, Steffen Hirsch, Nicola Dikow, Martin Hasselblatt, Ulrich Schüller, Nicolas U Gerber, Christine L White, Molly K Buntine, Kathryn Kinross, Elizabeth M Algar, Jordan R Hansford, Nicholas G Gottardo, Pablo Hernáiz Driever, Astrid Gnekow, Olaf Witt, Hermann L Müller, Gabriele Calaminus, Gudrun Fleischhack, Uwe Kordes, Martin Mynarek, Stefan Rutkowski, Michael C Frühwald, Christof M Kramm, Andreas von Deimling, Torsten Pietsch, Felix Sahm, Stefan M Pfister, David T W Jones.
      The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.
    DOI:  https://doi.org/10.1038/s41591-023-02255-1
  13. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad012
    Clinical outcome of biomarker-guided therapies in adult patients with tumors of the nervous system.
    Mirjam Renovanz, Sylvia C Kurz, Johannes Rieger, Bianca Walter, Hannes Becker, Hanni Hille, Paula Bombach, David Rieger, Lucia Grosse, Lara Häusser, Marco Skardelly, Daniel J Merk, Frank Paulsen, Elgin Hoffmann, Cihan Gani, Manuela Neumann, Rudi Beschorner, Olaf Rieß, Cristiana Roggia, Christopher Schroeder, Stephan Ossowski, Sorin Armeanu-Ebinger, Axel Gschwind, Saskia Biskup, Martin Schulze, Falko Fend, Stephan Singer, Lars Zender, Claudia Lengerke, Sara Yvonne Brucker, Tobias Engler, Andrea Forschner, Arnulf Stenzl, Oliver Kohlbacher, Sven Nahnsen, Gisela Gabernet, Sven Fillinger, Benjamin Bender, Ulrike Ernemann, Öznur Öner, Janina Beha, Holly Sundberg Malek, Yvonne Möller, Kristina Ruhm, Marcos Tatagiba, Jens Schittenhelm, Michael Bitzer, Nisar Malek, Daniel Zips, Ghazaleh Tabatabai.
      Background: The clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study.Methods: molecular tumor board (MTB)@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the MTB, and collected prospective clinical outcome data.
    Results: Here, we present initial data of 661 adult patients with tumors of the nervous system enrolled by December 31, 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival ratio >1.3 in 31.3% of patients.
    Conclusions: Our study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies, and even clinical care.
    Keywords:  MTB@ZPM-001 (NCT03503149); Molecular tumor board; precision medicine; real-world data; targeted therapy
    DOI:  https://doi.org/10.1093/noajnl/vdad012
This page is being maintained by Thomas Krichel. It was last updated on 2023‒03‒19 at 00:16:36.