bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024‒05‒19
nine papers selected by
Oltea Sampetrean, Keio University
  1. Spatial and molecular exploration of glioblastoma heterogeneity.
  2. A prognostic neural epigenetic signature in high-grade glioma.
  3. CAR T cells offer hope in glioblastoma.
  4. IDH inhibition in gliomas: from preclinical models to clinical trials.
  5. A triad between sex, necrosis, and inflammation shapes glioblastoma outcomes.
  6. Bystander effects, pharmacokinetics, and linker-payload stability of EGFR-targeting antibody-drug conjugates Losatuxizumab vedotin and Depatux-M in glioblastoma models.
  7. Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect survival.
  8. The gut-brain-axis: A positive relationship between gut microbial dysbiosis and glioblastoma brain tumour.
  9. Resistance, rebound, and recurrence regrowth patterns in pediatric low-grade glioma treated by MAPK inhibition: A modified Delphi approach to build international consensus-based definitions-International Pediatric Low-Grade Glioma Coalition.
  1. Nat Genet. 2024 May;56(5): 737
    Spatial and molecular exploration of glioblastoma heterogeneity.
    Michael Fletcher.
      
    DOI:  https://doi.org/10.1038/s41588-024-01772-0
  2. Nat Med. 2024 May 17.
    A prognostic neural epigenetic signature in high-grade glioma.
    Richard Drexler, Robin Khatri, Thomas Sauvigny, Malte Mohme, Cecile L Maire, Alice Ryba, Yahya Zghaibeh, Lasse Dührsen, Amanda Salviano-Silva, Katrin Lamszus, Manfred Westphal, Jens Gempt, Annika K Wefers, Julia E Neumann, Helena Bode, Fabian Hausmann, Tobias B Huber, Stefan Bonn, Kerstin Jütten, Daniel Delev, Katharina J Weber, Patrick N Harter, Julia Onken, Peter Vajkoczy, David Capper, Benedikt Wiestler, Michael Weller, Berend Snijder, Alicia Buck, Tobias Weiss, Pauline C Göller, Felix Sahm, Joelle Aline Menstel, David Niklas Zimmer, Michael B Keough, Lijun Ni, Michelle Monje, Dana Silverbush, Volker Hovestadt, Mario L Suvà, Saritha Krishna, Shawn L Hervey-Jumper, Ulrich Schüller, Dieter H Heiland, Sonja Hänzelmann, Franz L Ricklefs.
      Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients' plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.
    DOI:  https://doi.org/10.1038/s41591-024-02969-w
  3. Nat Rev Neurol. 2024 May 14.
    CAR T cells offer hope in glioblastoma.
    Ian Fyfe.
      
    DOI:  https://doi.org/10.1038/s41582-024-00972-w
  4. Nat Rev Neurol. 2024 May 17.
    IDH inhibition in gliomas: from preclinical models to clinical trials.
    Roberta Rudà, Craig Horbinski, Martin van den Bent, Matthias Preusser, Riccardo Soffietti.
      Gliomas are the most common malignant primary brain tumours in adults and cannot usually be cured with standard cancer treatments. Gliomas show intratumoural and intertumoural heterogeneity at the histological and molecular levels, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. IDH-mutant adult-type diffuse gliomas are subdivided into grade 2, 3 or 4 IDH-mutant astrocytomas and grade 2 or 3 IDH-mutant, 1p19q-codeleted oligodendrogliomas. The product of the mutated IDH genes, D-2-hydroxyglutarate (D-2-HG), induces global DNA hypermethylation and interferes with immunity, leading to stimulation of tumour growth. Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. The phase III INDIGO trial has demonstrated superiority of vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, over placebo in people with non-enhancing grade 2 IDH-mutant gliomas following surgery. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas.
    DOI:  https://doi.org/10.1038/s41582-024-00967-7
  5. Neuro Oncol. 2024 May 14. pii: noae086. [Epub ahead of print]
    A triad between sex, necrosis, and inflammation shapes glioblastoma outcomes.
    Brandon Emanuel León, Defne Bayik.
      
    DOI:  https://doi.org/10.1093/neuonc/noae086
  6. Clin Cancer Res. 2024 May 14.
    Bystander effects, pharmacokinetics, and linker-payload stability of EGFR-targeting antibody-drug conjugates Losatuxizumab vedotin and Depatux-M in glioblastoma models.
    Sonia Jain, Jessica I Griffith, Kendra A Porath, Sneha Rathi, Jiayan Le, Tugce I Pasa, Paul A Decker, Shiv K Gupta, Zeng Hu, Brett L Carlson, Katrina Bakken, Danielle M Burgenske, Thomas M Feldsien, Didier R Lefebvre, Rachael A Vaubel, Jeanette E Eckel-Passow, Edward B Reilly, William F Elmquist, Jann N Sarkaria.
      PURPOSE: Antibody-drug conjugates (ADCs) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given the molecular heterogeneity of GBM, bystander activity of ADCs may be important for determining treatment efficacy. In this study, the activity and toxicity of two EGFR-targeted ADCs, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), with similar auristatin toxins, were compared in GBM patient-derived xenografts (PDXs) and normal murine brain following direct infusion by convection enhanced delivery (CED).METHODS: EGFRviii-amplified and non-amplified GBM PDXs were used to determine in vitro cytotoxicity, in vivo efficacy, and bystander activities of ABBV-221 and Depatux-M. Non-tumor bearing mice were used to evaluate pharmacokinetics and toxicity of ADCs using LC-MS/MS and immunohistochemistry.
    RESULTS: CED improved intracranial efficacy of Depatux-M and ABBV-221 in three EGFRviii-amplified GBM PDX models (Median survival: 125 to >300 days vs 20-49 days with isotype-control AB095). Both ADCs had comparable in vitro and in vivo efficacy. However, neuronal toxicity and CD68+ microglia/macrophage infiltration were significantly higher in brains infused with ABBV-221, with the cell-permeable MMAE, as compared to Depatux-M, with the cell-impermeant MMAF. CED infusion of ABBV-221 into brain or incubation of ABBV-221 with normal brain homogenate resulted in significant release of MMAE, which is consistent with linker instability in the brain microenvironment.
    CONCLUSION: EGFR-targeting ADCs are promising therapeutic options for GBM when delivered intra-tumorally by CED. However, the linker and payload for the ADC must be carefully considered to maximize the therapeutic window.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-0426
  7. Sci Adv. 2024 May 17. 10(20): eadj3301
    Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect survival.
    Michael J Haley, Leoma Bere, James Minshull, Sokratia Georgaka, Natalia Garcia-Martin, Gareth Howell, David J Coope, Federico Roncaroli, Andrew King, David C Wedge, Stuart M Allan, Omar N Pathmanaban, David Brough, Kevin N Couper.
      Myeloid cells are highly prevalent in glioblastoma (GBM), existing in a spectrum of phenotypic and activation states. We now have limited knowledge of the tumor microenvironment (TME) determinants that influence the localization and the functions of the diverse myeloid cell populations in GBM. Here, we have utilized orthogonal imaging mass cytometry with single-cell and spatial transcriptomic approaches to identify and map the various myeloid populations in the human GBM tumor microenvironment (TME). Our results show that different myeloid populations have distinct and reproducible compartmentalization patterns in the GBM TME that is driven by tissue hypoxia, regional chemokine signaling, and varied homotypic and heterotypic cellular interactions. We subsequently identified specific tumor subregions in GBM, based on composition of identified myeloid cell populations, that were linked to patient survival. Our results provide insight into the spatial organization of myeloid cell subpopulations in GBM, and how this is predictive of clinical outcome.
    DOI:  https://doi.org/10.1126/sciadv.adj3301
  8. Heliyon. 2024 May 15. 10(9): e30494
    The gut-brain-axis: A positive relationship between gut microbial dysbiosis and glioblastoma brain tumour.
    Hafiz Muhammad Ishaq, Riffat Yasin, Imran Shair Mohammad, Yang Fan, Huan Li, Muhammad Shahzad, Jiru Xu.
      The glioblastoma brain tumour (GBM) stands out as the most aggressive and resistant-to-treatment malignancy. Nevertheless, the gut-brain connection plays a pivotal role in influencing the growth and activation of the central nervous system. In this particular investigation, we aimed to assess and characterize the gut microbial ecosystem in GBM patients, both quantitatively and qualitatively. We collected faecal samples from 15 healthy volunteers and 25 GBM patients. To delve into the microbial content, we employed PCR-DGGE, targeting the V3 region of the 16S rRNA gene, and conducted qPCR to measure the levels of crucial intestinal bacteria. For a more in-depth analysis, high-throughput sequencing was performed on a selection of 20 random faecal samples (10 from healthy individuals and 10 from GBM patients), targeting the V3+V4 region of the 16S rRNA gene. Our findings from examining the richness and diversity of the gut microbiota unveiled that GBM patients exhibited significantly higher microbial diversity compared to healthy individuals. At the phylum level, Proteobacteria saw a significant increase, while Firmicutes experienced a noteworthy decrease in the GBM group. Moving down to the family level, we observed significantly elevated levels of Enterobacteriaceae, Bacteroidaceae, and Lachnospiraceae in GBM patients, while levels of Veillonellaceae, Rikenellaceae, and Prevotellaceae were notably lower. Delving into genera statistics, we noted a substantial increase in the abundance of Parasutterella, Escherichia-Shigella, and Bacteroides, alongside significantly lower levels of Ruminococcus 2, Faecalibacterium, and Prevotella_9 in the GBM group compared to the control group. Furthermore, when examining specific species, we found a significant increase in Bacteroides vulgatus and Escherichia coli in the GBM group. These observations collectively indicate a marked dysbiosis in the gut microbial composition of GBM patients. Additionally, the GBM group exhibited notably higher levels of alpha diversity when compared to the control group. This increase in diversity suggests a significant bacterial overgrowth in the gut of GBM patients in contrast to the controls. As a result, this research opens up potential avenues to gain a better understanding of the underlying mechanisms, pathways, and potential treatments for GBM, stemming from the significant implications of gut microbial dysbiosis in these patients.
    Keywords:  Characterization; DGGE; GBM; Gut bacteria; Highthrough-put sequencing
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e30494
  9. Neuro Oncol. 2024 May 14. pii: noae074. [Epub ahead of print]
    Resistance, rebound, and recurrence regrowth patterns in pediatric low-grade glioma treated by MAPK inhibition: A modified Delphi approach to build international consensus-based definitions-International Pediatric Low-Grade Glioma Coalition.
    Patricia O'Hare, Tabitha Cooney, Peter de Blank, David H Gutmann, Mark Kieran, Till Milde, Jason Fangusaro, Michael Fisher, Shivaram Avula, Roger Packer, Kohei Fukuoka, Kshitij Mankad, Sabine Mueller, Angela J Waanders, Enrico Opocher, Eric Bouffet, Eric Raabe, Natacha Entz Werle, Amedeo A Azizi, Nathan J Robison, Pablo Hernáiz Driever, Mark Russo, Netteke Schouten, Cornelis M van Tilburg, Astrid Sehested, Jacques Grill, Pratiti Bandopadhayay, John-Paul Kilday, Olaf Witt, David M Ashley, Birgit Betina Ertl-Wagner, Uri Tabori, Darren R Hargrave.
      Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor regrowth can occur during therapy due to drug resistance, off treatment as tumor recurrence, or as reported in some patients as a rapid rebound growth within 3 months of discontinuing targeted therapy. Definitions of these patterns of regrowth have not been well described in pLGG. For this reason, the International Pediatric Low-Grade Glioma Coalition, a global group of physicians and scientists, formed the Resistance, Rebound, and Recurrence (R3) working group to study resistance, rebound, and recurrence. A modified Delphi approach was undertaken to produce consensus-based definitions and recommendations for regrowth patterns in pLGG with specific reference to targeted therapies.
    Keywords:  MAPK; child; low-grade glioma; pediatric brain tumor; rebound; recurrence; resistance
    DOI:  https://doi.org/10.1093/neuonc/noae074
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