bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–03–17
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Identification of transcriptomic signatures associated with glioblastoma recurrence.
  2. DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma.
  3. Advancements in chimeric antigen receptor-expressing T-cell therapy for glioblastoma multiforme: Literature review and future directions.
  4. Glioblastoma stem cell-derived exosomal miR-374b-3p promotes tumor angiogenesis and progression through inducing M2 macrophages polarization.
  5. OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.
  6. DNA methylation landscapes in DIPG reveal methylome variability that can be modified pharmacologically.
  7. Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma.
  8. Challenges, Limitations and Pitfalls of PET and Advanced MRI in Patients with Brain Tumors - A Report of the PET/RANO Group.
  9. Sex differences in glioblastoma response to treatment: Impact of MGMT methylation.
  10. Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma.
  11. Just a spoonful of metformin helps the medicine go down.
  1. Neuro Oncol. 2024 Mar 12. pii: noae044. [Epub ahead of print]
    Identification of transcriptomic signatures associated with glioblastoma recurrence.
    Sean Lawler.
      
    DOI:  https://doi.org/10.1093/neuonc/noae044
  2. Acta Neuropathol Commun. 2024 Mar 13. 12(1): 40
    DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma.
    Mio Harachi, Kenta Masui, Erika Shimizu, Kumiko Murakami, Hiromi Onizuka, Yoshihiro Muragaki, Takakazu Kawamata, Hisako Nakayama, Mariko Miyata, Takashi Komori, Webster K Cavenee, Paul S Mischel, Atsushi Kurata, Noriyuki Shibata.
      DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global "hypomethylator phenotype", are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.
    Keywords:  DNA hypomethylation; DNMT3A; EZH2; Glioblastoma; Glutamate metabolism; mTORC2
    DOI:  https://doi.org/10.1186/s40478-024-01750-x
  3. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae025
    Advancements in chimeric antigen receptor-expressing T-cell therapy for glioblastoma multiforme: Literature review and future directions.
    Michael Goutnik, Alexandria Iakovidis, Megan E H Still, Rachel S F Moor, Kaitlyn Melnick, Sandra Yan, Muhammad Abbas, Jianping Huang, Ashley P Ghiaseddin.
      Glioblastoma multiforme (GBM) is an aggressive cancer that has been difficult to treat and often requires multimodal therapy consisting of surgery, radiotherapy, and chemotherapy. Chimeric antigen receptor-expressing (CAR-T) cells have been efficacious in treating hematological malignancies, resulting in several FDA-approved therapies. CAR-T cells have been more recently studied for the treatment of GBM, with some promising preclinical and clinical results. The purpose of this literature review is to highlight the commonly targeted antigens, results of clinical trials, novel modifications, and potential solutions for challenges that exist for CAR-T cells to become more widely implemented and effective in eradicating GBM.
    Keywords:  CAR-T cells; antigen escape; glioblastoma multiforme; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1093/noajnl/vdae025
  4. iScience. 2024 Mar 15. 27(3): 109270
    Glioblastoma stem cell-derived exosomal miR-374b-3p promotes tumor angiogenesis and progression through inducing M2 macrophages polarization.
    Shilu Huang, Peng Zhang, Nanheng Yin, Zhipeng Xu, Xinglei Liu, Anyi Wu, Xiaopei Zhang, Zengyang Li, Zhicheng Zhang, Tao Zhong, Liang Liu, Yan Shi, Jun Dong.
      Glioblastoma stem cells (GSCs) reside in hypoxic periarteriolar niches of glioblastoma micro-environment, however, the crosstalk of GSCs with macrophages on regulating tumor angiogenesis and progression are not fully elucidated. GSCs-derived exosomes (GSCs-exos) are essential mediators during tumor immune-microenvironment remodeling initiated by GSCs, resulting in M2 polarization of tumor-associated macrophages (TAMs) as we reported previously. Our data disclosed aberrant upregulation of miR-374b-3p in both clinical glioblastoma specimens and human cell lines of GSCs. MiR-374b-3p level was high in GSCs-exos and can be internalized by macrophages. Mechanistically, GSCs exosomal miR-374b-3p induced M2 polarization of macrophages by downregulating phosphatase and tensin expression, thereby promoting migration and tube formation of vascular endothelial cells after coculture with M2 macrophages. Cumulatively, these data indicated that GSCs exosomal miR-374b-3p can enhance tumor angiogenesis by inducing M2 polarization of macrophages, as well as promote malignant progression of glioblastoma. Targeting exosomal miR-374b-3p may serve as a potential target against glioblastoma.
    Keywords:  Cancer; Immunology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109270
  5. JCI Insight. 2024 Mar 14. pii: e172565. [Epub ahead of print]
    OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.
    Trang Tt Nguyen, Consuelo Torrini, Enyuan Shang, Chang Shu, Jeong-Yeon Mun, Qiuqiang Gao, Nelson Humala, Hasan O Akman, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin.
      Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the alpha-ketoglutarate dehydrogenase (OGDH) gene, which encodes for an enzyme that is part of the tricarboxylic acid cycle (TCA cycle) as essential for GBM growth. Moreover, by combining a transcriptome and metabolite screening analyses we discovered that loss of function of OGDH by the clinically validated drug compound, CPI-613, was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3-mimetic, ABT263) in patient-derived xenograft as well neurosphere GBM cultures. CPI-613 mediated energy deprivation drove an integrated stress response with an up-regulation of the BH3-only domain protein, Noxa in an ATF4 dependent manner as demonstrated by genetic loss of function experiments. Consistently, silencing of Noxa attenuated cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with interference of the TCA-cycle might be a treatment strategy for GBM.
    Keywords:  Apoptosis pathways; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.172565
  6. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae023
    DNA methylation landscapes in DIPG reveal methylome variability that can be modified pharmacologically.
    Ashley R Tetens, Allison M Martin, Antje Arnold, Orlandi V Novak, Adrian Idrizi, Rakel Tryggvadottir, Jordyn Craig-Schwartz, Athanasia Liapodimitri, Kayleigh Lunsford, Michael I Barbato, Charles G Eberhart, Adam C Resnick, Eric H Raabe, Michael A Koldobskiy.
       Background: Diffuse intrinsic pontine glioma (DIPG) is a uniformly lethal brainstem tumor of childhood, driven by histone H3 K27M mutation and resultant epigenetic dysregulation. Epigenomic analyses of DIPG have shown global loss of repressive chromatin marks accompanied by DNA hypomethylation. However, studies providing a static view of the epigenome do not adequately capture the regulatory underpinnings of DIPG cellular heterogeneity and plasticity.
    Methods: To address this, we performed whole-genome bisulfite sequencing on a large panel of primary DIPG specimens and applied a novel framework for analysis of DNA methylation variability, permitting the derivation of comprehensive genome-wide DNA methylation potential energy landscapes that capture intrinsic epigenetic variation.
    Results: We show that DIPG has a markedly disordered epigenome with increasingly stochastic DNA methylation at genes regulating pluripotency and developmental identity, potentially enabling cells to sample diverse transcriptional programs and differentiation states. The DIPG epigenetic landscape was responsive to treatment with the hypomethylating agent decitabine, which produced genome-wide demethylation and reduced the stochasticity of DNA methylation at active enhancers and bivalent promoters. Decitabine treatment elicited changes in gene expression, including upregulation of immune signaling such as the interferon response, STING, and MHC class I expression, and sensitized cells to the effects of histone deacetylase inhibition.
    Conclusions: This study provides a resource for understanding the epigenetic instability that underlies DIPG heterogeneity. It suggests the application of epigenetic therapies to constrain the range of epigenetic states available to DIPG cells, as well as the use of decitabine in priming for immune-based therapies.
    Keywords:  DNA hypomethylating agents; diffuse intrinsic pontine glioma; diffuse midline glioma; epigenetic variability
    DOI:  https://doi.org/10.1093/noajnl/vdae023
  7. N Engl J Med. 2024 Mar 13.
    Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma.
    Bryan D Choi, Elizabeth R Gerstner, Matthew J Frigault, Mark B Leick, Christopher W Mount, Leonora Balaj, Sarah Nikiforow, Bob S Carter, William T Curry, Kathleen Gallagher, Marcela V Maus.
      In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell-engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.).
    DOI:  https://doi.org/10.1056/NEJMoa2314390
  8. Neuro Oncol. 2024 Mar 11. pii: noae049. [Epub ahead of print]
    Challenges, Limitations and Pitfalls of PET and Advanced MRI in Patients with Brain Tumors - A Report of the PET/RANO Group.
    Norbert Galldiks, Timothy J Kaufmann, Philipp Vollmuth, Philipp Lohmann, Marion Smits, Michael C Veronesi, Karl-Josef Langen, Roberta Rudá, Nathalie L Albert, Elke Hattingen, Ian Law, Markus Hutterer, Riccardo Soffietti, Michael A Vogelbaum, Patrick Y Wen, Michael Weller, Joerg-Christian Tonn.
      Brain tumor diagnostics have significantly evolved with the use of PET and advanced MRI techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the RANO group, the EANO, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g., MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care.
    Keywords:  CEST; MR spectroscopy; amino acid PET; diffusion-weighted imaging; perfusion-weighted imaging
    DOI:  https://doi.org/10.1093/neuonc/noae049
  9. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae031
    Sex differences in glioblastoma response to treatment: Impact of MGMT methylation.
    Gino Cioffi, Kristin A Waite, Mantas Dmukauskas, Michael Glantz, Sonikpreet Aulakh, Theodore Nicolaides, Soma Sengupta, Joanne Xiu, Jill S Barnholtz-Sloan.
      
    Keywords:  MGMT methylation; overall survival; primary brain tumors; sex differences
    DOI:  https://doi.org/10.1093/noajnl/vdae031
  10. Neuro Oncol. 2024 Mar 11. pii: noae048. [Epub ahead of print]
    Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma.
    Daniel C Moreira, Ibrahim Qaddoumi, Susan Spiller, Thomas W Bouldin, Alan Davidson, Nasjla Saba-Silva, Daniel V Sullivan, Ryuma Tanaka, Aaron S Wagner, Matthew Wood, Paul Klimo, Godwin Job, Meenakshi Devidas, Xiaoyu Li, Amar Gajjar, Giles W Robinson, Jason Chiang.
       BACKGROUND: Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies.
    METHODS: We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children's Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated.
    RESULTS: Thirty-three patients (18 male; median age, 5 y) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n=10, 30%). Most tumors were in the cerebral hemispheres (n=22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3±8.3%; the 5-year overall survival (OS) rate was 96.4±4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6±15.2% (p<0.01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways.
    CONCLUSIONS: pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors.
    Keywords:   MYB/MYBL1 alterations; Pediatric diffuse low-grade glioma; outcome; survival; treatment
    DOI:  https://doi.org/10.1093/neuonc/noae048
  11. J Clin Invest. 2024 Mar 15. pii: e179144. [Epub ahead of print]134(6):
    Just a spoonful of metformin helps the medicine go down.
    Theophilos Tzaridis, Robert J Wechsler-Reya.
      Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors.
    DOI:  https://doi.org/10.1172/JCI179144
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