bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–06–11
seventeen papers selected by
Oltea Sampetrean, Keio University
  1. The role of histone H3 lysine demethylases in glioblastoma.
  2. Exploring the Vital Link Between Glioma, Neuron, and Neural Activity in the Context of Invasion.
  3. The Tumor Suppressor CDKN2A Remodels the Lipidome of Glioblastoma.
  4. Lysine Catabolism Alters Antitumor Immunity in Glioblastoma Stem Cells.
  5. Isocitrate dehydrogenase mutations in gliomas: A review of current understanding and trials.
  6. Sialic acid metabolism orchestrates transcellular connectivity and signalling in glioblastoma.
  7. CGlioblastoma Stem Cell Targeting Peptide Isolated Through Phage Display Binds Cadherin 2.
  8. Current advances in temozolomide encapsulation for the enhancement of glioblastoma treatment.
  9. Combination of tumour-targeted TNF and chemotherapy shows promising results in glioblastoma.
  10. Dendritic cell vaccine trials in gliomas: Untangling the lines.
  11. Glioblastoma heterogeneity at single cell resolution.
  12. PKM2 rewires glucose metabolism during radiation therapy to promote an antioxidant response and glioblastoma radioresistance.
  13. EPIC-0307-mediated selective disruption of PRADX-EZH2 interaction and enhancement of temozolomide sensitivity to glioblastoma via inhibiting DNA repair and MGMT.
  14. Upstream Open Reading Frame-encoded MP31 Disrupts the Mitochondrial Quality Control Process and Inhibits Tumorigenesis in Glioblastoma.
  15. Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline.
  16. Tumor-neutrophil crosstalk promotes in vitro and in vivo glioblastoma progression.
  17. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.
  1. Cancer Metastasis Rev. 2023 Jun 08.
    The role of histone H3 lysine demethylases in glioblastoma.
    Dejauwne Young, Chandan Guha, Simone Sidoli.
      Glioblastoma (GBM) is the most aggressive primary brain tumor in adults with an average survival of 15-18 months. Part of its malignancy derives from epigenetic regulation that occurs as the tumor develops and after therapeutic treatment. Specifically, enzymes involved in removing methylations from histone proteins on chromatin, i.e., lysine demethylases (KDMs), have a significant impact on GBM biology and reoccurrence. This knowledge has paved the way to considering KDMs as potential targets for GBM treatment. For example, increases in trimethylation of histone H3 on the lysine 9 residue (H3K9me3) via inhibition of KDM4C and KDM7A has been shown to lead to cell death in Glioblastoma initiating cells. KDM6 has been shown to drive Glioma resistance to receptor tyrosine kinase inhibitors and its inhibition decreases tumor resistance. In addition, increased expression of the histone methyltransferase MLL4 and UTX histone demethylase are associated with prolonged survival in a subset of GBM patients, potentially by regulating histone methylation on the promoter of the mgmt gene. Thus, the complexity of how histone modifiers contribute to glioblastoma pathology and disease progression is yet to be fully understood. To date, most of the current work on histone modifying enzymes in GBM are centered upon histone H3 demethylase enzymes. In this mini-review, we summarize the current knowledge on the role of histone H3 demethylase enzymes in Glioblastoma tumor biology and therapy resistance. The objective of this work is to highlight the current and future potential areas of research for GBM epigenetics therapy.
    Keywords:  Glioblastoma; Histone methylation; Lysine demethylases; Post-translational modifications
    DOI:  https://doi.org/10.1007/s10555-023-10114-1
  2. Am J Pathol. 2023 Jun;pii: S0002-9440(23)00111-6. [Epub ahead of print]193(6): 669-679
    Exploring the Vital Link Between Glioma, Neuron, and Neural Activity in the Context of Invasion.
    Masafumi Miyai, Toru Iwama, Akira Hara, Hiroyuki Tomita.
      Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas.
    DOI:  https://doi.org/10.1016/j.ajpath.2023.02.018
  3. Cancer Discov. 2023 Jun 09. OF1
    The Tumor Suppressor CDKN2A Remodels the Lipidome of Glioblastoma.
      CDKN2A loss remodels the glioblastoma lipidome and sensitizes cells to lipid peroxidation and ferroptosis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-089
  4. Cancer Discov. 2023 Jun 09. OF1
    Lysine Catabolism Alters Antitumor Immunity in Glioblastoma Stem Cells.
      Glioblastoma stem cells reprogram lysine catabolism by enhancing GCDH to promote an immunosuppressive state.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-087
  5. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad053
    Isocitrate dehydrogenase mutations in gliomas: A review of current understanding and trials.
    Nikhil Sharma, Arka N Mallela, Diana D Shi, Lilly W Tang, Hussam Abou-Al-Shaar, Zachary C Gersey, Xiaoran Zhang, Samuel K McBrayer, Kalil G Abdullah.
      Isocitrate dehydrogenase (IDH) is a key enzyme in normal metabolism and homeostasis. However, mutant forms of IDH are also defining features of a subset of diffuse gliomas. In this review, we highlight current techniques targeting IDH-mutated gliomas and summarize current and completed clinical trials exploring these strategies. We discuss clinical data from peptide vaccines, mutant IDH (mIDH) inhibitors, and PARP inhibitors. Peptide vaccines have the unique advantage of targeting the specific epitope of a patient's tumor, inducing a highly tumor-specific CD4+ T-cell response. mIDH-inhibitors, on the other hand, specifically target mutant IDH proteins in cancer cell metabolism and thus help halt gliomagenesis. We also explore PARP inhibitors and their role in treating diffuse gliomas, which exploit IDH-mutant diffuse gliomas by allowing the persistence of unrepaired DNA complexes. We summarize various completed and current trials targeting IDH1 and IDH2 mutations in diffuse gliomas. Therapies targeting mutant IDH have significant promise in treating progressive or recurrent IDH-mutant gliomas and may significantly change treatment paradigms in the next decade.
    Keywords:  IDH inhibitors; IDH mutation; glioma; isocitrate dehydrogenase; peptide vaccine
    DOI:  https://doi.org/10.1093/noajnl/vdad053
  6. Neuro Oncol. 2023 Jun 08. pii: noad101. [Epub ahead of print]
    Sialic acid metabolism orchestrates transcellular connectivity and signalling in glioblastoma.
    Ugne Kuliesiute, Kevin Joseph, Jakob Straehle, Vidhya Madapusi Ravi, Jan Kueckelhaus, Jasim Kada Benotmane, Junyi Zhang, Andreas Vlachos, Juergen Beck, Oliver Schnell, Urte Neniskyte, Dieter Henrik Heiland.
       BACKGROUND: In glioblastoma (GBM), the effects of altered glycocalyx are largely unexplored. The terminal moiety of cell coating glycans, sialic acid, is of paramount importance for cell-cell contacts. However, sialic acid turnover in gliomas and its impact on tumor networks remain unknown.
    METHODS: We streamlined an experimental setup using organotypic human brain slice cultures as a framework for exploring brain glycobiology, including metabolic labeling of sialic acid moieties and quantification of glycocalyx changes. By live, 2-photon and high-resolution microscopy we have examined morphological and functional effects of altered sialic acid metabolism in GBM. By calcium imaging we investigated the effects of the altered glycocalyx on a functional level of GBM networks.
    RESULTS: The visualization and quantitative analysis of newly synthesized sialic acids revealed a high rate of de novo sialylation in GBM cells. Sialyltrasferases and sialidases were highly expressed in GBM, indicating that significant turnover of sialic acids is involved in GBM pathology. Inhibition of either sialic acid biosynthesis or desialylation affected the pattern of tumor growth and lead to the alterations in the connectivity of glioblastoma cells network.
    CONCLUSIONS: Our results indicate that sialic acid is essential for the establishment of GBM tumor and its cellular network. They highlight the importance of sialic acid for glioblastoma pathology and suggest that dynamics of sialylation have the potential to be targeted therapeutically.
    Keywords:  Glioblastoma; cancer neuroscience; glioma circuits; sialic acid; sialidases
    DOI:  https://doi.org/10.1093/neuonc/noad101
  7. Stem Cells. 2023 Jun 06. pii: sxad045. [Epub ahead of print]
    CGlioblastoma Stem Cell Targeting Peptide Isolated Through Phage Display Binds Cadherin 2.
    JongMyung Kim, Marine Potez, Chunhua She, Ping Huang, Qiulian Wu, Shideng Bao, Jeremy N Rich, James K C Liu.
      Glioblastoma stem cells (GSCs) have unique properties of self-renewal and tumor initiation that make them potential therapeutic targets. Development of effective therapeutic strategies against GSCs requires both specificity of targeting and intracranial penetration through the blood-brain barrier. We have previously demonstrated the use of in vitro and in vivo phage display biopanning strategies to isolate glioblastoma targeting peptides. Here we selected a 7-amino-acid peptide, AWEFYFP, which was independently isolated in both the in vitro and in vivo screens and demonstrated that it was able to target GSCs over differentiated glioma cells and non-neoplastic brain cells. When conjugated to Cyanine 5.5 and intravenously injected into mice with intracranially xenografted glioblastoma, the peptide localized to the site of the tumor, demonstrating intracranial tumor targeting specificity. Immunoprecipitation of the peptide with GSC proteins revealed Cadherin 2 as the glioblastoma cell surface receptor targeted by the peptides. Peptide targeting of Cadherin 2 on GSCs was confirmed through ELISA and in vitro binding analysis. Interrogation of glioblastoma databases demonstrated that Cadherin 2 expression correlated with tumor grade and survival. These results confirm that phage display can be used to isolate unique tumor-targeting peptides specific for glioblastoma. Furthermore, analysis of these cell specific peptides can lead to the discovery of cell specific receptor targets that may serve as the focus of future theragnostic tumor-homing modalities for the development of precision strategies for the treatment and diagnosis of glioblastomas.
    DOI:  https://doi.org/10.1093/stmcls/sxad045
  8. Theranostics. 2023 ;13(9): 2734-2756
    Current advances in temozolomide encapsulation for the enhancement of glioblastoma treatment.
    Nerea Iturrioz-Rodríguez, Nicolas Sampron, Ander Matheu.
      Glioblastoma is the most common and lethal brain tumor in adults. The incorporation of temozolomide (TMZ) into the standard treatment has increased the overall survival rate of glioblastoma patients. Since then, significant advances have been made in understanding the benefits and limitations of TMZ. Among the latter, the unspecific toxicity of TMZ, poor solubility, and hydrolyzation are intrinsic characteristics, whereas the presence of the blood-brain barrier and some tumor properties, such as molecular and cellular heterogeneity and therapy resistance, have limited the therapeutic effects of TMZ in treating glioblastoma. Several reports have revealed that different strategies for TMZ encapsulation in nanocarriers overcome those limitations and have shown that they increase TMZ stability, half-life, biodistribution, and efficacy, offering the promise for future nanomedicine therapies in handling glioblastoma. In this review, we analyze the different nanomaterials used for the encapsulation of TMZ to improve its stability, blood half-life and efficacy, paying special attention to polymer- and lipid-based nanosystems. To improve TMZ drug resistance, present in up to 50% of patients, we detail TMZ combined therapeutic with i) other chemotherapies, ii) inhibitors, iii) nucleic acids, iv) photosensitizers and other nanomaterials for photodynamic therapy, photothermal therapy, and magnetic hyperthermia, v) immunotherapy, and vi) other less explored molecules. Moreover, we describe targeting strategies, such as passive targeting, active targeting to BBB endothelial cells, glioma cells, and glioma cancer stem cells, and local delivery, where TMZ has demonstrated an improved outcome. To finish our study, we include possible future research directions that could help decrease the time needed to move from bench to bedside.
    Keywords:  encapsulation; glioblastoma; nanosystems; targeted delivery; temozolomide
    DOI:  https://doi.org/10.7150/thno.82005
  9. Nat Rev Immunol. 2023 Jun 07.
    Combination of tumour-targeted TNF and chemotherapy shows promising results in glioblastoma.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-023-00903-8
  10. Neuro Oncol. 2023 Jun 08. pii: noad088. [Epub ahead of print]
    Dendritic cell vaccine trials in gliomas: Untangling the lines.
    Kelly M Hotchkiss, Kristen A Batich, Aditya Mohan, Rifaquat Rahman, Steven Piantadosi, Mustafa Khasraw.
      Glioblastoma is a deadly brain tumor without any significantly successful treatments to date. Tumor antigen-targeted immunotherapy platforms including peptide and dendritic cell (DC) vaccines, have extended survival in hematologic malignancies. The relatively "cold" tumor immune microenvironment and heterogenous nature of glioblastoma have proven to be major limitations to translational application and efficacy of DC vaccines. Furthermore, many DC vaccine trials in glioblastoma are difficult to interpret due to a lack of contemporaneous controls, absence of any control comparison, or inconsistent patient populations. Here we review glioblastoma immunobiology aspects that are relevant to DC vaccines, review the clinical experience with DC vaccines targeting glioblastoma, discuss challenges in clinical trial design, and summarize conclusions and directions for future research for the development of effective DC vaccines for patients.
    Keywords:  Clinical trial; control arm; dc vaccine; glioblastoma; patient selection
    DOI:  https://doi.org/10.1093/neuonc/noad088
  11. Oncogene. 2023 Jun 05.
    Glioblastoma heterogeneity at single cell resolution.
    David Eisenbarth, Y Alan Wang.
      Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to therapy lies within the heterogeneity of the tumor and its associated microenvironment. The vast diversity of cell states, composition of cells, and phenotypical characteristics makes it difficult to accurately classify GBM into distinct subtypes and find effective therapies. The advancement of sequencing technologies in recent years has further corroborated the heterogeneity of GBM at the single cell level. Recent studies have only begun to elucidate the different cell states present in GBM and how they correlate with sensitivity to therapy. Furthermore, it has become clear that GBM heterogeneity not only depends on intrinsic factors but also strongly differs between new and recurrent GBM, and treatment naïve and experienced patients. Understanding and connecting the complex cellular network that underlies GBM heterogeneity will be indispensable in finding new ways to tackle this deadly disease. Here, we present an overview of the multiple layers of GBM heterogeneity and discuss novel findings in the age of single cell technologies.
    DOI:  https://doi.org/10.1038/s41388-023-02738-y
  12. Neuro Oncol. 2023 Jun 05. pii: noad103. [Epub ahead of print]
    PKM2 rewires glucose metabolism during radiation therapy to promote an antioxidant response and glioblastoma radioresistance.
    Justine Bailleul, Yangjingyi Ruan, Lobna Abdulrahman, Andrew J Scott, Taha Yazal, David Sung, Keunseok Park, Hanna Hoang, Juan Nathaniel, Fang-I Chu, Daisy Palomera, Anahita Sehgal, Jonathan E Tsang, David A Nathanson, Shili Xu, Junyoung O Park, Johanna Ten Hoeve, Kruttika Bhat, Nathan Qi, Harley I Kornblum, Dorthe Schaue, William H McBride, Costas A Lyssiotis, Daniel R Wahl, Erina Vlashi.
       BACKGROUND: Resistance to existing therapies is a significant challenge in improving outcomes for glioblastoma (GBM) patients. Metabolic plasticity has emerged as an important contributor to therapy resistance, including radiation therapy (RT). Here, we investigated how GBM cells reprogram their glucose metabolism in response to RT to promote radiation resistance.
    METHODS: Effects of radiation on glucose metabolism of human GBM specimens were examined in vitro and in vivo with the use of metabolic and enzymatic assays, targeted metabolomics, and FDG-PET. Radiosensitization potential of interfering with PKM2 activity was tested via gliomasphere formation assays and in vivo human GBM models.
    RESULTS: Here, we show that RT induces increased glucose utilization by GBM cells, and this is accompanied with translocation of GLUT3 transporters to the cell membrane. Irradiated GBM cells route glucose carbons through the pentose phosphate pathway (PPP) to harness the antioxidant power of the PPP and support survival after radiation. This response is regulated in part by the M2 isoform of pyruvate kinase (PKM2). Activators of PKM2 can antagonize the radiation-induced rewiring of glucose metabolism and radiosensitize GBM cells in vitro and in vivo.
    CONCLUSIONS: These findings open the possibility that interventions designed to target cancer-specific regulators of metabolic plasticity, such as PKM2, rather than specific metabolic pathways, have the potential to improve the radiotherapeutic outcomes in GBM patients.
    Keywords:  Glioblastoma; PPP; metabolism; plasticity; radiation resistance
    DOI:  https://doi.org/10.1093/neuonc/noad103
  13. Neuro Oncol. 2023 Jun 05. pii: noad102. [Epub ahead of print]
    EPIC-0307-mediated selective disruption of PRADX-EZH2 interaction and enhancement of temozolomide sensitivity to glioblastoma via inhibiting DNA repair and MGMT.
    Lei Xin, Yanli Tan, Yuanxue Zhu, Xiaoteng Cui, Qixue Wang, Jixing Zhao, Shaohui Tian, Can Xu, Menglin Xiao, Biao Hong, Jianglong Xu, Xiaoye Yuan, Changsheng Wang, Chunsheng Kang, Chuan Fang.
       BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) has been limited by resistance. The level of O-6-methylguanine-DNA methyltransferase (MGMT) and intrinsic DNA damage repair factors are important for the TMZ response in patients. Here, we reported a novel compound, called EPIC-0307, that increased TMZ sensitivity by inhibiting specific DNA damage repair proteins and MGMT expression.
    METHODS: EPIC-0307 was derived by molecular docking screening. RNA immunoprecipitation (RIP), and chromatin immunoprecipitation by RNA (ChIRP) assays were used to verify the blocking effect. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) assays were performed to explore the mechanism of EPIC-0307. A series of in vivo and in vitro experiments were designed to evaluate the efficacy of EPIC-0307 in sensitizing GBM cells to TMZ.
    RESULTS: EPIC-0307 selectively disrupted the binding of PRADX to EZH2 and upregulated the expression of P21 and PUMA, leading to cell-cycle arrest and apoptosis in GBM cells. EPIC-0307 exhibited a synergistic inhibitory effect on GBM when combined with TMZ by downregulating TMZ-induced DNA damage repair responses and epigenetically silencing MGMT expression through modulating the recruitment of ATF3-pSTAT3-HDAC1 regulatory complex to the MGMT promoter. EPIC-0307 demonstrated significant efficacy in suppressing the tumorigenesis of GBM cells, restoring TMZ sensitivity.
    CONCLUSION: This study identified a potential small-molecule inhibitor EPIC-0307 that selectively disrupted the PRADX-EZH2 interaction to upregulate expressions of tumor suppressor genes, thereby exerting its antitumor effects on GBM cells. EPIC-0307 treatment also increased the chemotherapeutic efficacy of TMZ by epigenetically downregulating DNA repair-associate genes and MGMT expression in GBM cells.
    Keywords:  DNA repair; MGMT; glioblastoma; small-molecule inhibitor; temozolomide
    DOI:  https://doi.org/10.1093/neuonc/noad102
  14. Neuro Oncol. 2023 Jun 06. pii: noad099. [Epub ahead of print]
    Upstream Open Reading Frame-encoded MP31 Disrupts the Mitochondrial Quality Control Process and Inhibits Tumorigenesis in Glioblastoma.
    Nunu Huang, Zhipeng Chen, Xuesong Yang, Yixin Gao, Jian Zhong, Yan Li, Feizhe Xiao, Xiuxing Wang, Yu Shi, Nu Zhang.
       BACKGROUND: Mitochondrial hyperpolarization achieved by the elevation of mitochondrial quality control (MQC) activity is a hallmark of glioblastoma (GBM). Therefore, targeting the MQC process to disrupt mitochondrial homeostasis should be a promising approach for GBM therapy.
    METHOD: We used two-photon fluorescence microscopy, FACS and confocal microscopy with specific fluorescent dyes to detect the mitochondrial membrane potential (MMP) and mitochondrial structures. Mitophagic flux was measured with mKeima.
    RESULTS: MP31, a PTEN uORF-translated and mitochondria-localized micropeptide, disrupted the MQC process and inhibited GBM tumorigenesis. Re-expression of MP31 in patient-derived GBM cells induced MMP loss to trigger mitochondrial fission but blocked mitophagic flux, leading to the accumulation of damaged mitochondria in cells, followed by ROS production and DNA damage. Mechanistically, MP31 inhibited lysosome function and blocked lysosome fusion with mitophagosomes by competing with V-ATPase A1 for LDHB binding to induce lysosomal alkalinization. Furthermore, MP31 enhanced the sensitivity of GBM cells to TMZ by suppressing protective mitophay in vitro and in vivo, but showed no side effects on normal human astrocytes (NHAs) or microglia cells (MG).
    CONCLUSION: MP31 disrupts cancerous mitochondrial homeostasis and sensitizes GBM cells to current chemotherapy, without inducing toxicity in NHA and MG. MP31 is a promising candidate for GBM treatment.
    Keywords:  GBM; MP31; MQC; V-ATPase A1; mitophagy
    DOI:  https://doi.org/10.1093/neuonc/noad099
  15. Neuro Oncol. 2023 Jun 02. pii: noad100. [Epub ahead of print]
    Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline.
    Felix Sahm, Sebastian Brandner, Luca Bertero, David Capper, Pim J French, Dominique Figarella-Branger, Felice Giangaspero, Christine Haberler, Monika E Hegi, Bjarne W Kristensen, Kathreena M Kurian, Matthias Preusser, Bastiaan B J Tops, Martin van den Bent, Wolfgang Wick, Guido Reifenberger, Pieter Wesseling.
      In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types. For those tumors, an integrated, 'histomolecular' diagnosis is required. A variety of approaches exists for determining the status of the underyling molecular markers. The present guideline focuses on the methods that can be used for assessment of the currently most informative diagnostic and prognostic molecular markers for the diagnosis of gliomas, glioneuronal and neuronal tumors. The main characteristics of the molecular methods are systematically discussed, followed by recommendations and information on available evidence levels for diagnostic measures. The recommendations cover DNA and RNA next-generation-sequencing, methylome profiling, and select assays for single/limited target analysis, including immunohistochemistry. Additionally, because of its importance as a predictive marker in IDH-wildtype glioblastomas, tools for the analysis of MGMT promoter status are covered. A structured overview of the different assays with their characteristics, especially their advantages and limitations, is provided, and requirements for input material and reporting of results are clarified. General aspects of molecular diagnostic testing regarding clinical relevance, accessibility, cost, implementation, regulatory and ethical aspects are discussed as well. Finally, we provide an outlook on new developments in the landscape of molecular testing technologies in neuro-oncology.
    Keywords:  WHO classification; glioma; glioneuronal tumors; molecular classification; neuronal tumors
    DOI:  https://doi.org/10.1093/neuonc/noad100
  16. Front Immunol. 2023 ;14 1183465
    Tumor-neutrophil crosstalk promotes in vitro and in vivo glioblastoma progression.
    Dominique S Rubenich, Priscila O de Souza, Natalia Omizzollo, Mariana R Aubin, Paulo J Basso, Luisa M Silva, Eloisa M da Silva, Fernanda C Teixeira, Gabriela F S Gentil, Jordana L Domagalski, Maico T Cunha, Kerolainy A Gadelha, Leonardo F Diel, Nicolly E Gelsleichter, Aline S Rubenich, Gabriela S Lenz, Aline M de Abreu, Giselle M Kroeff, Ana H Paz, Fernanda Visioli, Marcelo L Lamers, Marcia R Wink, Paulo V Worm, Anelise B Araújo, Jean Sévigny, Niels O S Câmara, Nils Ludwig, Elizandra Braganhol.
       Introduction: The tumor microenvironment (TME) of glioblastoma (GB) is characterized by an increased infiltration of immunosuppressive cells that attenuate the antitumor immune response. The participation of neutrophils in tumor progression is still controversial and a dual role in the TME has been proposed. In this study, we show that neutrophils are reprogrammed by the tumor to ultimately promote GB progression.
    Methods: Using in vitro and in vivo assays, we demonstrate the existence of bidirectional GB and neutrophil communication, directly promoting an immunosuppressive TME.
    Results and discussion: Neutrophils have shown to play an important role in tumor malignancy especially in advanced 3D tumor model and Balb/c nude mice experiments, implying a time- and neutrophil concentration-dependent modulation. Studying the tumor energetic metabolism indicated a mitochondria mismatch shaping the TME secretome. The given data suggests a cytokine milieu in patients with GB that favors the recruitment of neutrophils, sustaining an anti-inflammatory profile which is associated with poor prognosis. Besides, glioma-neutrophil crosstalk has sustained a tumor prolonged activation via NETs formation, indicating the role of NFκB signaling in tumor progression. Moreover, clinical samples have indicated that neutrophil-lymphocyte ratio (NLR), IL-1β, and IL-10 are associated with poor outcomes in patients with GB.
    Conclusion: These results are relevant for understanding how tumor progression occurs and how immune cells can help in this process.
    Keywords:  cancer; glioblastoma; neutrophil extracellular traps; tumor associated neutrophils; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1183465
  17. N Engl J Med. 2023 Jun 04.
    Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.
    Ingo K Mellinghoff, Martin J van den Bent, Deborah T Blumenthal, Mehdi Touat, Katherine B Peters, Jennifer Clarke, Joe Mendez, Shlomit Yust-Katz, Liam Welsh, Warren P Mason, François Ducray, Yoshie Umemura, Burt Nabors, Matthias Holdhoff, Andreas F Hottinger, Yoshiki Arakawa, Juan M Sepulveda, Wolfgang Wick, Riccardo Soffietti, James R Perry, Pierre Giglio, Macarena de la Fuente, Elizabeth A Maher, Steven Schoenfeld, Dan Zhao, Shuchi S Pandya, Lori Steelman, Islam Hassan, Patrick Y Wen, Timothy F Cloughesy.
       BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas.
    METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.
    RESULTS: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo.
    CONCLUSIONS: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).
    DOI:  https://doi.org/10.1056/NEJMoa2304194
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