bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–10–20
ten papers selected by
Oltea Sampetrean, Keio University
  1. Pivotal Role of Cranial Irradiation-Induced Peripheral, Intrinsic, and Brain-Engrafting Macrophages in Malignant Glioma.
  2. Immunotherapy for glioblastoma: current state, challenges, and future perspectives.
  3. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.
  4. The EP3-ZNF488 Axis Promotes Self-Renewal of Glioma Stem-like Cells to Induce Resistance to Tumor Treating Fields.
  5. MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes.
  6. Microglia and monocyte-derived macrophages drive progression of pediatric high-grade gliomas and are transcriptionally shaped by histone mutations.
  7. Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint-blocking monoclonal antibodies in patients with recurrent high-grade glioma.
  8. Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection - Update 1.
  9. Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders.
  10. Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma.
  1. Clin Med Insights Oncol. 2024 ;18 11795549241282098
    Pivotal Role of Cranial Irradiation-Induced Peripheral, Intrinsic, and Brain-Engrafting Macrophages in Malignant Glioma.
    Seidu A Richard, Sagor Kumar Roy, Emmanuel Akomanin Asiamah.
      Malignant (high-grade) gliomas are aggressive intrinsic brain tumors that diffusely infiltrate the brain parenchyma. They comprise of World Health Organization (WHO) grade III and IV gliomas. Ionizing radiation or irradiation (IR) is frequently utilized in the treatment of both primary as well as metastatic brain tumors. On the contrary, macrophages (MΦ) are the most copious infiltrating immune cells of all the different cell types colonizing glioma. MΦ at tumor milieu are referred to as tumor-associated macrophages (TAMΦ). In malignant gliomas milieu, TAMΦ are also polarized into two distinct phenotypes such as M1 TAMΦ or M2 TAMΦ, which are capable of inhibiting or promoting tumor growth, respectively. Cranial-IR such as x- and γ-IR are sufficient to induce the migration of peripherally derived MΦ into the brain parenchyma. The IR facilitate a more immunosuppressive milieu via the stimulation of efferocytosis in TAMΦ, and an upsurge of tumor cell engulfment by TAMΦ exhibited detrimental effect of the anti-tumoral immune response in glioma. The MΦ inside the tumor mass are associated with multiple phenomena that include IR resistance and enrichment of the M2 MΦ after IR is able to facilitate glioblastoma multiforme (GBM) recurrence. Reviews on the role of cranial IR-induced peripheral and brain-engrafting macrophages (BeMΦ) in glioma are lacking. Specifically, most studies on peripheral, intrinsic as well as beMΦ on IR focus on WHO grade III and IV. Thus, this review precisely focuses primary on WHO grade III as well as IV gliomas.
    Keywords:  Irradiation; glioma; macrophages; malignant; radioresistance; radiosensitization
    DOI:  https://doi.org/10.1177/11795549241282098
  2. Cell Mol Immunol. 2024 Oct 15.
    Immunotherapy for glioblastoma: current state, challenges, and future perspectives.
    Yang Liu, Fei Zhou, Heba Ali, Justin D Lathia, Peiwen Chen.
      Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.
    Keywords:  Adoptive T-cell therapies; Glioblastoma; Immune checkpoint inhibitors (ICIs); Immunotherapy combination; Oncolytic viral therapies; Tumor vaccines
    DOI:  https://doi.org/10.1038/s41423-024-01226-x
  3. Nat Commun. 2024 Oct 17. 15(1): 8983
    Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.
    Nneka E Mbah, Amy L Myers, Peter Sajjakulnukit, Chan Chung, Joyce K Thompson, Hanna S Hong, Heather Giza, Derek Dang, Zeribe C Nwosu, Mengrou Shan, Stefan R Sweha, Daniella D Maydan, Brandon Chen, Li Zhang, Brian Magnuson, Zirui Zhu, Megan Radyk, Brooke Lavoie, Viveka Nand Yadav, Imhoi Koo, Andrew D Patterson, Daniel R Wahl, Luigi Franchi, Sameer Agnihotri, Carl J Koschmann, Sriram Venneti, Costas A Lyssiotis.
      H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.
    DOI:  https://doi.org/10.1038/s41467-024-52973-4
  4. Cancer Res. 2024 Oct 16.
    The EP3-ZNF488 Axis Promotes Self-Renewal of Glioma Stem-like Cells to Induce Resistance to Tumor Treating Fields.
    Dongjiang Chen, Son B Le, Harshit Manektalia, Tianyi Liu, Tarun E Hutchinson, Adam O'Dell, Bodour Salhia, David D Tran.
      Tumor Treating Fields (TTFields) employ low-intensity, alternating electric fields to exert antitumor activity and have demonstrated efficacy against multiple cancers, including glioblastoma (GBM). Unfortunately, cancer cells inevitably develop resistance to TTFields, highlighting the need to elucidate the underlying mechanisms to develop approaches to induce durable responses. Using a gene network-based machine-learning algorithm, we interrogated TTFields-resistant GBM cells and uncovered a regulatory axis anchored by the prostaglandin E receptor 3 (EP3) and the transcription factor zinc finger 488 (ZNF488). Mechanistically, TTFields induced EP3 upregulation and nuclear envelope localization, where it formed a complex with ZNF488 to induce resistance to TTFields by promoting self-renewal of glioma stem-like cells (GSC). Overexpression of EP3 and/or ZNF488 in TTFields-sensitive GSC conferred resistance and enhanced self-renewal, while expression of non-interacting mutants of these proteins abrogated formation of the nuclear complex and prevented resistance. Inhibition of either partner in this protein complex in resistant GSC, including those freshly isolated from TTFields-resistant GBM tumors, re-sensitized cells to the cytotoxic effects of TTFields, concomitant with reduced self-renewal and in vivo tumorigenicity. Importantly, inhibition of EP3 in TTFields-sensitive GSC preemptively halted the development of resistance. The EP3-ZNF488 axis was significantly upregulated in TTFields-resistant GBM tumors, and co-expression of EP3 and ZNF488 in other cancers correlated with lower survival rates. Collectively, these results indicate that the nuclear EP3-ZNF488 axis is necessary and sufficient to establish TTFields resistance, underscoring the potential to target this axis to prevent or reverse resistance in GBM and possibly other cancers.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3643
  5. Acta Neuropathol. 2024 Oct 18. 148(1): 54
    MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes.
    Hye-Jung Chung, Sharika Rajan, Zhichao Wu, Christina K Ferrone, Mark Raffeld, Ina Lee, Jeffrey Gagan, Christopher Dampier, Zied Abdullaev, Manoj Tyagi, Patrick J Cimino, Martha Quezado, Kenneth Aldape.
      Astrocytomas that harbor recurrent genomic alterations in MYB or MYBL1 are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in MYB or MYBL1. In this report, we examine 14 consecutive cases in which a MYB or MYBL1 alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, MYB- or MYBL1-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the MYB or MYBL1 genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the MYB(L1) genes, regardless of the presence of a productive fusion. In addition, QKI, a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising >1000 CNS tumors of various types, regardless of whether a genomic alteration in QKI was present. Overall, the results show that truncations, in the absence of a productive fusion, of the MYB(L1) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, MYB- or MYBL1-altered, especially for cases that are tested on panels designed to focus on fusion detection.
    Keywords:   MYB ; MYBL1 ; Glioma
    DOI:  https://doi.org/10.1007/s00401-024-02803-0
  6. Immunity. 2024 Oct 08. pii: S1074-7613(24)00451-5. [Epub ahead of print]
    Microglia and monocyte-derived macrophages drive progression of pediatric high-grade gliomas and are transcriptionally shaped by histone mutations.
    James L Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Piñero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda M Tsankova, Maria G Castro, Matthew Schniederjan, Nitin R Wadhwani, G Praveen Raju, Peter Morgenstern, Oren J Becher, Adam L Green, Alexander M Tsankov, Dolores Hambardzumyan.
      Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent de novo mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them.
    Keywords:  CCR1; CCR5; TAM; diffuse midline glioma; disease-associated macrophage; high-grade glioma; macrophage; microglia; monocyte; pediatric glioma
    DOI:  https://doi.org/10.1016/j.immuni.2024.09.007
  7. Neuro Oncol. 2024 Oct 16. pii: noae177. [Epub ahead of print]
    Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint-blocking monoclonal antibodies in patients with recurrent high-grade glioma.
    Johnny Duerinck, Louise Lescrauwaet, Iris Dirven, Jacomi Del'haye, Latoya Stevens, Xenia Geeraerts, Freya Vaeyens, Wietse Geens, Stefanie Brock, Anne-Marie Vanbinst, Hendrik Everaert, Ben Caljon, Michaël Bruneau, Laetitia Lebrun, Isabelle Salmon, Marc Kockx, Sandra Tuyaerts, Bart Neyns.
       BACKGROUND: Recurrent high-grade glioma (rHGG) lacks effective life-prolonging treatments and the efficacy of systemic PD-1 and CTLA-4 immune checkpoint inhibitors is limited. The multi-cohort Glitipni phase I trial investigates the safety and feasibility of intraoperative intracerebral (iCer) and postoperative intracavitary (iCav) nivolumab (NIVO) ± ipilimumab (IPI) treatment following maximal safe resection (MSR) in rHGG.
    MATERIALS AND METHODS: Patients received 10 mg IV NIVO within 24 h before surgery, followed by MSR, iCer 5 mg IPI and 10 mg NIVO, and Ommaya catheter placement in the resection cavity. Biweekly postoperative iCav administrations of 1-5-10 mg NIVO (cohort 4) or 10 mg NIVO plus 1-5-10 mg IPI (cohort 7) were combined with 10 mg IV NIVO for 11 cycles.
    RESULTS: 42 rHGG patients underwent MSR with iCer NIVO + IPI. 16 pts were treated in cohort 4 (postoperative iCav NIVO at escalating doses) while 28 patients were treated in cohort 7 (intra and postoperative iCav NIVO and escalating doses of IPI). The most common TRAE was fatigue; no grade 5 AE occurred. Dose-limiting toxicity was grade 3 neutrophilic pleocytosis (4 pts) receiving iCav NIVO plus 5 or 10 mg IPI. PFS and OS did not significantly differ between cohorts (median OS: 42 [95% CI 26-57] vs. 35 [29-40] weeks; 1-year OS rate: 37% vs. 29%). Baseline B7-H3 expression significantly correlated with worse survival. OS compared favorably to a historical pooled cohort (n = 469) of Belgian rHGG pts treated with anti-VEGF therapies (log-rank P = .015).
    CONCLUSION: Intraoperative iCer IPI + NIVO with postoperative iCav NIVO ± IPI up to biweekly doses of 1 mg IPI + 10 mg NIVO is feasible and safe, showing encouraging OS in rHGG patients. ClinicalTrials.gov registration: NCT03233152.
    Keywords:  glioblastoma; high-grade glioma; immune checkpoint inhibition; immunotherapy; local administration
    DOI:  https://doi.org/10.1093/neuonc/noae177
  8. Neuro Oncol. 2024 Oct 10. pii: noae213. [Epub ahead of print]
    Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection - Update 1.
    Martin J van den Bent, Enrico Franceschi, Mehdi Touat, Pim J French, Ahmed Idbaih, Giuseppe Lombardi, Roberta Rudaà, Leonille Schweizer, David Capper, Marc Sanson, Pieter Wesseling, Michael Weller, Marica Eoli, Elena Anghileri, Franck Bielle, Phillipp Euskirchen, Marjolein Geurts, Patrick Y Wen, Matthias Preusser.
      The standard of care for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment, however, the predictive significance of most of the targets for treatment in systemic cancer are less well established in central nervous system (CNS) tumors . In 2023 the EANO Guideline Committee presented evidence based recommendations for rational testing of molecular targets for targeted treatments. From all targets reviewed, only testing for BRAF V600E mutations was of proven clinical benefit; despite regulatory approvals for tumor agnostic treatment of NTRK gene fusions and high Tumor Mutational Burden (TMB) for patients with adult brain tumors, the evidence of clinical benefit for patients was still limited . This guideline has a modular structure, allowing regular updating of individual sections and adding new ones. The present version (Update 1) presents a review of the rationale of testing for PTEN, H3F3A, MTAP, RET and IDH, and presents an update of the text on TMB high and mismatch repair deficiency. It also presents an overview of therapeutic yield of routine next generation sequencing for mutations and fusion detection. The supplement accompanying this version contains the in depth review of all targets, whereas in the main manuscript the final recommendations of the revised and new targets are presented. Updates will be made on a regular basis.
    Keywords:  (glio)neuronal tumors; Diffuse glioma; EANO guideline; IDH; targeted treatment
    DOI:  https://doi.org/10.1093/neuonc/noae213
  9. Nat Biomed Eng. 2024 Oct 17.
    Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders.
    Zhen Xia, Qihan Jin, Zhilin Long, Yexuan He, Fuyi Liu, Chengfang Sun, Jinyang Liao, Chun Wang, Chentong Wang, Jian Zheng, Weixi Zhao, Tianxin Zhang, Jeremy N Rich, Yongdeng Zhang, Longxing Cao, Qi Xie.
      Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers.
    DOI:  https://doi.org/10.1038/s41551-024-01258-8
  10. Neuro Oncol. 2024 Oct 12. pii: noae215. [Epub ahead of print]
    Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma.
    Matthew Gallitto, Xu Zhang, Genesis De Los Santos, Hong-Jian Wei, Ester Calvo Fernández, Shoufu Duan, Geoffrey Sedor, Nina Yoh, Danae Kokosi, J Carlos Angel, Yi-Fang Wang, Erin White, Connor J Kinslow, Xander Berg, Lorenzo Tomassoni, Fereshteh Zandkarimi, Iok In Christine Chio, Peter D Canoll, Jeffrey N Bruce, Neil A Feldstein, Robyn D Gartrell, Simon Cheng, James H Garvin, Stergios Zacharoulis, Robert J Wechsler-Reya, Jovana Pavisic, Andrea Califano, Zhiguo Zhang, Cheng-Chia Wu.
       BACKGROUND: Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT). Successful implementation of radiosensitization strategies in DMG remains an essential and promising avenue of investigation. We explore the use of Napabucasin, an NAD(P)H quinone dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS)-inducer, as a potential therapeutic radiosensitizer in DMG.
    METHODS: In this study, we conduct in vitro and in vivo assays using patient-derived DMG cultures to elucidate the mechanism of action of Napabucasin and its radiosensitizing properties. As penetration of systemic therapy through the blood-brain barrier (BBB) is a significant limitation to the success of DMG therapies, we explore focused ultrasound (FUS) and convection-enhanced delivery (CED) to overcome the BBB and maximize therapeutic efficacy.
    RESULTS: Napabucasin is a potent ROS-inducer and radiosensitizer in DMG, and treatment-mediated ROS production and cytotoxicity are dependent on NQO1. In subcutaneous xenograft models, combination therapy with RT improves local control. After optimizing targeted drug delivery using CED in an orthotopic mouse model, we establish the novel feasibility and survival benefit of CED of Napabucasin concurrent with RT.
    CONCLUSIONS: As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.
    Keywords:  Radiosensitization; blood-brain barrier; convection-enhanced drug delivery; diffuse midline glioma; focused ultrasound
    DOI:  https://doi.org/10.1093/neuonc/noae215
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