bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–05–28
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Mitochondria Transfer Enhances Tumorigenicity in Glioblastoma.
  2. Convection-enhanced delivery of immunomodulatory therapy for high-grade glioma.
  3. PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma.
  4. AAV-Mediated Gene Delivery of LIGHT Prolongs Survival in Glioblastoma.
  5. Current approaches in enhancing TRAIL therapies in glioblastoma.
  6. Antibody-cytokine fusion breathes new life into glioblastoma therapy.
  7. Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell-dependent regression of glioblastoma.
  8. Taming Glioblastoma in "Real Time": Integrating Multimodal Advanced Neuroimaging/AI Tools Towards Creating a Robust and Therapy Agnostic Model for Response Assessment in Neuro-Oncology.
  9. CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis.
  10. A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment.
  11. A skull bone marrow niche for antitumour neutrophils in glioblastoma.
  1. Cancer Discov. 2023 May 26. OF1
    Mitochondria Transfer Enhances Tumorigenicity in Glioblastoma.
      Glioblastoma cells acquire mitochondria from astrocytes in a GAP43-dependent manner.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-080
  2. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad044
    Convection-enhanced delivery of immunomodulatory therapy for high-grade glioma.
    Colin P Sperring, Michael G Argenziano, William M Savage, Damian E Teasley, Pavan S Upadhyayula, Nathan J Winans, Peter Canoll, Jeffrey N Bruce.
      The prognosis for glioblastoma has remained poor despite multimodal standard of care treatment, including temozolomide, radiation, and surgical resection. Further, the addition of immunotherapies, while promising in a number of other solid tumors, has overwhelmingly failed in the treatment of gliomas, in part due to the immunosuppressive microenvironment and poor drug penetrance to the brain. Local delivery of immunomodulatory therapies circumvents some of these challenges and has led to long-term remission in select patients. Many of these approaches utilize convection-enhanced delivery (CED) for immunological drug delivery, allowing high doses to be delivered directly to the brain parenchyma, avoiding systemic toxicity. Here, we review the literature encompassing immunotherapies delivered via CED-from preclinical model systems to clinical trials-and explore how their unique combination elicits an antitumor response by the immune system, decreases toxicity, and improves survival among select high-grade glioma patients.
    Keywords:  convection-enhanced delivery; drug delivery; glioma; immunotherapy
    DOI:  https://doi.org/10.1093/noajnl/vdad044
  3. Cancer Res. 2023 May 23. pii: CAN-22-3382. [Epub ahead of print]
    PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma.
    Isha Mondal, Oishika Das, Raymond Sun, Jian Gao, Bohyeon Yu, Aaron Diaz, Jinan Behnan, Abhishek Dubey, Zhipeng Meng, Emad Eskandar, Beisi Xu, Rongze Olivia Lu, Winson S Ho.
      Glioblastoma (GBM) is an immunologically "cold" tumor that does not respond to current immunotherapy. Here, we demonstrate a fundamental role for the α-isoform of the catalytic subunit of protein phosphatase-2A (PP2Ac) in regulating glioma immunogenicity. Genetic ablation of PP2Ac in glioma cells enhanced double stranded DNA (dsDNA) production and cGAS-type I interferon (IFN) signaling, MHC-I expression, and tumor mutational burden. In co-culture experiments, PP2Ac deficiency in glioma cells promoted dendritic cell (DC) cross presentation and clonal expansion of CD8+ T cells. In vivo, PP2Ac depletion sensitized tumors to immune checkpoint blockade and radiotherapy treatment. Single cell analysis demonstrated that PP2Ac deficiency increased CD8+ T cell, NK cell, and DC accumulation and reduced immunosuppressive tumor associated macrophages. Furthermore, loss of PP2Ac increased IFN signaling in myeloid and tumor cells and reduced expression of a tumor gene signature associated with worse patient survival in TCGA. Collectively, this study establishes a novel role for PP2Ac in inhibiting dsDNA-cGAS-STING signaling to suppress anti-tumor immunity in glioma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3382
  4. Cancer Discov. 2023 May 26. OF1
    AAV-Mediated Gene Delivery of LIGHT Prolongs Survival in Glioblastoma.
      Therapeutic induction of LIGHT using an adeno-associated viral vector prolongs survival in glioblastoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-078
  5. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad047
    Current approaches in enhancing TRAIL therapies in glioblastoma.
    Morrent Thang, Clara Mellows, Alison Mercer-Smith, Phuong Nguyen, Shawn Hingtgen.
      Glioblastoma (GBM) is the most prevalent, aggressive, primary brain cancer in adults and continues to pose major medical challenges due in part to its high rate of recurrence. Extensive research is underway to discover new therapies that target GBM cells and prevent the inevitable recurrence in patients. The pro-apoptotic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted attention as an ideal anticancer agent due to its ability to selectively kill cancer cells with minimal toxicity in normal cells. Although initial clinical evaluations of TRAIL therapies in several cancers were promising, later stages of clinical trial results indicated that TRAIL and TRAIL-based therapies failed to demonstrate robust efficacies due to poor pharmacokinetics, resulting in insufficient concentrations of TRAIL at the therapeutic site. However, recent studies have developed novel ways to prolong TRAIL bioavailability at the tumor site and efficiently deliver TRAIL and TRAIL-based therapies using cellular and nanoparticle vehicles as drug loading cargos. Additionally, novel techniques have been developed to address monotherapy resistance, including modulating biomarkers associated with TRAIL resistance in GBM cells. This review highlights the promising work to overcome the challenges of TRAIL-based therapies with the aim to facilitate improved TRAIL efficacy against GBM.
    Keywords:  TRAIL-sensitizing agents; gene and cell therapy; glioblastoma; nanoparticle-mediated delivery; tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
    DOI:  https://doi.org/10.1093/noajnl/vdad047
  6. Sci Transl Med. 2023 May 24. 15(697): eadh7674
    Antibody-cytokine fusion breathes new life into glioblastoma therapy.
    Juyeun Lee, Michael Nicosia, Justin D Lathia.
      An antibody-cytokine fusion molecule combined with chemotherapy induces tumor regression in mice and patients with recurrent glioblastoma by boosting antitumor immunity (Look et al.).
    DOI:  https://doi.org/10.1126/scitranslmed.adh7674
  7. Sci Transl Med. 2023 May 24. 15(697): eadf2281
    Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell-dependent regression of glioblastoma.
    Thomas Look, Emanuele Puca, Marcel Bühler, Daniel Kirschenbaum, Roberto De Luca, Riccardo Stucchi, Domenico Ravazza, Cesare Di Nitto, Patrick Roth, Yonatan Katzenelenbogen, Assaf Weiner, Lukas Rindlisbacher, Burkhard Becher, Ido Amit, Michael Weller, Dario Neri, Teresa Hemmerle, Tobias Weiss.
      Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here, we investigated combination therapies based on L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes to cancer neovasculature. Using immunocompetent orthotopic glioma mouse models, we identified strong anti-glioma activity of L19TNF in combination with the alkylating agent CCNU, which cured the majority of tumor-bearing mice, whereas monotherapies only had limited efficacy. In situ and ex vivo immunophenotypic and molecular profiling in the mouse models revealed that L19TNF and CCNU induced tumor DNA damage and treatment-associated tumor necrosis. In addition, this combination also up-regulated tumor endothelial cell adhesion molecules, promoted the infiltration of immune cells into the tumor, induced immunostimulatory pathways, and decreased immunosuppression pathways. MHC immunopeptidomics demonstrated that L19TNF and CCNU increased antigen presentation on MHC class I molecules. The antitumor activity was T cell dependent and completely abrogated in immunodeficient mouse models. On the basis of these encouraging results, we translated this treatment combination to patients with glioblastoma. The clinical translation is ongoing but already shows objective responses in three of five patients in the first recurrent glioblastoma patient cohort treated with L19TNF in combination with CCNU (NCT04573192).
    DOI:  https://doi.org/10.1126/scitranslmed.adf2281
  8. Clin Cancer Res. 2023 May 25. OF1-OF5
    Taming Glioblastoma in "Real Time": Integrating Multimodal Advanced Neuroimaging/AI Tools Towards Creating a Robust and Therapy Agnostic Model for Response Assessment in Neuro-Oncology.
    Laiz Laura de Godoy, Sanjeev Chawla, Steven Brem, Suyash Mohan.
      The highly aggressive nature of glioblastoma carries a dismal prognosis despite aggressive multimodal therapy. Alternative treatment regimens, such as immunotherapies, are known to intensify the inflammatory response in the treatment field. Follow-up imaging in these scenarios often mimics disease progression on conventional MRI, making accurate evaluation extremely challenging. To this end, revised criteria for assessment of treatment response in high-grade gliomas were successfully proposed by the RANO Working Group to distinguish pseudoprogression from true progression, with intrinsic constraints related to the postcontrast T1-weighted MRI sequence. To address these existing limitations, our group proposes a more objective and quantifiable "treatment agnostic" model, integrating into the RANO criteria advanced multimodal neuroimaging techniques, such as diffusion tensor imaging (DTI), dynamic susceptibility contrast-perfusion weighted imaging (DSC-PWI), dynamic contrast enhanced (DCE)-MRI, MR spectroscopy, and amino acid-based positron emission tomography (PET) imaging tracers, along with artificial intelligence (AI) tools (radiomics, radiogenomics, and radiopathomics) and molecular information to address this complex issue of treatment-related changes versus tumor progression in "real-time", particularly in the early posttreatment window. Our perspective delineates the potential of incorporating multimodal neuroimaging techniques to improve consistency and automation for the assessment of early treatment response in neuro-oncology.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0009
  9. Cancer Cell. 2023 May 18. pii: S1535-6108(23)00168-X. [Epub ahead of print]
    CDKN2A deletion remodels lipid metabolism to prime glioblastoma for ferroptosis.
    Jenna K Minami, Danielle Morrow, Nicholas A Bayley, Elizabeth G Fernandez, Jennifer J Salinas, Christopher Tse, Henan Zhu, Baolong Su, Rhea Plawat, Anthony Jones, Alessandro Sammarco, Linda M Liau, Thomas G Graeber, Kevin J Williams, Timothy F Cloughesy, Scott J Dixon, Steven J Bensinger, David A Nathanson.
      Malignant tumors exhibit heterogeneous metabolic reprogramming, hindering the identification of translatable vulnerabilities for metabolism-targeted therapy. How molecular alterations in tumors promote metabolic diversity and distinct targetable dependencies remains poorly defined. Here we create a resource consisting of lipidomic, transcriptomic, and genomic data from 156 molecularly diverse glioblastoma (GBM) tumors and derivative models. Through integrated analysis of the GBM lipidome with molecular datasets, we identify CDKN2A deletion remodels the GBM lipidome, notably redistributing oxidizable polyunsaturated fatty acids into distinct lipid compartments. Consequently, CDKN2A-deleted GBMs display higher lipid peroxidation, selectively priming tumors for ferroptosis. Together, this study presents a molecular and lipidomic resource of clinical and preclinical GBM specimens, which we leverage to detect a therapeutically exploitable link between a recurring molecular lesion and altered lipid metabolism in GBM.
    Keywords:  CDKN2A; GPX4; RNA sequencing; ferroptosis; glioblastoma; lipid droplet; lipid peroxidation; shotgun lipidomics; triacylglyceride
    DOI:  https://doi.org/10.1016/j.ccell.2023.05.001
  10. iScience. 2023 May 19. 26(5): 106687
    A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment.
    Diana Pelizzari-Raymundo, Dimitrios Doultsinos, Raphael Pineau, Chloé Sauzay, Thodoris Koutsandreas, Timothy Langlais, Antonio Carlesso, Elena Gkotsi, Luc Negroni, Tony Avril, Aristotelis Chatziioannou, Eric Chevet, Leif A Eriksson, Xavier Guillory.
      Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood-brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB.
    Keywords:  Biological sciences; Medicine; Molecular neuroscience; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2023.106687
  11. Nat Rev Immunol. 2023 May 26.
    A skull bone marrow niche for antitumour neutrophils in glioblastoma.
    Austeja Baleviciute, Lily Keane.
      
    DOI:  https://doi.org/10.1038/s41577-023-00895-5
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