bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–01–01
six papers selected by
Oltea Sampetrean, Keio University
  1. Small Molecule-mediated Disruption of Ribosome Biogenesis Synergizes With FGFR Inhibitors to Suppress Glioma Cell Growth.
  2. Nanobodies targeting ABCC3 for immunotargeted applications in glioblastoma.
  3. Inter and intra-tumor heterogeneity of paediatric type diffuse high-grade gliomas revealed by single-cell mass cytometry.
  4. Mitotic count is prognostic in IDH-mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trials 26053 and EORTC 22033-26033.
  5. Upfront BRAF/MEK inhibitors for treatment of high-grade glioma: A case report and review of the literature.
  6. DNA damage repair kinase DNA-PK and cGAS synergize to induce cancer-related inflammation in glioblastoma.
  1. Neuro Oncol. 2022 Dec 30. pii: noac286. [Epub ahead of print]
    Small Molecule-mediated Disruption of Ribosome Biogenesis Synergizes With FGFR Inhibitors to Suppress Glioma Cell Growth.
    Asimina Zisi, Dimitris C Kanellis, Simon Moussaud, Ida Karlsson, Helena Carén, Lars Bräutigam, Jiri Bartek, Mikael S Lindström.
       BACKGROUND: High-grade gliomas are malignant brain tumors characterized by aggressiveness and resistance to chemotherapy. Prognosis remains dismal, highlighting the need to identify novel molecular dependencies and targets. Ribosome biogenesis (RiBi), taking place in the nucleolus, represents a promising target as several cancer types rely on high RiBi rates to sustain proliferation. Publicly available transcriptomics data of glioma patients revealed a positive correlation between RiBi rates and histological grades. We, therefore, hypothesized that glioma cells could be susceptible to RiBi inhibition.
    METHODS: Transcriptomics data from glioma patients were analyzed for RiBi-related processes. BMH-21, a small molecule inhibitor of RNA polI transcription, was tested in adult and pediatric high-grade glioma cell lines and a zebrafish transplant model. Cellular phenotypes were evaluated by transcriptomics, cell cycle analysis, and viability assays. A chemical synergy screen was performed to identify drugs potentiating BMH-21-mediated effects.
    RESULTS: BMH-21 reduced glioma cell viability, induced apoptosis, and impaired the growth of transplanted glioma cells in zebrafish. Combining BMH-21 with TMZ potentiated cytotoxic effects. Moreover, BMH-21 synergized with FGFR inhibitor Erdafitinib, a top hit in the chemical synergy screen. RiBi inhibition using BMH-21, POLR1A siRNA, or Actinomycin D revealed engagement of the FGFR-FGF2 pathway. BMH-21 downregulated FGFR1 and SOX2 levels, whereas FGF2 was induced and released from the nucleolus.
    CONCLUSIONS: This study conceptualizes the implementation of RiBi inhibition as a viable future therapeutic strategy for glioma and reveals an FGFR connection to the cellular response upon RiBi inhibition with potential translational value.
    Keywords:  Combination therapy; FGFR1/FGF2 signaling; Glioblastoma; RNA polymerase I; Ribosome biogenesis
    DOI:  https://doi.org/10.1093/neuonc/noac286
  2. Sci Rep. 2022 Dec 30. 12(1): 22581
    Nanobodies targeting ABCC3 for immunotargeted applications in glioblastoma.
    Eduardo Ruiz-López, Ivana Jovčevska, Ruth González-Gómez, Héctor Tejero, Fátima Al-Shahrour, Serge Muyldermans, Alberto J Schuhmacher.
      The cancer "omics" reveal many clinically relevant alterations that are transforming the molecular characterization of glioblastomas. However, many of these findings are not yet translated into clinical practice due, in part, to the lack of non-invasive biomarkers and the limitations imposed by the blood-brain barrier. Nanobodies, camelid single-domain antibody fragments, emerge as a promising tool for immunotargeted applications for diagnosing and treating glioblastomas. Performing agnostic bioinformatic analysis from glioblastoma patient datasets, we identified ATP Binding Cassette subfamily C member 3 (ABCC3) as a suitable target for immunotargeted applications. The expression of ABCC3 is associated with poor survival and impaired response to temozolomide. Importantly, high expression of ABCC3 is restricted to glioblastoma, with negligible levels in healthy brain tissue, and further correlates with tumor grade and stemness markers. We identified three immunogenic epitopes of ABCC3 which were used to isolate nanobodies from a glioblastoma-specific phage-display nanobody library. Two nanobodies targeting ABCC3 (NbA42 and NbA213) were further characterized and demonstrated in vivo selective recognition of ABCC3 in glioblastoma xenograft mouse models upon systemic administration. We designate NbA42 and NbA213 as new candidates to implement immunotargeted applications guiding a more personalized and precise diagnosis, monitoring, and treatment of glioblastoma patients.
    DOI:  https://doi.org/10.1038/s41598-022-27161-3
  3. Front Oncol. 2022 ;12 1016343
    Inter and intra-tumor heterogeneity of paediatric type diffuse high-grade gliomas revealed by single-cell mass cytometry.
    Lucia Lisa Petrilli, Claudia Fuoco, Alessandro Palma, Luca Pasquini, Giulia Pericoli, Yura Grabovska, Alan Mackay, Sabrina Rossi, Angel M Carcaboso, Andrea Carai, Angela Mastronuzzi, Chris Jones, Gianni Cesareni, Franco Locatelli, Maria Vinci.
      Paediatric-type diffuse high-grade gliomas (PDHGG) are aggressive tumors affecting children and young adults, with no effective treatment. These highly heterogeneous malignancies arise in different sites of the Central Nervous System (CNS), carrying distinctive molecular alterations and clinical outcomes (inter-tumor heterogeneity). Moreover, deep cellular and molecular profiling studies highlighted the coexistence of genetically and phenotypically different subpopulations within the same tumor mass (intra-tumor heterogeneity). Despite the recent advances made in the field, the marked heterogeneity of PDHGGs still impedes the development of effective targeted therapies and the identification of suitable biomarkers. In order to fill the existing gap, we used mass cytometry to dissect PDHGG inter- and intra-heterogeneity. This is one of the most advanced technologies of the "-omics" era that, using antibodies conjugated to heavy metals, allows the simultaneous measurement of more than 40 markers at single-cell level. To this end, we analyzed eight PDHGG patient-derived cell lines from different locational and molecular subgroups. By using a panel of 15 antibodies, directly conjugated to metals or specifically customized to detect important histone variants, significant differences were highlighted in the expression of the considered antigens. The single-cell multiparametric approach realized has deepened our understanding of PDHGG, confirming a high degree of intra- and inter-tumoral heterogeneity and identifying some antigens that could represent useful biomarkers for the specific PDHGG locational or molecular subgroups.
    Keywords:  DIPG; DMG; GBM; heterogeneity; mass cytometry; paediatric-type diffuse high-grade gliomas (PDHGG); single-cell
    DOI:  https://doi.org/10.3389/fonc.2022.1016343
  4. Neuro Oncol. 2022 Dec 26. pii: noac282. [Epub ahead of print]
    Mitotic count is prognostic in IDH-mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trials 26053 and EORTC 22033-26033.
    Johan M Kros, Elisabeth Rushing, Aimé L Uwimana, Aurelio Hernández-Laín, Alex Michotte, Maysa Al-Hussaini, Franck Bielle, Christian Mawrin, Gianluca Marucci, C Mircea S Tesileanu, Roger Stupp, Brigitta Baumert, Martin van den Bent, Pim J French, Thierry Gorlia.
       BACKGROUND: Gliomas with IDH1/2 mutations without 1p19q codeletion have been identified as the distinct diagnostic entity of IDH mutant astrocytoma (IDHmut astrocytoma). Homozygous deletion of Cyclin-dependent kinase 4 inhibitor A/B (CDKN2A/B) has recently been incorporated in the grading of these tumors. The question of whether histologic parameters still contribute to prognostic information on top of the molecular classification, remains unanswered. Here we evaluated consensus histologic parameters for providing additional prognostic value in IDHmut astrocytomas.
    METHODS: An international panel of seven neuropathologists scored 13 well-defined histologic features in virtual microscopy images of 192 IDHmut astrocytomas from EORTC trial 22033-26033 (low-grade gliomas) and 263 from EORTC 26053 (CATNON) (1p19q non-codeleted anaplastic glioma). For 192 gliomas the CDKN2A/B status was known. Consensus (agreement ≥ 4/7 panelists) histologic features were tested together with homozygous deletion (HD) of CDKN2A/B for independent prognostic power.
    RESULTS: Among consensus histologic parameters, the mitotic count (cut-off of 2 mitoses per 10 high power fields standardized to a field diameter of 0.55 mm and an area of 0.24 mm 2) significantly influences PFS (p = 0.0098) and marginally the OS (p = 0.07). Mitotic count also significantly affects the PFS of tumors with HD CDKN2A/B, but not the OS, possibly due to limited follow-up data.
    CONCLUSION: The mitotic index (cut-off 2 per 10 40x HPF) is of prognostic significance in IDHmut astrocytomas without HD CDKN2A/B. Therefore, the mitotic index may direct the therapeutic approach for patients with IDHmut astrocytomas with native CDKN2A/B status.
    Keywords:  CDKN2A/B; IDH mutation; astrocytoma; glioma; grading; molecular pathology; prognosis; proliferation
    DOI:  https://doi.org/10.1093/neuonc/noac282
  5. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac174
    Upfront BRAF/MEK inhibitors for treatment of high-grade glioma: A case report and review of the literature.
    Gabrielle Arbour, Benjamin Ellezam, Alexander G Weil, Romain Cayrol, Magimairajan Issai Vanan, Hallie Coltin, Valérie Larouche, Craig Erker, Nada Jabado, Sébastien Perreault.
       Background: High-grade gliomas (HGG) with BRAFV600E mutation represent a unique subset of central nervous system tumors. Targeted therapies including BRAF and MEK inhibitors are now being explored as possible new treatment options.
    Methods: We report an 18-year-old female with a grade 3 pleomorphic xanthoastrocytoma treated upfront with dabrafenib and trametinib. We also conducted a systematic literature review of patients with HGG and BRAFV600E mutations treated with BRAF inhibitors.
    Results: Despite local recurrences resected surgically, the patient has been on dabrafenib and trametinib for more than 54 months. Thirty-two patients with HGG and BRAFV600E mutations treated with BRAF inhibitors were retrieved through our systematic review of the literature. Only 1 young patient with an anaplastic ganglioglioma was treated upfront with a BRAF inhibitor with a curative intent. Best response reported with radiation therapy and systemic therapy was a stable disease (SD) for 18 patients (56.3%) and progressive disease (PD) for 9 patients (28.1%). Responses to treatment regimens that included BRAF inhibitors were reported in 31 patients and included 4 complete responses (12.9%), 23 partial responses (74.2%), 2 SDs (6.5%), and 2 PDs (6.5%).
    Conclusions: Our patient had durable disease control with dabrafenib and trametinib. Given favorable responses reported in patients with HGG treated with BRAF inhibitors, we believe that upfront targeted therapy is a possible treatment approach that should be studied in the context of a clinical trial.
    Keywords:  BRAF V600E; BRAF inhibitors; MEK inhibitors; high-grade glioma
    DOI:  https://doi.org/10.1093/noajnl/vdac174
  6. EMBO J. 2022 Dec 27. e111961
    DNA damage repair kinase DNA-PK and cGAS synergize to induce cancer-related inflammation in glioblastoma.
    Clara Taffoni, Johanna Marines, Hanane Chamma, Soumyabrata Guha, Mathilde Saccas, Amel Bouzid, Ana-Luiza Chaves Valadao, Clément Maghe, Jane Jardine, Mi Kyung Park, Katarzyna Polak, Mara De Martino, Claire Vanpouille-Box, Maguy Del Rio, Celine Gongora, Julie Gavard, Nicolas Bidère, Min Sup Song, Donovan Pineau, Jean-Philippe Hugnot, Karima Kissa, Laura Fontenille, Fabien P Blanchet, Isabelle K Vila, Nadine Laguette.
      Cytosolic DNA promotes inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that show undetectable cGAS levels to address if alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex (i) drives cGAS-independent IRF3-mediated type I Interferon responses and (ii) that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment in a glioblastoma model, a process that impairs early tumorigenesis but correlates with poor outcome in glioblastoma patients. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity.
    Keywords:  DNA-PK; cGAS; inflammation; tumor immunogenicity
    DOI:  https://doi.org/10.15252/embj.2022111961
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