bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–11–26
ten papers selected by
Oltea Sampetrean, Keio University
  1. LncRNA INHEG promotes glioma stem cell maintenance and tumorigenicity through regulating rRNA 2'-O-methylation.
  2. Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families.
  3. Exploiting iron metabolism as a therapeutic vulnerability in glioblastoma.
  4. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma.
  5. Efficacy of combined tumor irradiation and KCa3.1-targeting with TRAM-34 in a syngeneic glioma mouse model.
  6. Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?
  7. EGFR promotes ALKBH5 nuclear retention to attenuate N6-methyladenosine and protect against ferroptosis in glioblastoma.
  8. Drivers of heterogeneity in the glioblastoma immune microenvironment.
  9. Adhesion GPCRs in glioblastoma revisited.
  10. Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures.
  1. Nat Commun. 2023 11 18. 14(1): 7526
    LncRNA INHEG promotes glioma stem cell maintenance and tumorigenicity through regulating rRNA 2'-O-methylation.
    Lihui Liu, Ziyang Liu, Qinghua Liu, Wei Wu, Peng Lin, Xing Liu, Yuechuan Zhang, Dongpeng Wang, Briana C Prager, Ryan C Gimple, Jichuan Yu, Weixi Zhao, Qiulian Wu, Wei Zhang, Erzhong Wu, Xiaomin Chen, Jianjun Luo, Jeremy N Rich, Qi Xie, Tao Jiang, Runsheng Chen.
      Glioblastoma (GBM) ranks among the most lethal of human cancers, containing glioma stem cells (GSCs) that display therapeutic resistance. Here, we report that the lncRNA INHEG is highly expressed in GSCs compared to differentiated glioma cells (DGCs) and promotes GSC self-renewal and tumorigenicity through control of rRNA 2'-O-methylation. INHEG induces the interaction between SUMO2 E3 ligase TAF15 and NOP58, a core component of snoRNP that guides rRNA methylation, to regulate NOP58 sumoylation and accelerate the C/D box snoRNP assembly. INHEG activation enhances rRNA 2'-O-methylation, thereby increasing the expression of oncogenic proteins including EGFR, IGF1R, CDK6 and PDGFRB in glioma cells. Taken together, this study identifies a lncRNA that connects snoRNP-guided rRNA 2'-O-methylation to upregulated protein translation in GSCs, supporting an axis for potential therapeutic targeting of gliomas.
    DOI:  https://doi.org/10.1038/s41467-023-43113-5
  2. Acta Neuropathol Commun. 2023 Nov 21. 11(1): 184
    Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families.
    Christine A M Weber, Nicole Krönke, Valery Volk, Bernd Auber, Alisa Förster, Detlef Trost, Robert Geffers, Majid Esmaeilzadeh, Michael Lalk, Arya Nabavi, Amir Samii, Joachim K Krauss, Friedrich Feuerhake, Christian Hartmann, Bettina Wiese, Frank Brand, Ruthild G Weber.
      Pathogenic germline variants in the DNA polymerase genes POLE and POLD1 cause polymerase proofreading-associated polyposis, a dominantly inherited disorder with increased risk of colorectal carcinomas and other tumors. POLE/POLD1 variants may result in high somatic mutation and neoantigen loads that confer susceptibility to immune checkpoint inhibitors (ICIs). To explore the role of POLE/POLD1 germline variants in glioma predisposition, whole-exome sequencing was applied to leukocyte DNA of glioma patients from 61 tumor families with at least one glioma case each. Rare heterozygous POLE/POLD1 missense variants predicted to be deleterious were identified in glioma patients from 10 (16%) families, co-segregating with the tumor phenotype in families with available DNA from several tumor patients. Glioblastoma patients carrying rare POLE variants had a mean overall survival of 21 months. Additionally, germline variants in POLD1, located at 19q13.33, were detected in 2/34 (6%) patients with 1p/19q-codeleted oligodendrogliomas, while POLE variants were identified in 2/4 (50%) glioblastoma patients with a spinal metastasis. In 13/15 (87%) gliomas from patients carrying POLE/POLD1 variants, features of defective polymerase proofreading, e.g. hypermutation, POLE/POLD1-associated mutational signatures, multinucleated cells, and increased intratumoral T cell response, were observed. In a CRISPR/Cas9-derived POLE-deficient LN-229 glioblastoma cell clone, a mutator phenotype and delayed S phase progression were detected compared to wildtype POLE cells. Our data provide evidence that rare POLE/POLD1 germline variants predispose to gliomas that may be susceptible to ICIs. Data compiled here suggest that glioma patients carrying POLE/POLD1 variants may be recognized by cutaneous manifestations, e.g. café-au-lait macules, and benefit from surveillance colonoscopy.
    Keywords:  Glioma risk; Immune checkpoint inhibitors; POLD1; POLE; Polymerase proofreading defect
    DOI:  https://doi.org/10.1186/s40478-023-01689-5
  3. Clin Cancer Res. 2023 Nov 20.
    Exploiting iron metabolism as a therapeutic vulnerability in glioblastoma.
    Ali Nabavizadeh, Stephen J Bagley.
      In this CCR Translations, we discuss pharmacological ascorbate as a novel therapeutic for glioblastoma. Aberrant iron metabolism in glioblastoma can be assessed noninvasively by MRI and exploited to potentially improve the efficacy of chemoradiotherapy. We contextualize the study's results and discuss the next steps to further develop this paradigm.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3027
  4. JCI Insight. 2023 Nov 22. pii: e167081. [Epub ahead of print]8(22):
    Quisinostat is a brain-penetrant radiosensitizer in glioblastoma.
    Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna-Melendez, James B McNamara, Connor I White, William Knight, Saisrinidhi Ganta, Zorana Opachich, Claudia Cantoni, Wonsuk Yoo, Nader Sanai, Artak Tovmasyan, Shwetal Mehta.
      Histone deacetylase (HDAC) inhibitors have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDAC inhibitors have failed to provide substantial clinical benefit to patients with glioblastoma (GBM) to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. Although no isoform-specific HDAC inhibitors are currently available, the second-generation hydroxamic acid-based HDAC inhibitor quisinostat possesses subnanomolar specificity for class I HDAC isoforms, particularly HDAC1 and HDAC2. It has been shown that HDAC1 is the essential HDAC in GBM. This study analyzed the neuropharmacokinetic, pharmacodynamic, and radiation-sensitizing properties of quisinostat in preclinical models of GBM. It was found that quisinostat is a well-tolerated and brain-penetrant molecule that extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.
    Keywords:  Brain cancer; Drug therapy; Oncology; Radiation therapy; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.167081
  5. Sci Rep. 2023 Nov 23. 13(1): 20604
    Efficacy of combined tumor irradiation and KCa3.1-targeting with TRAM-34 in a syngeneic glioma mouse model.
    Nicolai Stransky, Katrin Ganser, Leticia Quintanilla-Martinez, Irene Gonzalez-Menendez, Ulrike Naumann, Franziska Eckert, Pierre Koch, Stephan M Huber, Peter Ruth.
      The intermediate-conductance calcium-activated potassium channel KCa3.1 has been proposed to be a new potential target for glioblastoma treatment. This study analyzed the effect of combined irradiation and KCa3.1-targeting with TRAM-34 in the syngeneic, immune-competent orthotopic SMA-560/VM/Dk glioma mouse model. Whereas neither irradiation nor TRAM-34 treatment alone meaningfully prolonged the survival of the animals, the combination significantly prolonged the survival of the mice. We found an irradiation-induced hyperinvasion of glioma cells into the brain, which was inhibited by concomitant TRAM-34 treatment. Interestingly, TRAM-34 did neither radiosensitize nor impair SMA-560's intrinsic migratory capacities in vitro. Exploratory findings hint at increased TGF-β1 signaling after irradiation. On top, we found a marginal upregulation of MMP9 mRNA, which was inhibited by TRAM-34. Last, infiltration of CD3+, CD8+ or FoxP3+ T cells was not impacted by either irradiation or KCa3.1 targeting and we found no evidence of adverse events of the combined treatment. We conclude that concomitant irradiation and TRAM-34 treatment is efficacious in this preclinical glioma model.
    DOI:  https://doi.org/10.1038/s41598-023-47552-4
  6. Neuro Oncol. 2023 Nov 23. pii: noad211. [Epub ahead of print]
    Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?
    Ethan Chen, Alexander L Ling, David A Reardon, E Antonio Chiocca.
      Glioblastoma (GBM)'s median overall survival is almost 21 months. Six phase 3 immunotherapy clinical trials have recently been published, yet 5/6 did not meet approval by regulatory bodies. For the sixth, approval is uncertain. Trial failures result from multiple factors, ranging from intrinsic tumor biology to clinical trial design. Understanding the clinical and basic science of these 6 trials is compelled by other immunotherapies reaching the point of advanced phase 3 clinical trial testing. We need to understand more of the science in human GBMs in early trials: the "window of opportunity" design may not be best to understand complex changes brought about by immunotherapeutic perturbations of the GBM microenvironment. The convergence of increased safety of image-guided biopsies with "multi-omics" of small cell numbers now permits longitudinal sampling of tumor and biofluids to dissect the complex temporal changes in the GBM microenvironment as a function of the immunotherapy.
    Keywords:  image-guided biopsy; multi-omics; phase 0 clinical trial; tumor microenvironment; window of opportunity clinical trial
    DOI:  https://doi.org/10.1093/neuonc/noad211
  7. Mol Cell. 2023 Nov 08. pii: S1097-2765(23)00862-6. [Epub ahead of print]
    EGFR promotes ALKBH5 nuclear retention to attenuate N6-methyladenosine and protect against ferroptosis in glioblastoma.
    Deguan Lv, Cuiqing Zhong, Deobrat Dixit, Kailin Yang, Qiulian Wu, Bhaskar Godugu, Briana C Prager, Guofeng Zhao, Xiuxing Wang, Qi Xie, Shideng Bao, Chuan He, Dieter Henrik Heiland, Michael G Rosenfeld, Jeremy N Rich.
      Growth factor receptors rank among the most important oncogenic pathways, but pharmacologic inhibitors often demonstrate limited benefit as monotherapy. Here, we show that epidermal growth factor receptor (EGFR) signaling repressed N6-methyladenosine (m6A) levels in glioblastoma stem cells (GSCs), whereas genetic or pharmacologic EGFR targeting elevated m6A levels. Activated EGFR induced non-receptor tyrosine kinase SRC to phosphorylate the m6A demethylase, AlkB homolog 5 (ALKBH5), thereby inhibiting chromosomal maintenance 1 (CRM1)-mediated nuclear export of ALKBH5 to permit sustained mRNA m6A demethylation in the nucleus. ALKBH5 critically regulated ferroptosis through m6A modulation and YTH N6-methyladenosine RNA binding protein (YTHDF2)-mediated decay of the glutamate-cysteine ligase modifier subunit (GCLM). Pharmacologic targeting of ALKBH5 augmented the anti-tumor efficacy of EGFR and GCLM inhibitors, supporting an EGFR-ALKBH5-GCLM oncogenic axis. Collectively, EGFR reprograms the epitranscriptomic landscape through nuclear retention of the ALKBH5 demethylase to protect against ferroptosis, offering therapeutic paradigms for the treatment of lethal cancers.
    Keywords:  ALKBH5; EGFR; GCLM; SRC; YTHDF2; cancer stem cell; ferroptosis; glioblastoma; glioblastoma stem cell; m(6)A
    DOI:  https://doi.org/10.1016/j.molcel.2023.10.025
  8. Curr Opin Cell Biol. 2023 Nov 18. pii: S0955-0674(23)00128-X. [Epub ahead of print]85 102279
    Drivers of heterogeneity in the glioblastoma immune microenvironment.
    Alina Brosque, Dinorah Friedmann-Morvinski.
      Glioblastoma is the most common and aggressive primary brain tumor, characterized by a highly complex and heterogeneous tumor immune microenvironment (TIME). In this review, we discuss the impact of tumor-intrinsic and tumor-extrinsic drivers that contribute to heterogeneity in the adult glioblastoma TIME, focusing on four main factors: genetic drivers, sex, age, and standard of care therapy. We describe recent insights into how each of these factors affects key aspects ranging from TIME composition to therapy response, with an emphasis on the cross-talk between tumor and immune cells. Deciphering these local interactions is fundamental to understanding therapy resistance and identifying novel immunomodulatory strategies.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102279
  9. Cell Rep. 2023 Nov 22. pii: S2211-1247(23)01486-9. [Epub ahead of print]42(12): 113474
    Adhesion GPCRs in glioblastoma revisited.
    Tobias Langenhan.
      Glioblastoma is a devastating brain malignancy that has remained intractable to modern cancer treatments. Ravn-Boess et al.1 have discovered that the adhesion G protein-coupled receptor CD97/ADGRE5 contributes to glioblastogenesis and makes for an excellent molecular surface marker flagging the tumor cells.
    DOI:  https://doi.org/10.1016/j.celrep.2023.113474
  10. Nat Commun. 2023 Nov 24. 14(1): 7717
    Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures.
    Melanie Schoof, Shweta Godbole, Thomas K Albert, Matthias Dottermusch, Carolin Walter, Annika Ballast, Nan Qin, Marlena Baca Olivera, Carolin Göbel, Sina Neyazi, Dörthe Holdhof, Catena Kresbach, Levke-Sophie Peter, Gefion Dorothea Epplen, Vanessa Thaden, Michael Spohn, Mirjam Blattner-Johnson, Franziska Modemann, Martin Mynarek, Stefan Rutkowski, Martin Sill, Julian Varghese, Ann-Kristin Afflerbach, Alicia Eckhardt, Daniel Münter, Archana Verma, Nina Struve, David T W Jones, Marc Remke, Julia E Neumann, Kornelius Kerl, Ulrich Schüller.
      Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding hGFAP-cre::Trp53Fl/Fl::lsl-MYCN mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from.
    DOI:  https://doi.org/10.1038/s41467-023-43564-w
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