bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021‒05‒02
nineteen papers selected by
Oltea Sampetrean
Keio University
  1. A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma.
  2. Interstitial Photodynamic Therapy Using 5-ALA for Malignant Glioma Recurrences.
  3. HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells.
  4. Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History.
  5. Prognostic significance of genome-wide DNA methylation profiles within the randomised, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma.
  6. An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma.
  7. Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth.
  8. Insights into Multifunctional Nanoparticle-Based Drug Delivery Systems for Glioblastoma Treatment.
  9. CK2 Activity Mediates the Aggressive Molecular Signature of Glioblastoma Multiforme by Inducing Nerve/Glial Antigen (NG)2 Expression.
  10. MicroRNA-138 suppresses glioblastoma proliferation through downregulation of CD44.
  11. Towards an Image-Informed Mathematical Model of In Vivo Response to Fractionated Radiation Therapy.
  12. EGFR Activates a TAZ-driven Oncogenic Program in Glioblastoma.
  13. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma.
  14. FGFR3 overexpression is a useful detection tool for FGFR3 fusions and sequence variations in glioma.
  15. The Leloir Cycle in Glioblastoma: Galactose Scavenging and Metabolic Remodeling.
  16. The imitation game: How glioblastoma outmaneuvers immune attack.
  17. Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness.
  18. Glioma stem cells invasive phenotype at optimal stiffness is driven by MGAT5 dependent mechanosensing.
  19. Hypoxia and Microvascular Alterations Are Early Predictors of IDH-Mutated Anaplastic Glioma Recurrence.
  1. Int J Mol Sci. 2021 Apr 21. pii: 4322. [Epub ahead of print]22(9):
    A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma.
    Sakthi Lenin, Elise Ponthier, Kaitlin G Scheer, Erica C F Yeo, Melinda N Tea, Lisa M Ebert, Mariana Oksdath Mansilla, Santosh Poonnoose, Ulrich Baumgartner, Bryan W Day, Rebecca J Ormsby, Stuart M Pitson, Guillermo A Gomez.
      Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6-9 months is common. To overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microenvironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cultures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma.
    Keywords:  drug screening; glioblastoma; organoids; personalized medicine; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms22094322
  2. Cancers (Basel). 2021 Apr 07. pii: 1767. [Epub ahead of print]13(8):
    Interstitial Photodynamic Therapy Using 5-ALA for Malignant Glioma Recurrences.
    Stefanie Lietke, Michael Schmutzer, Christoph Schwartz, Jonathan Weller, Sebastian Siller, Maximilian Aumiller, Christian Heckl, Robert Forbrig, Maximilian Niyazi, Rupert Egensperger, Herbert Stepp, Ronald Sroka, Jörg-Christian Tonn, Adrian Rühm, Niklas Thon.
      Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) as a cytotoxic photosensitizer could be a feasible treatment option for malignant gliomas. In a monocentric cohort of consecutive patients treated between 2006 and 2018, a risk profile analysis of salvage iPDT for local malignant glioma recurrences and associated outcome measures are presented here. It was considered indicated in patients with circumscribed biopsy-proven malignant glioma recurrences after standard therapy, if not deemed eligible for safe complete resection. A 3D treatment-planning software was used to determine the number and suitable positions of the cylindrical diffusing fibers placed stereotactically to ensure optimal interstitial irradiation of the target volume. Outcome measurements included the risk profile of the procedure, estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and prognostic factors. Forty-seven patients were treated, of which 44 (median age, 49.4 years, range, 33.4-87.0 years, 27 males) could be retrospectively evaluated. Recurrent gliomas included 37 glioblastomas (WHO grade IV) and 7 anaplastic astrocytomas (WHO grade III). Thirty (68.2%) tumors were O-6-methylguanine-DNA methyltransferase (MGMT)-methylated, 29 (65.9%)-isocitrate dehydrogenase (IDH)-wildtype. Twenty-six (59.1%) patients were treated for their first, 9 (20.5%)-for their second, 9 (20.5%)-for the third or further recurrence. The median iPDT target volume was 3.34 cm3 (range, 0.50-22.8 cm3). Severe neurologic deterioration lasted for more than six weeks in one patient only. The median TTF was 7.1 (95% confidence interval (CI), 4.4-9.8) months and the median PRS was 13.0 (95% CI, 9.2-16.8) months. The 2- and 5-year PRS rates were 25.0% and 4.5%, respectively. The treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. The promising outcome and acceptable risk profile deserve further prospective evaluation particularly to identify mechanisms and prognostic factors of favorable treatment response.
    Keywords:  5-ALA; glioblastoma; malignant glioma; outcome; photodynamic therapy; recurrence; stereotactic surgery
    DOI:  https://doi.org/10.3390/cancers13081767
  3. Cancers (Basel). 2021 Apr 01. pii: 1644. [Epub ahead of print]13(7):
    HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells.
    Ping Shi, Lan B Hoang-Minh, Jia Tian, Alice Cheng, Reemsha Basrai, Neil Kalaria, Joseph J Lebowitz, Habibeh Khoshbouei, Loic P Deleyrolle, Matthew R Sarkisian.
      Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts glioma proliferation, but whether this effect is dependent on tumor cell primary cilia is unknown. We found that HDAC6 inhibitors ACY-1215 (1215) and ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse glioma cells. While both inhibitors triggered rapid increases in acetylated alpha-tubulin (aaTub) in the cytosol and led to increased frequencies of primary cilia, they unexpectedly reduced the levels of aaTub in the cilia. To test whether the antiproliferative effects of HDAC6 inhibitors are dependent on tumor cell cilia, we generated patient-derived glioma lines devoid of cilia through depletion of ciliogenesis genes ARL13B or KIF3A. At low concentrations, 1215 or 738 did not decrease the proliferation of cilia-depleted cells. Moreover, the differentiation of glioma cells that was induced by HDAC6 inhibition did not occur after the inhibition of cilia formation. These data suggest HDAC6 signaling at primary cilia promotes the proliferation of glioma cells by restricting their ability to differentiate. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia.
    Keywords:  ARL13B; alpha-tubulin; glioblastoma; histone deacetylase 6; primary cilium
    DOI:  https://doi.org/10.3390/cancers13071644
  4. Cancers (Basel). 2021 Apr 23. pii: 2044. [Epub ahead of print]13(9):
    Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History.
    Sara Franceschi, Prospero Civita, Francesco Pasqualetti, Francesca Lessi, Martina Modena, Serena Barachini, Mariangela Morelli, Orazio Santonocito, Riccardo Vannozzi, Geoffrey J Pilkington, Valerio Ortenzi, Antonio Giuseppe Naccarato, Paolo Aretini, Chiara Maria Mazzanti.
      Glioblastoma is one of the most common and lethal primary neoplasms of the brain. Patient survival has not improved significantly over the past three decades and the patient median survival is just over one year. Tumor heterogeneity is thought to be a major determinant of therapeutic failure and a major reason for poor overall survival. This work aims to comprehensively define intra- and inter-tumor heterogeneity by mapping the genomic and mutational landscape of multiple areas of three primary IDH wild-type (IDH-WT) glioblastomas. Using whole exome sequencing, we explored how copy number variation, chromosomal and single loci amplifications/deletions, and mutational burden are spatially distributed across nine different tumor regions. The results show that all tumors exhibit a different signature despite the same diagnosis. Above all, a high inter-tumor heterogeneity emerges. The evolutionary dynamics of all identified mutations within each region underline the questionable value of a single biopsy and thus the therapeutic approach for the patient. Multiregional collection and subsequent sequencing are essential to try to address the clinical challenge of precision medicine. Especially in glioblastoma, this approach could provide powerful support to pathologists and oncologists in evaluating the diagnosis and defining the best treatment option.
    Keywords:  clonal evolution; glioblastoma; multiregional sequencing; spatial heterogeneity; temporal heterogeneity; tumor phylogeny; tumor progression
    DOI:  https://doi.org/10.3390/cancers13092044
  5. Neuro Oncol. 2021 Apr 29. pii: noab088. [Epub ahead of print]
    Prognostic significance of genome-wide DNA methylation profiles within the randomised, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma.
    C M S Tesileanu, M J van den Bent, M Sanson, W Wick, A A Brandes, P M Clement, S C Erridge, M A Vogelbaum, A K Nowak, J F Baurain, W P Mason, H Wheeler, O L Chinot, S Gill, M Griffin, L Rogers, W Taal, R Rudà, M Weller, C McBain, M E van Linde, T S Sabedot, Y Hoogstrate, A von Deimling, I de Heer, W F J van IJcken, R W W Brouwer, K Aldape, R B Jenkins, H J Dubbink, J M Kros, P Wesseling, K J Cheung, V Golfinopoulos, B G Baumert, T Gorlia, H Noushmehr, P J French.
      BACKGROUND: Survival in patients with IDH1/2 mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients.METHODS: The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumour classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using one of two glioma-tailored NGS panels. The primary endpoint was overall survival measured from date of randomization.
    RESULTS: Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumours. Of these, 432 tumours were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazards model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication.
    CONCLUSION: Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.
    Keywords:  1p/19q non-codeleted; DNA methylation profiling; IDH mutant; anaplastic glioma; patient prognostication
    DOI:  https://doi.org/10.1093/neuonc/noab088
  6. Cancers (Basel). 2021 Apr 18. pii: 1953. [Epub ahead of print]13(8):
    An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma.
    Seán B Lyne, Bakhtiar Yamini.
      The treatment of glioblastoma (GBM) remains a significant challenge, with outcome for most pa-tients remaining poor. Although novel therapies have been developed, several obstacles restrict the incentive of drug developers to continue these efforts including the exorbitant cost, high failure rate and relatively small patient population. Repositioning drugs that have well-characterized mechanistic and safety profiles is an attractive alternative for drug development in GBM. In ad-dition, the relative ease with which repurposed agents can be transitioned to the clinic further supports their potential for examination in patients. Here, a systematic analysis of the literature and clinical trials provides a comprehensive review of primary articles and unpublished trials that use repurposed drugs for the treatment of GBM. The findings demonstrate that numerous drug classes that have a range of initial indications have efficacy against preclinical GBM models and that certain agents have shown significant potential for clinical benefit. With examination in randomized, placebo-controlled trials and the targeting of particular GBM subgroups, it is pos-sible that repurposing can be a cost-effective approach to identify agents for use in multimodal anti-GBM strategies.
    Keywords:  GBM; chemosensitization; glioblastoma; radiosensitization; repositioning; repurposing; therapeutics
    DOI:  https://doi.org/10.3390/cancers13081953
  7. Cell Rep. 2021 Apr 27. pii: S2211-1247(21)00338-7. [Epub ahead of print]35(4): 109024
    Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth.
    Denise Sighel, Michela Notarangelo, Shintaro Aibara, Angela Re, Gianluca Ricci, Marianna Guida, Alessia Soldano, Valentina Adami, Chiara Ambrosini, Francesca Broso, Emanuele Filiberto Rosatti, Sara Longhi, Mariachiara Buccarelli, Quintino G D'Alessandris, Stefano Giannetti, Simone Pacioni, Lucia Ricci-Vitiani, Joanna Rorbach, Roberto Pallini, Sandrine Roulland, Alexey Amunts, Ines Mancini, Angelika Modelska, Alessandro Quattrone.
      Glioblastoma stem cells (GSCs) resist current glioblastoma (GBM) therapies. GSCs rely highly on oxidative phosphorylation (OXPHOS), whose function requires mitochondrial translation. Here we explore the therapeutic potential of targeting mitochondrial translation and report the results of high-content screening with putative blockers of mitochondrial ribosomes. We identify the bacterial antibiotic quinupristin/dalfopristin (Q/D) as an effective suppressor of GSC growth. Q/D also decreases the clonogenicity of GSCs in vitro, consequently dysregulating the cell cycle and inducing apoptosis. Cryoelectron microscopy (cryo-EM) reveals that Q/D binds to the large mitoribosomal subunit, inhibiting mitochondrial protein synthesis and functionally dysregulating OXPHOS complexes. These data suggest that targeting mitochondrial translation could be explored to therapeutically suppress GSC growth in GBM and that Q/D could potentially be repurposed for cancer treatment.
    Keywords:  OXPHOS; cryo-EM; dalfopristin; drug repurposing; glioblastoma; glioblastoma stem cells; high-content screening; mitochondrial translation; mitoribosome; quinupristin
    DOI:  https://doi.org/10.1016/j.celrep.2021.109024
  8. Molecules. 2021 Apr 14. pii: 2262. [Epub ahead of print]26(8):
    Insights into Multifunctional Nanoparticle-Based Drug Delivery Systems for Glioblastoma Treatment.
    Mohd Khan, Subuhi Sherwani, Saif Khan, Sultan Alouffi, Mohammad Alam, Khalid Al-Motair, Shahper Khan.
      Glioblastoma (GB) is an aggressive cancer with high microvascular proliferation, resulting in accelerated invasion and diffused infiltration into the surrounding brain tissues with very low survival rates. Treatment options are often multimodal, such as surgical resection with concurrent radiotherapy and chemotherapy. The development of resistance of tumor cells to radiation in the areas of hypoxia decreases the efficiency of such treatments. Additionally, the difficulty of ensuring drugs effectively cross the natural blood-brain barrier (BBB) substantially reduces treatment efficiency. These conditions concomitantly limit the efficacy of standard chemotherapeutic agents available for GB. Indeed, there is an urgent need of a multifunctional drug vehicle system that has potential to transport anticancer drugs efficiently to the target and can successfully cross the BBB. In this review, we summarize some nanoparticle (NP)-based therapeutics attached to GB cells with antigens and membrane receptors for site-directed drug targeting. Such multicore drug delivery systems are potentially biodegradable, site-directed, nontoxic to normal cells and offer long-lasting therapeutic effects against brain cancer. These models could have better therapeutic potential for GB as well as efficient drug delivery reaching the tumor milieu. The goal of this article is to provide key considerations and a better understanding of the development of nanotherapeutics with good targetability and better tolerability in the fight against GB.
    Keywords:  blood–brain barrier; glioblastoma; multicore; multifunctional; nanotherapeutic; polymeric nanoparticles
    DOI:  https://doi.org/10.3390/molecules26082262
  9. Cancers (Basel). 2021 Apr 02. pii: 1678. [Epub ahead of print]13(7):
    CK2 Activity Mediates the Aggressive Molecular Signature of Glioblastoma Multiforme by Inducing Nerve/Glial Antigen (NG)2 Expression.
    Beate M Schmitt, Anne S Boewe, Claudia Götz, Stephan E Philipp, Steffi Urbschat, Joachim Oertel, Michael D Menger, Matthias W Laschke, Emmanuel Ampofo.
      Nerve/glial antigen (NG)2 expression crucially determines the aggressiveness of glioblastoma multiforme (GBM). Recent evidence suggests that protein kinase CK2 regulates NG2 expression. Therefore, we investigated in the present study whether CK2 inhibition suppresses proliferation and migration of NG2-positive GBM cells. For this purpose, CK2 activity was suppressed in the NG2-positive cell lines A1207 and U87 by the pharmacological inhibitor CX-4945 and CRISPR/Cas9-mediated knockout of CK2α. As shown by quantitative real-time PCR, luciferase-reporter assays, flow cytometry and western blot, this significantly reduced NG2 gene and protein expression when compared to vehicle-treated and wild type controls. In addition, CK2 inhibition markedly reduced NG2-dependent A1207 and U87 cell proliferation and migration. The Cancer Genome Atlas (TCGA)-based data further revealed not only a high expression of both NG2 and CK2 in GBM but also a positive correlation between the mRNA expression of the two proteins. Finally, we verified a decreased NG2 expression after CX-4945 treatment in patient-derived GBM cells. These findings indicate that the inhibition of CK2 represents a promising approach to suppress the aggressive molecular signature of NG2-positive GBM cells. Therefore, CX-4945 may be a suitable drug for the future treatment of NG2-positive GBM.
    Keywords:  CK2; CRISPR/Cas9; CX-4945; GBM; NG2; glioblastoma multiforme; migration; nerve/glial antigen 2; proliferation
    DOI:  https://doi.org/10.3390/cancers13071678
  10. Sci Rep. 2021 Apr 28. 11(1): 9219
    MicroRNA-138 suppresses glioblastoma proliferation through downregulation of CD44.
    Margaret Yeh, Yin-Ying Wang, Ji Young Yoo, Christina Oh, Yoshihiro Otani, Jin Muk Kang, Eun S Park, Eunhee Kim, Sangwoon Chung, Young-Jun Jeon, George A Calin, Balveen Kaur, Zhongming Zhao, Tae Jin Lee.
      Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to determine the therapeutic potential of putative tumor suppressive miRNA, miR-138, against glioblastoma (GBM). Whole transcriptome and miRNA expression profiling analyses on human GBM patient tissues identified miR-138 as one of the significantly downregulated miRNAs with an inverse correlation with CD44 expression. Transient overexpression of miR-138 in GBM cells inhibited cell proliferation, cell cycle, migration, and wound healing capability. We unveiled that miR-138 negatively regulates the expression of CD44 by directly binding to the 3' UTR of CD44. CD44 inhibition by miR-138 resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In conclusion, we demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 for the treatment of primary GBM.
    DOI:  https://doi.org/10.1038/s41598-021-88615-8
  11. Cancers (Basel). 2021 Apr 07. pii: 1765. [Epub ahead of print]13(8):
    Towards an Image-Informed Mathematical Model of In Vivo Response to Fractionated Radiation Therapy.
    David A Hormuth, Angela M Jarrett, Tessa Davis, Thomas E Yankeelov.
      Fractionated radiation therapy is central to the treatment of numerous malignancies, including high-grade gliomas where complete surgical resection is often impractical due to its highly invasive nature. Development of approaches to forecast response to fractionated radiation therapy may provide the ability to optimize or adapt treatment plans for radiotherapy. Towards this end, we have developed a family of 18 biologically-based mathematical models describing the response of both tumor and vasculature to fractionated radiation therapy. Importantly, these models can be personalized for individual tumors via quantitative imaging measurements. To evaluate this family of models, rats (n = 7) with U-87 glioblastomas were imaged with magnetic resonance imaging (MRI) before, during, and after treatment with fractionated radiotherapy (with doses of either 2 Gy/day or 4 Gy/day for up to 10 days). Estimates of tumor and blood volume fractions, provided by diffusion-weighted MRI and dynamic contrast-enhanced MRI, respectively, were used to calibrate tumor-specific model parameters. The Akaike Information Criterion was employed to select the most parsimonious model and determine an ensemble averaged model, and the resulting forecasts were evaluated at the global and local level. At the global level, the selected model's forecast resulted in less than 16.2% error in tumor volume estimates. At the local (voxel) level, the median Pearson correlation coefficient across all prediction time points ranged from 0.57 to 0.87 for all animals. While the ensemble average forecast resulted in increased error (ranging from 4.0% to 1063%) in tumor volume predictions over the selected model, it increased the voxel wise correlation (by greater than 12.3%) for three of the animals. This study demonstrates the feasibility of calibrating a model of response by serial quantitative MRI data collected during fractionated radiotherapy to predict response at the conclusion of treatment.
    Keywords:  U87; computational oncology; glioblastoma; magnetic resonance imaging; perfusion
    DOI:  https://doi.org/10.3390/cancers13081765
  12. Cancer Res. 2021 Apr 28. pii: canres.2773.2020. [Epub ahead of print]
    EGFR Activates a TAZ-driven Oncogenic Program in Glioblastoma.
    Minling Gao, Yi Fu, Weiqiang Zhou, Gege Gui, Bachchu Lal, Yunqing Li, Shuli Xia, Hongkai Ji, Charles G Eberhart, John Laterra, Mingyao Ying.
      Hyperactivated EGFR signaling is a driver of various human cancers, including glioblastoma (GBM). Effective EGFR-targeted therapies rely on knowledge of key signaling hubs that transfer and amplify EGFR signaling. Here we focus on the transcription factor TAZ, a potential signaling hub in the EGFR signaling network. TAZ expression was positively associated with EGFR expression in clinical GBM specimens. In patient-derived GBM neurospheres, EGF induced TAZ through EGFR-ERK and EGFR-STAT3 signaling, and the constitutively active EGFRvIII mutation caused EGF-independent hyperactivation of TAZ. Genome-wide analysis showed that the EGFR-TAZ axis activates multiple oncogenic signaling mechanisms, including an EGFR-TAZ-RTK positive feedback loop, as well as upregulating HIF1α and other oncogenic genes. TAZ hyperactivation in GBM stem-like cells induced exogenous mitogen-independent growth and promoted GBM invasion, radioresistance, and tumorigenicity. Screening a panel of brain-penetrating EGFR inhibitors identified osimertinib as the most potent inhibitor of the EGFR-TAZ signaling axis. Systemic osimertinib treatment inhibited the EGFR-TAZ axis and in vivo growth of GBM stem-like cell xenografts. Overall these results show that the therapeutic efficacy of osimertinib relies on effective TAZ inhibition, thus identifying TAZ as a potential biomarker of osimertinib sensitivity.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2773
  13. Sci Transl Med. 2021 Apr 28. pii: eabe7378. [Epub ahead of print]13(591):
    SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma.
    Joseph H Choe, Payal B Watchmaker, Milos S Simic, Ryan D Gilbert, Aileen W Li, Nira A Krasnow, Kira M Downey, Wei Yu, Diego A Carrera, Anna Celli, Juhyun Cho, Jessica D Briones, Jason M Duecker, Yitzhar E Goretsky, Ruth Dannenfelser, Lia Cardarelli, Olga Troyanskaya, Sachdev S Sidhu, Kole T Roybal, Hideho Okada, Wendell A Lim.
      Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glycoprotein (MOG), can be used to locally induce expression of a CAR. This enables thorough but controlled tumor cell killing by targeting antigens that are homogeneous but not absolutely tumor specific. Moreover, synNotch-regulated CAR expression averts tonic signaling and exhaustion, maintaining a higher fraction of the T cells in a naïve/stem cell memory state. In immunodeficient mice bearing intracerebral patient-derived xenografts (PDXs) with heterogeneous expression of EGFRvIII, a single intravenous infusion of EGFRvIII synNotch-CAR T cells demonstrated higher antitumor efficacy and T cell durability than conventional constitutively expressed CAR T cells, without off-tumor killing. T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.
    DOI:  https://doi.org/10.1126/scitranslmed.abe7378
  14. Neurooncol Pract. 2021 Apr;8(2): 209-221
    FGFR3 overexpression is a useful detection tool for FGFR3 fusions and sequence variations in glioma.
    Jens Schittenhelm, Lukas Ziegler, Jan Sperveslage, Michel Mittelbronn, David Capper, Isabel Burghardt, Antti Poso, Saskia Biskup, Marco Skardelly, Ghazaleh Tabatabai.
      Background: Fibroblast growth factor receptor (FGFR) inhibitors are currently used in clinical development. A subset of glioblastomas carries gene fusion of FGFR3 and transforming acidic coiled-coil protein 3. The prevalence of other FGFR3 alterations in glioma is currently unclear.Methods: We performed RT-PCR in 101 glioblastoma samples to detect FGFR3-TACC3 fusions ("RT-PCR cohort") and correlated results with FGFR3 immunohistochemistry (IHC). Further, we applied FGFR3 IHC in 552 tissue microarray glioma samples ("TMA cohort") and validated these results in two external cohorts with 319 patients. Gene panel sequencing was carried out in 88 samples ("NGS cohort") to identify other possible FGFR3 alterations. Molecular modeling was performed on newly detected mutations.
    Results: In the "RT-PCR cohort," we identified FGFR3-TACC3 fusions in 2/101 glioblastomas. Positive IHC staining was observed in 73/1024 tumor samples of which 10 were strongly positive. In the "NGS cohort," we identified FGFR3 fusions in 9/88 cases, FGFR3 amplification in 2/88 cases, and FGFR3 gene mutations in 7/88 cases in targeted sequencing. All FGFR3 fusions and amplifications and a novel FGFR3 K649R missense mutation were associated with FGFR3 overexpression (sensitivity and specificity of 93% and 95%, respectively, at cutoff IHC score > 7). Modeling of these data indicated that Tyr647, a residue phosphorylated as a part of FGFR3 activation, is affected by the K649R mutation.
    Conclusions: FGFR3 IHC is a useful screening tool for the detection of FGFR3 alterations and could be included in the workflow for isocitrate dehydrogenase (IDH) wild-type glioma diagnostics. Samples with positive FGFR3 staining could then be selected for NGS-based diagnostic tools.
    Keywords:  FGFR3; glioma; panel sequencing; targeted treatment
    DOI:  https://doi.org/10.1093/nop/npaa075
  15. Cancers (Basel). 2021 Apr 10. pii: 1815. [Epub ahead of print]13(8):
    The Leloir Cycle in Glioblastoma: Galactose Scavenging and Metabolic Remodeling.
    Martyn A Sharpe, Omkar B Ijare, David S Baskin, Alexandra M Baskin, Brianna N Baskin, Kumar Pichumani.
      BACKGROUND: Glioblastoma (GBM) can use metabolic fuels other than glucose (Glc). The ability of GBM to use galactose (Gal) as a fuel via the Leloir pathway is investigated.METHODS: Gene transcript data were accessed to determine the association between expression of genes of the Leloir pathway and patient outcomes. Growth studies were performed on five primary patient-derived GBM cultures using Glc-free media supplemented with Gal. The role of Glut3/Glut14 in sugar import was investigated using antibody inhibition of hexose transport. A specific inhibitor of GALK1 (Cpd36) was used to inhibit Gal catabolism. Gal metabolism was examined using proton, carbon and phosphorous NMR spectroscopy, with 13C-labeled Glc and Gal as tracers.
    RESULTS: Data analysis from published databases revealed that elevated levels of mRNA transcripts of SLC2A3 (Glut3), SLC2A14 (Glut14) and key Leloir pathway enzymes correlate with poor patient outcomes. GBM cultures proliferated when grown solely on Gal in Glc-free media and switching Glc-grown GBM cells into Gal-enriched/Glc-free media produced elevated levels of Glut3 and/or Glut14 enzymes. The 13C NMR-based metabolic flux analysis demonstrated a fully functional Leloir pathway and elevated pentose phosphate pathway activity for efficient Gal metabolism in GBM cells.
    CONCLUSION: Expression of Glut3 and/or Glut14 together with the enzymes of the Leloir pathway allows GBM to transport and metabolize Gal at physiological glucose concentrations, providing GBM cells with an alternate energy source. The presence of this pathway in GBM and its selective targeting may provide new treatment strategies.
    Keywords:  GBM; Glut14; Leloir pathway; galactose scavenging; pentose phosphate pathway
    DOI:  https://doi.org/10.3390/cancers13081815
  16. Cell. 2021 Apr 29. pii: S0092-8674(21)00443-8. [Epub ahead of print]184(9): 2278-2281
    The imitation game: How glioblastoma outmaneuvers immune attack.
    Ilon Liu, Olivia A Hack, Mariella G Filbin.
      Immune evasion and resistance to immunotherapy mark major roadblocks in treating glioblastoma, the deadliest form of brain cancer. In this issue of Cell, Gangoso et al. demonstrate that the immune microenvironment drives glioblastoma cells to hijack myeloid-characteristic transcriptional and epigenetic circuits as a mode of immune evasion.
    DOI:  https://doi.org/10.1016/j.cell.2021.04.008
  17. Cancer Metab. 2021 Apr 28. 9(1): 18
    Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness.
    Yollanda E Moreira Franco, Maria Jose Alves, Miyuki Uno, Isabele Fattori Moretti, Marina Trombetta-Lima, Suzana de Siqueira Santos, Ancely Ferreira Dos Santos, Gabriel Santos Arini, Mauricio S Baptista, Antonio Marcondes Lerario, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie.
      BACKGROUND: Glioblastoma is the most frequent and high-grade adult malignant central nervous system tumor. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. Metabolic reprogramming currently is recognized as one of the hallmarks of cancer. Glutamine metabolism through glutaminolysis has been associated with tumor cell maintenance and survival, and with antioxidative stress through glutathione (GSH) synthesis.METHODS: In the present study, we analyzed the glutaminolysis-related gene expression levels in our cohort of 153 astrocytomas of different malignant grades and 22 non-neoplastic brain samples through qRT-PCR. Additionally, we investigated the protein expression profile of the key regulator of glutaminolysis (GLS), glutamate dehydrogenase (GLUD1), and glutamate pyruvate transaminase (GPT2) in these samples. We also investigated the glutathione synthase (GS) protein profile and the GSH levels in different grades of astrocytomas. The differential gene expressions were validated in silico on the TCGA database.
    RESULTS: We found an increase of glutaminase isoform 2 gene (GLSiso2) expression in all grades of astrocytoma compared to non-neoplastic brain tissue, with a gradual expression increment in parallel to malignancy. Genes coding for GLUD1 and GPT2 expression levels varied according to the grade of malignancy, being downregulated in glioblastoma, and upregulated in lower grades of astrocytoma (AGII-AGIII). Significant low GLUD1 and GPT2 protein levels were observed in the mesenchymal subtype of GBM.
    CONCLUSIONS: In glioblastoma, particularly in the mesenchymal subtype, the downregulation of both genes and proteins (GLUD1 and GPT2) increases the source of glutamate for GSH synthesis and enhances tumor cell fitness due to increased antioxidative capacity. In contrast, in lower-grade astrocytoma, mainly in those harboring the IDH1 mutation, the gene expression profile indicates that tumor cells might be sensitized to oxidative stress due to reduced GSH synthesis. The measurement of GLUD1 and GPT2 metabolic substrates, ammonia, and alanine, by noninvasive MR spectroscopy, may potentially allow the identification of IDH1mut AGII and AGIII progression towards secondary GBM.
    Keywords:  Astrocytoma progression; GBM; Glutaminolysis; IDH1 mutation; Low-grade astrocytoma
    DOI:  https://doi.org/10.1186/s40170-021-00255-8
  18. J Exp Clin Cancer Res. 2021 Apr 24. 40(1): 139
    Glioma stem cells invasive phenotype at optimal stiffness is driven by MGAT5 dependent mechanosensing.
    Emilie Marhuenda, Christine Fabre, Cunjie Zhang, Martà Martin-Fernandez, Thomas Iskratsch, Ali Saleh, Luc Bauchet, Julien Cambedouzou, Jean-Philippe Hugnot, Hugues Duffau, James W Dennis, David Cornu, Norbert Bakalara.
      BACKGROUND: Glioblastomas stem-like cells (GSCs) by invading the brain parenchyma, remains after resection and radiotherapy and the tumoral microenvironment become stiffer. GSC invasion is reported as stiffness sensitive and associated with altered N-glycosylation pattern. Glycocalyx thickness modulates integrins mechanosensing, but details remain elusive and glycosylation enzymes involved are unknown. Here, we studied the association between matrix stiffness modulation, GSC migration and MGAT5 induced N-glycosylation in fibrillar 3D context.METHOD: To mimic the extracellular matrix fibrillar microenvironments, we designed 3D-ex-polyacrylonitrile nanofibers scaffolds (NFS) with adjustable stiffnesses by loading multiwall carbon nanotubes (MWCNT). GSCs neurosphere were plated on NFSs, allowing GSCs migration and MGAT5 was deleted using CRISPR-Cas9.
    RESULTS: We found that migration of GSCs was maximum at 166 kPa. Migration rate was correlated with cell shape, expression and maturation of focal adhesion (FA), Epithelial to Mesenchymal Transition (EMT) proteins and (β1,6) branched N-glycan binding, galectin-3. Mutation of MGAT5 in GSC inhibited N-glycans (β1-6) branching, suppressed the stiffness dependence of migration on 166 kPa NFS as well as the associated FA and EMT protein expression.
    CONCLUSION: MGAT5 catalysing multibranched N-glycans is a critical regulators of stiffness induced invasion and GSCs mechanotransduction, underpinning MGAT5 as a serious target to treat cancer.
    Keywords:  3D-nanofibre scaffold; Biomaterial; EMT; Focal adhesion; Galectin; Glioblastoma; Glycosylation; Mechanotransduction; Mgat5; Migration; Stiffness
    DOI:  https://doi.org/10.1186/s13046-021-01925-7
  19. Cancers (Basel). 2021 Apr 09. pii: 1797. [Epub ahead of print]13(8):
    Hypoxia and Microvascular Alterations Are Early Predictors of IDH-Mutated Anaplastic Glioma Recurrence.
    Andreas Stadlbauer, Stefan Oberndorfer, Gertraud Heinz, Max Zimmermann, Thomas M Kinfe, Arnd Doerfler, Michael Buchfelder, Natalia Kremenevski, Franz Marhold.
      Anaplastic gliomas (AG) represents aggressive brain tumors that often affect young adults. Although isocitrate-dehydrogenase (IDH) gene mutation has been identified as a more favorable prognostic factor, most IDH-mutated AG patients are confronted with tumor recurrence. Hence, increased knowledge about pathophysiological precursors of AG recurrence is urgently needed in order to develop precise diagnostic monitoring and tailored therapeutic approaches. In this study, 142 physiological magnetic resonance imaging (phyMRI) follow-up examinations in 60 AG patients after standard therapy were evaluated and magnetic resonance imaging (MRI) biomarker maps for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia calculated. From these 60 patients, 34 patients developed recurrence of the AG, and 26 patients showed no signs for AG recurrence during the study period. The time courses of MRI biomarker changes were analyzed regarding early pathophysiological alterations over a one-year period before radiological AG recurrence or a one-year period of stable disease for patients without recurrence, respectively. We detected intensifying local tissue hypoxia 250 days prior to radiological recurrence which initiated upregulation of neovascularization activity 50 to 70 days later. These changes were associated with a switch from an avascular infiltrative to a vascularized proliferative phenotype of the tumor cells another 30 days later. The dynamic changes of blood perfusion, microvessel density, neovascularization activity, and oxygen metabolism showed a close physiological interplay in the one-year period prior to radiological recurrence of IDH-mutated AG. These findings may path the wave for implementing both new MR-based imaging modalities for routine follow-up monitoring of AG patients after standard therapy and furthermore may support the development of novel, tailored therapy options in recurrent AG.
    Keywords:  IDH gene mutation; anaplastic glioma; hypoxia; isocitrate-dehydrogenase; neovascularization; physiological MRI; recurrence; treatment failure; vascular cooption
    DOI:  https://doi.org/10.3390/cancers13081797
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