bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2020‒10‒25
thirteen papers selected by
Oltea Sampetrean
Keio University


  1. Cancers (Basel). 2020 Oct 21. pii: E3068. [Epub ahead of print]12(10):
    Griffin M, Khan R, Basu S, Smith S.
      Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14-15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.
    Keywords:  glioblastoma multiforme; glioma; ion channel; ion channel inhibitor; membrane potential
    DOI:  https://doi.org/10.3390/cancers12103068
  2. Oncogene. 2020 Oct 19.
    Angel I, Pilo Kerman O, Rousso-Noori L, Friedmann-Morvinski D.
      Interconversion of transformed non-stem cells to cancer stem cells, termed cancer cell plasticity, contributes to intra-tumor heterogeneity and its molecular mechanisms are currently unknown. Here, we have identified Tenascin C (TNC) to be upregulated and secreted in mesenchymal glioblastoma (MES GBM) subtype with high NF-κB signaling activity. Silencing TNC decreases proliferation, migration and suppresses self-renewal of glioma stem cells. Loss of TNC in MES GBM compromises de-differentiation of transformed astrocytes and blocks the ability of glioma stem cells to differentiate into tumor derived endothelial cells (TDEC). Inhibition of NF-κB activity or TNC knockdown in tumor cells decreased their tumorigenic potential in vivo. Our results uncover a link between NF-κB activation in MES GBM and high levels of TNC in GBM extracellular matrix. We suggest that TNC plays an important role in the autocrine regulation of glioma cell plasticity and hence can be a potential molecular target for MES GBM.
    DOI:  https://doi.org/10.1038/s41388-020-01506-6
  3. Eur J Cancer. 2020 Oct 19. pii: S0959-8049(20)30525-6. [Epub ahead of print]140 130-139
    Rauschenbach L, Wieland A, Reinartz R, Kebir S, Till A, Darkwah Oppong M, Dobersalske C, Ullrich V, Ahmad A, Jabbarli R, Pierscianek D, Fröhlich H, Simon M, Brüstle O, Sure U, Glas M, Scheffler B.
      BACKGROUND: The protease inhibitor ritonavir (RTV) is a clinical-stage inhibitor of the human immunodeficiency virus. In a drug repositioning approach, we here exhibit the additional potential of RTV to augment current treatment of glioblastoma, the most aggressive primary brain tumour of adulthood.METHODS: We explored the antitumour activity of RTV and mechanisms of action in a broad spectrum of short-term expanded clinical cell samples from primary and recurrent glioblastoma and in a cohort of conventional cell lines and non-tumour human neural controls in vitro. To validate RTV efficacy in monotherapeutic and in combinatorial settings, we used patient-derived xenograft models in a series of in vivo studies.
    RESULTS: RTV monotherapy induced a selective antineoplastic response and demonstrated cytostatic and anti-migratory activity at clinical plasma peak levels. Additional exposure to temozolomide or irradiation further enhanced the effects synergistically, fostered by mechanisms of autophagy and increased endoplasmic reticulum stress. In xenograft models, we consequently observed increasing overall survival under the combinatorial effect of RTV and temozolomide.
    CONCLUSIONS: Our data establish RTV as a valuable repositioning candidate for further exploration as an adjunct therapeutic in the clinical care of glioblastoma.
    Keywords:  Autophagy; Glioblastoma; Repositioning; Ritonavir; Temozolomide
    DOI:  https://doi.org/10.1016/j.ejca.2020.09.017
  4. Mod Pathol. 2020 Oct 19.
    Satomi K, Ohno M, Matsushita Y, Takahashi M, Miyakita Y, Narita Y, Ichimura K, Yoshida A.
      Homozygous deletion (HD) of CDKN2A is one of the most promising biomarkers for predicting poor prognosis of IDH-mutant diffuse gliomas. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommendations propose that IDH-mutant lower-grade astrocytomas with CDKN2A/B HD be classified as grade IV tumors. Loss of methylthioadenosine phosphorylase (MTAP) immunohistochemistry staining has been proposed as a surrogate of CDKN2A HD in various tumors but its performance has not been fully investigated in diffuse glioma. This study determined whether MTAP immunoreactivity could serve as a proxy for CDKN2A HD in adult-type diffuse glioma, thereby contributing to stratifying patient outcome. MTAP immunohistochemistry staining using clone EPR6893 was scored in 178 diffuse glioma specimens consisting of 77 IDH-mutant astrocytomas, 13 IDH-mutant oligodendrogliomas, and 88 IDH-wildtype glioblastomas. The use of MTAP immunohistochemical deficiency to predict CDKN2A HD was good for IDH-mutant astrocytomas (sensitivity, 88%; specificity, 98%) and IDH-wildtype glioblastomas (sensitivity, 89%; specificity, 100%), but poor for IDH-mutant oligodendrogliomas (sensitivity, 67%; specificity, 57%). Both CDKN2A HD and MTAP immunohistochemical deficiency were significant adverse prognostic factors of overall survival for IDH-mutant astrocytoma (P < 0.001 each), but neither were prognostically significant for oligodendroglioma or IDH-wildtype glioblastoma. IDH-mutant lower-grade astrocytoma with CDKN2A HD and deficient MTAP immunoreactivity exhibited overlapping unfavorable outcome with IDH-mutant glioblastoma. MTAP immunostaining was easily interpreted in 61% of the cases tested, but scoring required greater care in the remaining cases. An alternative MTAP antibody clone (2G4) produced identical scoring results in all but 1 case, and a slightly larger proportion (66%) of cases were considered easy to interpret compared to using EPR6893. In summary, loss of MTAP immunoreactivity could serve as a reasonable predictive surrogate for CDKN2A HD in IDH-mutant astrocytomas and IDH-wildtype glioblastomas and could provide significant prognostic value for IDH-mutant astrocytoma, comparable to CDKN2A HD.
    DOI:  https://doi.org/10.1038/s41379-020-00701-w
  5. Cancers (Basel). 2020 Oct 19. pii: E3040. [Epub ahead of print]12(10):
    Kondo N, Hikida M, Nakada M, Sakurai Y, Hirata E, Takeno S, Suzuki M.
      As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. 10B(n,α)7Li capture reaction produces alpha particles whose short paths (5-9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO2 incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA+ or CD98+ cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2-4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2+ or Nestin+ GSLCs were BPA+, whereas only 36.9% of glial fibrillary acidic protein (GFAP)+ DCs were BPA+. Therefore, GSLCs may take up BPA and could be targeted by BNCT.
    Keywords:  boron neutron capture therapy; boronophenylalanine; glioma stem cell; mass cytometry
    DOI:  https://doi.org/10.3390/cancers12103040
  6. Oncogene. 2020 Oct 19.
    Eustace NJ, Anderson JC, Warram JM, Widden HN, Pedersen RT, Alrefai H, Patel Z, Hicks PH, Placzek WJ, Gillespie GY, Hjelmeland AB, Willey CD.
      Glioblastoma (GBM) is an aggressive malignancy with limited effectiveness of standard of care therapies including surgery, radiation, and temozolomide chemotherapy necessitating novel therapeutics. Unfortunately, GBMs also harbor several signaling alterations that protect them from traditional therapies that rely on apoptotic programmed cell death. Because almost all GBM tumors have dysregulated phosphoinositide signaling as part of that process, we hypothesized that peptide mimetics derived from the phospholipid binding domain of Myristoylated alanine-rich C-kinase substrate (MARCKS) could serve as a novel GBM therapeutic. Using molecularly classified patient-derived xenograft (PDX) lines, cultured in stem-cell conditions, we demonstrate that cell permeable MARCKS effector domain (ED) peptides potently target all GBM molecular classes while sparing normal human astrocytes. Cell death mechanistic testing revealed that these peptides produce rapid cytotoxicity in GBM that overcomes caspase inhibition. Moreover, we identify a GBM-selective cytolytic death mechanism involving plasma membrane targeting and intracellular calcium accumulation. Despite limited relative partitioning to the brain, tail-vein peptide injection revealed tumor targeting in intracranially implanted GBM PDX. These results indicate that MARCKS ED peptide therapeutics may overcome traditional GBM resistance mechanisms, supporting further development of similar agents.
    DOI:  https://doi.org/10.1038/s41388-020-01511-9
  7. Neuro Oncol. 2020 Oct 17. pii: noaa231. [Epub ahead of print]
    Beig N, Singh S, Bera K, Prasanna P, Singh G, Chen J, SaeedBamashmos A, Barnett A, Hunter K, Statsevych V, Hill VB, Varadan V, Madabhushi A, Ahluwalia MS, Tiwari P.
      BACKGROUND: Recent epidemiological studies have suggested that sexual dimorphism influences treatment response and prognostic outcome in Glioblastoma (GBM). To this end, we sought to (1) identify distinct sex-specific radiomic phenotypes, from tumor sub-compartments (peri-tumoral edema, enhancing tumor, and necrotic-core) using pretreatment MRI scans, that are prognostic of overall survival (OS) in GBMs, and (2) investigate radiogenomic associations of the MRI-based phenotypes with corresponding transcriptomic data, to identify the signaling pathways that drive sex-specific tumor biology and treatment response in GBM.METHODS: In a retrospective setting, 313 GBM patients (male=196, female=117) were curated from multiple institutions for radiomic analysis, where 130 were used for training and independently validated on a cohort of 183 patients. For the radiogenomic analysis, 147 GBM patients (male=94, female = 53) were used, with 125 patients in training and 22 cases for independent validation.
    RESULTS: Cox regression models of radiomic features from Gd-T1w MRI allowed for developing more precise prognostic models, when trained separately on male and female cohorts. Our radiogenomic analysis revealed higher expression of Laws energy features that capture spots and ripples-like patterns (representative of increased heterogeneity) from the enhancing tumor region, as well as aggressive biological processes of cell adhesion, and angiogenesis to be more enriched in the 'high-risk' group of poor OS in the male population. In contrast, higher expressions of Laws energy features (that detect levels and edges) from the necrotic core with significant involvement of immune related signaling pathways was observed in the 'low-risk' group of the female population.
    CONCLUSIONS: Sexually-dimorphic radiogenomic models could help risk-stratify GBM patients for personalized treatment decisions.
    Keywords:  Glioblastoma; machine learning; radiogenomics; sexual dimorphism
    DOI:  https://doi.org/10.1093/neuonc/noaa231
  8. Cancers (Basel). 2020 Oct 21. pii: E3069. [Epub ahead of print]12(10):
    Filippova N, Nabors LB.
      Homotypic and heterotypic cell fusions via permanent membrane fusions and temporal tunneling nanotube formations in the glioma microenvironment were recently documented in vitro and in vivo and mediate glioma survival, plasticity, and recurrence. Chronic inflammation, a hypoxic environment, aberrant mitochondrial function, and ER stress due to unfolded protein accumulation upregulate cell fusion events, which leads to tumor heterogeneity and represents an adaptive mechanism to promote tumor cell survival and plasticity in cytotoxic, nutrient-deprived, mechanically stressed, and inflammatory microenvironments. Cell fusion is a multistep process, which consists of the activation of the cellular stress response, autophagy formation, rearrangement of cytoskeletal architecture in the areas of cell-to-cell contacts, and the expression of proinflammatory cytokines and fusogenic proteins. The mRNA-binding protein of ELAV-family HuR is a critical node, which orchestrates the stress response, autophagy formation, cytoskeletal architecture, and the expression of proinflammatory cytokines and fusogenic proteins. HuR is overexpressed in gliomas and is associated with poor prognosis and treatment resistance. Our review provides a link between the HuR role in the regulation of cell fusion and tunneling nanotube formations in the glioma microenvironment and the potential suppression of these processes by different classes of HuR inhibitors.
    Keywords:  HuR; cell fusion; cell-to-cell communication; glioma; heterogeneity; inhibitors; tumor microenvironment; tunneling membrane nanotubes
    DOI:  https://doi.org/10.3390/cancers12103069
  9. Cancers (Basel). 2020 Oct 19. pii: E3039. [Epub ahead of print]12(10):
    Hsu JB, Lee GA, Chang TH, Huang SW, Le NQK, Chen YC, Kuo DP, Li YT, Chen CY.
      Characterization of immunophenotypes in glioblastoma (GBM) is important for therapeutic stratification and helps predict treatment response and prognosis. Radiomics can be used to predict molecular subtypes and gene expression levels. However, whether radiomics aids immunophenotyping prediction is still unknown. In this study, to classify immunophenotypes in patients with GBM, we developed machine learning-based magnetic resonance (MR) radiomic models to evaluate the enrichment levels of four immune subsets: Cytotoxic T lymphocytes (CTLs), activated dendritic cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). Independent testing data and the leave-one-out cross-validation method were used to evaluate model effectiveness and model performance, respectively. We identified five immunophenotypes (G1 to G5) based on the enrichment level for the four immune subsets. G2 had the worst prognosis and comprised highly enriched MDSCs and lowly enriched CTLs. G3 had the best prognosis and comprised lowly enriched MDSCs and Tregs and highly enriched CTLs. The average accuracy of T1-weighted contrasted MR radiomics models of the enrichment level for the four immune subsets reached 79% and predicted G2, G3, and the "immune-cold" phenotype (G1) according to our radiomics models. Our radiomic immunophenotyping models feasibly characterize the immunophenotypes of GBM and can predict patient prognosis.
    Keywords:  first-order statistics; glioblastoma; gray-level co-occurrence matrix; gray-level run length matrix; immunophenotypes; radiogenomics
    DOI:  https://doi.org/10.3390/cancers12103039
  10. Cell Rep. 2020 Oct 20. pii: S2211-1247(20)31275-4. [Epub ahead of print]33(3): 108286
    Balakrishnan I, Danis E, Pierce A, Madhavan K, Wang D, Dahl N, Sanford B, Birks DK, Davidson N, Metselaar DS, Meel MH, Lemma R, Donson A, Vijmasi T, Katagi H, Sola I, Fosmire S, Alimova I, Steiner J, Gilani A, Hulleman E, Serkova NJ, Hashizume R, Hawkins C, Carcaboso AM, Gupta N, Monje M, Jabado N, Jones K, Foreman N, Green A, Vibhakar R, Venkataraman S.
      Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
    Keywords:  BH3 mimetics; BMI1; DIPG; H3K27M mutant; H3WT; PTC 028; RNAi screen; SASP; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2020.108286
  11. Clin Cancer Res. 2020 Oct 21.
    Bruzek AK, Ravi K, Muruganand A, Wadden J, Babila CM, Cantor E, Tunkle L, Wierzbicki K, Stallard S, Dickson RP, Wolfe I, Mody R, Schwartz J, Franson A, Robertson PL, Muraszko KM, Maher CO, Garton HJL, Qin T, Koschmann C.
      PURPOSE: Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods.EXPERIMENTAL DESIGN: We performed ultra-short fragment (100-200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed.
    RESULTS: Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response.
    CONCLUSIONS: Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-2066
  12. Front Oncol. 2020 ;10 563840
    Karmur BS, Philteos J, Abbasian A, Zacharia BE, Lipsman N, Levin V, Grossman S, Mansouri A.
      The blood-brain barrier (BBB) presents a formidable challenge in the development of effective therapeutics in neuro-oncology. This has fueled several decades of efforts to develop strategies for disrupting the BBB, but progress has not been satisfactory. As such, numerous drug- and device-based methods are currently being investigated in humans. Through a focused assessment of completed, active, and pending clinical trials, our first aim in this review is to outline the scientific foundation, successes, and limitations of the BBBD strategies developed to date. Among 35 registered trials relevant to BBBD in neuro-oncology in the ClinicalTrials.gov database, mannitol was the most common drug-based method, followed by RMP-7 and regadenoson. MR-guided focused ultrasound was the most common device-based method, followed by MR-guided laser ablation, ultrasound, and transcranial magnetic stimulation. While most early-phase studies focusing on safety and tolerability have met stated objectives, advanced-phase studies focusing on survival differences and objective tumor response have been limited by heterogeneous populations and tumors, along with a lack of control arms. Based on shared challenges among all methods, our second objective is to discuss strategies for confirmation of BBBD, choice of systemic agent and drug design, alignment of BBBD method with real-world clinical workflow, and consideration of inadvertent toxicity associated with disrupting an evolutionarily-refined barrier. Finally, we conclude with a strategic proposal to approach future studies assessing BBBD.
    Keywords:  blood-brain barrier; clinical trial; drug delivery; glioma; neuro-oncolgy; neurosurgical oncology
    DOI:  https://doi.org/10.3389/fonc.2020.563840