At the Frontiers of Human Glioblastoma: Challenges in Introducing New Therapeutic Strategies

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (15 June 2021) | Viewed by 21525

Special Issue Editors


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Department of Neurobiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
Interests: molecular neurooncology; glioblastoma; tumor microenvironment; 3D cultures; innovative anticancer drugs
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Guest Editor
Pilar Sánchez-Gómez, Instituto de Salud Carlos III-UFIEC, Neuro-oncology Unit, Crtra. Majadahonda-Pozuelo, Km 2, Majadahonda, UNK 28922, Spain.
Interests: neurooncology, glioblastoma, egfr, tumor microenvironment, preclinical assays

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Guest Editor
Nantes-Angers Cancer and Immunology Research Center, Institute of Health Research of the University of Nantes, Nantes, France
Interests: apoptosis; mitochondria; neurocology; glioblastoma; 3D-bioprinting; tumor microenvironment

Special Issue Information

Dear Colleagues,

Adult Glioblastoma is a highly aggressive malignant brain tumor. Although numerous mechanistic studies have revealed and underlined the unique behavior of Glioblastoma, still, only a few chemotherapeutics are used for its treatment. The standard procedure, which has not been modified in the last two decades, includes surgical resection followed by radiotherapy with concomitant temozolomide chemotherapy. Unfortunately, glioblastoma recurrence is extremely frequent, and the median patient survival remains 15 to 18 months from diagnosis. Problems with the introduction of new therapies, even as adjuvants, include the low penetration of anticancer drugs in the brain due to the blood–brain barrier, the high inter- and intra-tumor heterogeneity of glioblastoma cells, as well as their invasiveness and resistance to therapy. Many promising targeted therapies based on preclinical studies failed to prolong glioblastoma patient survival and the stagnation implementing new therapeutic strategies is evident. Therefore, new glioblastoma models that will improve our knowledge and allow investigation of new therapeutic strategies under conditions that mimic the situation in patients with high fidelity are demanded.

This Special Issue will assemble preclinical and clinical studies of glioblastoma, from pathophysiological mechanisms to new therapeutic strategies. Studies based on new glioblastoma models (including 3D cultures, bioprinting, microfluidic devices, and animal models); clinical investigations; bioinformatics; and mathematical modeling of the patient’s response are highly welcome. In addition, reviews referring to glioblastoma research and therapy will be appreciated.

Dr. Milica Pešić
Dr. Pilar Sánchez Gómez
Dr. Lisa Oliver

Guest Editors

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Keywords

  • glioblastoma
  • new therapeutic strategies
  • preclinical models
  • novel clinical studies
  • bioinformatics
  • mathematical modeling
  • resistance to therapy

Published Papers (8 papers)

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Research

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9 pages, 667 KiB  
Article
PD-L1/miR-155 Interplay in Pediatric High-Grade Glioma
by Jakub Litak, Wiesława Grajkowska, Jacek Bogucki, Paweł Kowalczyk, Alicja Petniak, Arkadiusz Podkowiński, Justyna Szumiło, Janusz Kocki, Jacek Roliński, Mansur Rahnama-Hezavah, Marcin Roszkowski and Cezary Grochowski
Brain Sci. 2022, 12(3), 324; https://doi.org/10.3390/brainsci12030324 - 28 Feb 2022
Cited by 2 | Viewed by 2054
Abstract
High-grade pediatric glioma (p-HGG—WHO 2021, formerly GBM—WHO 2016), as a common, aggressive, and highly lethal primary brain malignancy in adults, accounts for only 3–15% of primary brain tumors in pediatric patients. After leukemia, brain malignancies are the second most common in the pediatric [...] Read more.
High-grade pediatric glioma (p-HGG—WHO 2021, formerly GBM—WHO 2016), as a common, aggressive, and highly lethal primary brain malignancy in adults, accounts for only 3–15% of primary brain tumors in pediatric patients. After leukemia, brain malignancies are the second most common in the pediatric population and first in incidences concerning solid tumors. This study was designed on the basis of 14 pediatric patients hospitalized at Children’s Memorial Health Institute in Warsaw, Poland, due to p-HGG treatment. All the patients had a histopathological diagnosis performed by an experienced neuropathologist according to WHO guidelines (WHO 2016 Grade IV Glioblastoma). A significant correlation was found between the miR-155 concentration and the level of PD-L1 expression in p-HGG tumor tissue. Very few reports have indicated PD-L1 expression in pediatric patients. Full article
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12 pages, 1990 KiB  
Article
Development and Validation of a Long-Term 3D Glioblastoma Cell Culture in Alginate Microfibers as a Novel Bio-Mimicking Model System for Preclinical Drug Testing
by Miodrag Dragoj, Jasmina Stojkovska, Tijana Stanković, Jelena Dinić, Ana Podolski-Renić, Bojana Obradović and Milica Pešić
Brain Sci. 2021, 11(8), 1025; https://doi.org/10.3390/brainsci11081025 - 31 Jul 2021
Cited by 10 | Viewed by 2594
Abstract
Background: Various three-dimensional (3D) glioblastoma cell culture models have a limited duration of viability. Our aim was to develop a long-term 3D glioblastoma model, which is necessary for reliable drug response studies. Methods: Human U87 glioblastoma cells were cultured in alginate microfibers for [...] Read more.
Background: Various three-dimensional (3D) glioblastoma cell culture models have a limited duration of viability. Our aim was to develop a long-term 3D glioblastoma model, which is necessary for reliable drug response studies. Methods: Human U87 glioblastoma cells were cultured in alginate microfibers for 28 days. Cell growth, viability, morphology, and aggregation in 3D culture were monitored by fluorescent and confocal microscopy upon calcein-AM/propidium iodide (CAM/PI) staining every seven days. The glioblastoma 3D model was validated using temozolomide (TMZ) treatments 3 days in a row with a recovery period. Cell viability by MTT and resistance-related gene expression (MGMT and ABCB1) by qPCR were assessed after 28 days. The same TMZ treatment schedule was applied in 2D U87 cell culture for comparison purposes. Results: Within a long-term 3D model system in alginate fibers, U87 cells remained viable for up to 28 days. On day 7, cells formed visible aggregates oriented to the microfiber periphery. TMZ treatment reduced cell growth but increased drug resistance-related gene expression. The latter effect was more pronounced in 3D compared to 2D cell culture. Conclusion: Herein, we described a long-term glioblastoma 3D model system that could be particularly helpful for drug testing and treatment optimization. Full article
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14 pages, 1442 KiB  
Article
Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells
by Ana Kostić, Sofija Jovanović Stojanov, Ana Podolski-Renić, Marija Nešović, Miodrag Dragoj, Igor Nikolić, Goran Tasić, Silvia Schenone, Milica Pešić and Jelena Dinić
Brain Sci. 2021, 11(7), 884; https://doi.org/10.3390/brainsci11070884 - 30 Jun 2021
Cited by 11 | Viewed by 2126
Abstract
Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-oxidative effects of two pyrazolo[3,4- [...] Read more.
Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-oxidative effects of two pyrazolo[3,4-d]pyrimidine derivatives—Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306—were investigated in human GBM cells U87 and patient-derived GBM-6. ROS production and changes in mitochondrial membrane potential were assessed by flow cytometry. The expression levels of superoxide dismutase 1 (SOD1) and 2 (SOD2) were studied by Western blot. DNA damage, cell death induction and senescence were also examined in GBM-6 cells. Results: Si306 and pro-Si306 more prominently triggered ROS production and expression of antioxidant enzymes in primary GBM cells. These effects were followed by mitochondrial membrane potential disruption, double-strand DNA breaks and senescence that eventually led to necrosis. Conclusion: Src kinase inhibitors, Si306 and pro-Si306, showed significant pro-oxidative potential in patient-derived GBM cells. This feature contributes to the already demonstrated anti-glioblastoma properties of these compounds in vitro and in vivo and encourages clinical investigations. Full article
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15 pages, 3339 KiB  
Article
Crosstalk between 17β-Estradiol and TGF-β Signaling Modulates Glioblastoma Progression
by Ana M. Hernández-Vega and Ignacio Camacho-Arroyo
Brain Sci. 2021, 11(5), 564; https://doi.org/10.3390/brainsci11050564 - 28 Apr 2021
Cited by 9 | Viewed by 2131
Abstract
Epithelial–mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream [...] Read more.
Epithelial–mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream components of 17β-estradiol (E2) and transforming growth factor β (TGF-β) signaling pathways crosstalk in estrogen-sensitive tumors. However, little is known about the interaction between the E2 and TGF-β signaling components in brain tumors. We have investigated the relationship between E2 and TGF-β signaling pathways and their effects on EMT induction in human GBM-derived cells. Here, we showed that E2 and TGF-β negatively regulated the expression of estrogen receptor α (ER-α) and Smad2/3. TGF-β induced Smad2 phosphorylation and its subsequent nuclear translocation, which E2 inhibited. Both TGF-β and E2 induced cellular processes related to EMT, such as morphological changes, actin filament reorganization, and mesenchymal markers (N-cadherin and vimentin) expression. Interestingly, we found that the co-treatment of E2 and TGF-β blocked EMT activation. Our results suggest that E2 and TGF-β signaling pathways interact through ER-α and Smad2/3 mediators in cells derived from human GBM and inhibit EMT activation induced by both factors alone. Full article
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9 pages, 685 KiB  
Article
PD-L1 Expression Correlated with p53 Expression in Pediatric Glioblastoma Multiforme
by Jakub Litak, Wiesława Grajkowska, Justyna Szumiło, Paweł Krukow, Ryszard Maciejewski, Jacek Roliński and Cezary Grochowski
Brain Sci. 2021, 11(2), 262; https://doi.org/10.3390/brainsci11020262 - 19 Feb 2021
Cited by 5 | Viewed by 2311
Abstract
High-grade gliomas are infrequent in the pediatric population compared to adults, nevertheless, mortality and morbidity caused by malignant gliomas in this group of patients remain significant. PD-L1 and PD-1 Immune checkpoints (IC) molecules maintain immunological balance between activation and suppression. Eighteen patients with [...] Read more.
High-grade gliomas are infrequent in the pediatric population compared to adults, nevertheless, mortality and morbidity caused by malignant gliomas in this group of patients remain significant. PD-L1 and PD-1 Immune checkpoints (IC) molecules maintain immunological balance between activation and suppression. Eighteen patients with a histopathological diagnosis of pediatric glioblastoma multiforme (GBM, WHO IV) were studied. In total, PD-L1 expression was detected in 8 patients (44%). The molecular aspect of IC and immunotherapy targeted on PD-1/PD-L1 axis in pediatric population may be a promising adjuvant therapy in pediatric glioblastoma multiform treatment, however, this subject requires further investigation. Full article
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13 pages, 1470 KiB  
Article
The Evaluation of AREG, MMP-2, CHI3L1, GFAP, and OPN Serum Combined Value in Astrocytic Glioma Patients’ Diagnosis and Prognosis
by Rūta Urbanavičiūtė, Kęstutis Skauminas and Daina Skiriutė
Brain Sci. 2020, 10(11), 872; https://doi.org/10.3390/brainsci10110872 - 19 Nov 2020
Cited by 4 | Viewed by 2485
Abstract
Gliomas account for approximately 70% of primary brain tumors in adults. Of all gliomas, grade IV astrocytoma, also called glioblastoma, has the poorest overall survival, with <5% of patients surviving five years after diagnosis. Due to the aggressiveness, lethal nature, and impaired surgical [...] Read more.
Gliomas account for approximately 70% of primary brain tumors in adults. Of all gliomas, grade IV astrocytoma, also called glioblastoma, has the poorest overall survival, with <5% of patients surviving five years after diagnosis. Due to the aggressiveness, lethal nature, and impaired surgical accessibility of the tumor, early diagnosis of the tumor and, in addition, prediction of the patient’s survival time are important. We hypothesize that combining the protein level values of highly recognizable glioblastoma serum biomarkers could help to achieve higher specificity and sensitivity in predicting glioma patient outcome as compared to single markers. The aim of this study was to select the most promising astrocytoma patient overall survival prediction variables from five secretory proteins—glial fibrillary acidic protein (GFAP), matrix metalloproteinase-2 (MMP-2), chitinase 3-like 1 (CHI3L1), osteopontin (OPN), and amphiregulin (AREG)—combining them with routinely used tumor markers to create a Patient Survival Score calculation tool. The study group consisted of 70 astrocytoma patients and 31 healthy controls. We demonstrated that integrating serum CHI3L1 and OPN protein level values and tumor isocitrate dehydrogenase 1 IDH1 mutational status into one parameter could predict low-grade astrocytoma patients’ two-year survival with 93.8% accuracy. Full article
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Review

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27 pages, 4094 KiB  
Review
Against the Resilience of High-Grade Gliomas: Gene Therapies (Part II)
by Alice Giotta Lucifero and Sabino Luzzi
Brain Sci. 2021, 11(8), 976; https://doi.org/10.3390/brainsci11080976 - 23 Jul 2021
Cited by 10 | Viewed by 2574
Abstract
Introduction: High-grade gliomas (HGGs) still have a high rate of recurrence and lethality. Gene therapies were projected to overcome the therapeutic resilience of HGGs, due to the intrinsic genetic heterogenicity and immune evasion pathways. The present literature review strives to provide an updated [...] Read more.
Introduction: High-grade gliomas (HGGs) still have a high rate of recurrence and lethality. Gene therapies were projected to overcome the therapeutic resilience of HGGs, due to the intrinsic genetic heterogenicity and immune evasion pathways. The present literature review strives to provide an updated overview of the novel gene therapies for HGGs treatment, highlighting evidence from clinical trials, molecular mechanisms, and future perspectives. Methods: An extensive literature review was conducted through PubMed/Medline and ClinicalTrials.gov databases, using the keywords “high-grade glioma,” “glioblastoma,” and “malignant brain tumor”, combined with “gene therapy,” “oncolytic viruses,” “suicide gene therapies,” “tumor suppressor genes,” “immunomodulatory genes,” and “gene target therapies”. Only articles in English and published in the last 15 years were chosen, further screened based on best relevance. Data were analyzed and described according to the PRISMA guidelines. Results: Viruses were the most vehicles employed for their feasibility and transduction efficiency. Apart from liposomes, other viral vehicles remain largely still experimental. Oncolytic viruses and suicide gene therapies proved great results in phase I, II preclinical, and clinical trials. Tumor suppressor, immunomodulatory, and target genes were widely tested, showing encouraging results especially for recurrent HGGs. Conclusions: Oncolytic virotherapy and suicide genes strategies are valuable second-line treatment options for relapsing HGGs. Immunomodulatory approaches, tumor suppressor, and target genes therapies may implement and upgrade standard chemoradiotherapy. Future research aims to improve safety profile and prolonging therapeutic effectiveness. Further clinical trials are needed to assess the efficacy of gene-based therapies. Full article
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30 pages, 2538 KiB  
Review
Against the Resilience of High-Grade Gliomas: The Immunotherapeutic Approach (Part I)
by Alice Giotta Lucifero and Sabino Luzzi
Brain Sci. 2021, 11(3), 386; https://doi.org/10.3390/brainsci11030386 - 18 Mar 2021
Cited by 16 | Viewed by 3783
Abstract
The resilience of high-grade gliomas (HGGs) against conventional chemotherapies is due to their heterogeneous genetic landscape, adaptive phenotypic changes, and immune escape mechanisms. Innovative immunotherapies have been developed to counteract the immunosuppressive capability of gliomas. Nevertheless, further research is needed to assess the [...] Read more.
The resilience of high-grade gliomas (HGGs) against conventional chemotherapies is due to their heterogeneous genetic landscape, adaptive phenotypic changes, and immune escape mechanisms. Innovative immunotherapies have been developed to counteract the immunosuppressive capability of gliomas. Nevertheless, further research is needed to assess the efficacy of the immuno-based approach. The aim of this study is to review the newest immunotherapeutic approaches for glioma, focusing on the drug types, mechanisms of action, clinical pieces of evidence, and future challenges. A PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis)-based literature search was performed on PubMed/Medline and ClinicalTrials.gov databases using the keywords “active/adoptive immunotherapy,” “monoclonal antibodies,” “vaccine,” and “engineered T cell.”, combined with “malignant brain tumor”, “high-grade glioma.” Only articles written in English published in the last 10 years were selected, filtered based on best relevance. Active immunotherapies include systemic temozolomide, monoclonal antibodies, and vaccines. In several preclinical and clinical trials, adoptive immunotherapies, including T, natural killer, and natural killer T engineered cells, have been shown to be potential treatment options for relapsing gliomas. Systemic temozolomide is considered the backbone for newly diagnosed HGGs. Bevacizumab and rindopepimut are promising second-line treatments. Adoptive immunotherapies have been proven for relapsing tumors, but further evidence is needed. Full article
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