Identification of Molecular Targets and Anti-cancer Agents in Glioblastoma Multiforme: New Perspectives for Cancer Therapy

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 (5 February 2023) | Viewed by 14154

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Department of Drug and Health Sciences, University of Catania, 95100 Catania, Italy
Interests: neuroanatomy; neuroscience; neuropeptides; neural stem cells; identification of carcinogenic bi-omarkers; study of molecular mechanisms involved in cancers progression
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Department of Biomedicine, Neurosciences and Advanced Diagnostic (BiND), Human Anatomy Section, University of Palermo, 90127 Palermo, Italy
Interests: extracellular vesicles; exosomes; miRNA; liquid biopsy; cancerogenesis; anatomy; molecular chaperones; heat shock proteins; extracellular chaperones
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Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ''Luigi Vanvitelli", 80138 Naples, Italy
Interests: central nervous system plasticity; glioblastoma microenvironment; tumor–glia inter-action; blood–brain barrier; peripheral nerve injury
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glioblastoma multiforme (GBM) or grade IV astrocytoma is the deadliest form of brain tumor. To date, the standard therapy consists of a multimodal approach combining surgery, radiation and chemotherapy with temozolomide. However, tumor relapse frequently occurs, and survival rates are poor in patients. GBM’s poor prognosis is also attributable to therapeutic resistance to standard therapy. The therapeutic resistance is mainly due to the presence of glioblastoma stem cells (GSCs) inside the tumor core, and could be dependent on innate differences in clonogenic GSCs’ sensitivity to conventional therapy. GSCs and mature cells reside in specific regions of the cancer mass forming tumor niches, including hypoxic, vascular and perivascular niches that support GSCs’ quiescent status and contribute to create a microenvironmental cue sustaining their pluripotent potential which determines cancer aggressiveness and therapy resistance. The resident cells of the central nervous system and blood-derived elements are recruited into the niches for a functional symbiosis that ensures energy sources, invasiveness, immune escape, and drug resistance to the GBM, allowing its progression.

Furthermore, GBM is characterized by intratumor and inter-patient molecular heterogeneity that may underlie differences in patient sensitivity to therapy and prognosis.

Although the research in this field is rapidly evolving, there is a persistent variability of treatment effectiveness and difficulty in performing early diagnosis. The identification of non-invasive alternatives to standard diagnostic approaches, such as liquid biopsy, as well as novel treatment strategies and effective therapeutic targets, could offer new directions for future therapeutic management.

This Special Issue considers original research articles, review articles, and commentaries on the following themes: i) identification of new molecular targeted and/or prognostic biomarkers for GBM; ii) recent advances in combined therapy to existing gold-standard treatment; iii) ongoing clinical trials in the treatment of GBM.

Prof. Dr. Agata Grazia D'Amico
Prof. Dr. Celeste Caruso Bavisotto
Dr. Assunta Virtuoso
Guest Editors

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Keywords

  • glioblastoma multiforme
  • tumor microenvironment
  • hypoxic niches
  • vascular niches
  • liquid biopsy
  • extracellular vesicles
  • immunotherapy
  • glial cells
  • neurons
  • macrophages

Published Papers (7 papers)

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Editorial

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3 pages, 174 KiB  
Editorial
Identification of Molecular Targets and Anti-Cancer Agents in GBM: New Perspectives for Cancer Therapy
by Agata Grazia D’Amico, Celeste Caruso Bavisotto and Assunta Virtuoso
Brain Sci. 2023, 13(7), 1078; https://doi.org/10.3390/brainsci13071078 - 17 Jul 2023
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Abstract
The authors of the present literature piece were invited to participate in the present Special Issue at the beginning of 2022, and we were all very enthusiastic at the prospect of assembling a series of articles on new molecular targets and anti-cancer agents [...] Read more.
The authors of the present literature piece were invited to participate in the present Special Issue at the beginning of 2022, and we were all very enthusiastic at the prospect of assembling a series of articles on new molecular targets and anti-cancer agents in glioblastoma multiforme (GBM) [...] Full article

Research

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11 pages, 1582 KiB  
Article
Inducible Knockout of 14-3-3β Attenuates Proliferation and Spheroid Formation in a Human Glioblastoma Cell Line U87MG
by Kellie Gallo, Bhairavi Srinageshwar, Avery Ward, Carlos Diola, Gary Dunbar, Julien Rossignol and Jesse Bakke
Brain Sci. 2023, 13(6), 868; https://doi.org/10.3390/brainsci13060868 - 27 May 2023
Cited by 2 | Viewed by 1849
Abstract
Glioblastomas (GBs) are the most common and malignant brain tumors in adults. A protein encoded by the gene YWHAB, 14-3-3β, is commonly found to be upregulated throughout the initiation and progression of GB. The 14-3-3β has oncogenic roles in several different types of [...] Read more.
Glioblastomas (GBs) are the most common and malignant brain tumors in adults. A protein encoded by the gene YWHAB, 14-3-3β, is commonly found to be upregulated throughout the initiation and progression of GB. The 14-3-3β has oncogenic roles in several different types of cancer cells through interactions with proteins such as Bad, FBI1, Raf-1, Cdc25b, and others. Previous RNA interference studies have shown that 14-3-3β promotes proliferation, cell cycle progression, and migration and invasion of GB cells. However, despite the many oncogenic functions of 14-3-3β, a CRISPR/Cas9 knockout model of 14-3-3β has not been investigated. This study confirmed previous findings and showed that siRNA inhibition of 14-3-3β results in reduced cellular proliferation in a human glioblastoma cell line, U87MG. We also used a YWHAB Tet-On CRISPR/Cas9 U87MG cell line that, upon doxycycline induction, leads to robust Cas9 expression and subsequent knockout of 14-3-3β. Using this model, we show that loss of 14-3-3β significantly reduces cellular proliferation and spheroid formation of U87MG cells. Full article
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17 pages, 2738 KiB  
Article
Single-Cell Transcriptomics Reveals Evidence of Endothelial Dysfunction in the Brains of COVID-19 Patients with Implications for Glioblastoma Progression
by Abhimanyu Thakur, Lifan Liang, Sourav Banerjee and Kui Zhang
Brain Sci. 2023, 13(5), 762; https://doi.org/10.3390/brainsci13050762 - 05 May 2023
Cited by 3 | Viewed by 3920
Abstract
Background: Endothelial dysfunction is implicated in various inflammatory diseases such as ischemic stroke, heart attack, organ failure, and COVID-19. Recent studies have shown that endothelial dysfunction in the brain is attributed to excessive inflammatory responses caused by the SARS-CoV-2 infection, leading to increased [...] Read more.
Background: Endothelial dysfunction is implicated in various inflammatory diseases such as ischemic stroke, heart attack, organ failure, and COVID-19. Recent studies have shown that endothelial dysfunction in the brain is attributed to excessive inflammatory responses caused by the SARS-CoV-2 infection, leading to increased permeability of the blood-brain barrier and consequently neurological damage. Here, we aim to examine the single-cell transcriptomic landscape of endothelial dysfunction in COVID-19 and its implications for glioblastoma (GBM) progression. Methods: Single-cell transcriptome data GSE131928 and GSE159812 were obtained from the gene expression omnibus (GEO) to analyze the expression profiles of key players in innate immunity and inflammation between brain endothelial dysfunction caused by COVID-19 and GBM progression. Results: Single-cell transcriptomic analysis of the brain of COVID-19 patients revealed that endothelial cells had undergone significant transcriptomic changes, with several genes involved in immune responses and inflammation upregulated. Moreover, transcription factors were observed to modulate this inflammation, including interferon-regulated genes. Conclusions: The results indicate a significant overlap between COVID-19 and GBM in the context of endothelial dysfunction, suggesting that there may be an endothelial dysfunction link connecting severe SARS-CoV-2 infection in the brain to GBM progression. Full article
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8 pages, 5089 KiB  
Communication
Technical Pearls to Effectively Use 5-ALA in Fluorescence-Guided Tumor Resection—5 Lessons from the Operating Room
by Giuseppe Maria Della Pepa, Grazia Menna and Alessandro Olivi
Brain Sci. 2023, 13(3), 411; https://doi.org/10.3390/brainsci13030411 - 27 Feb 2023
Cited by 4 | Viewed by 1469
Abstract
Background: Since its introduction in 2007 in Europe and in 2017 in the United States, 5-ALA has demonstrated an undisputed advantage in providing real-time tumor visualization. The aim of the present paper is to summarize our institutional experience over a decade of routine [...] Read more.
Background: Since its introduction in 2007 in Europe and in 2017 in the United States, 5-ALA has demonstrated an undisputed advantage in providing real-time tumor visualization. The aim of the present paper is to summarize our institutional experience over a decade of routine 5-ALA-guided procedures in order to provide five surgical tricks to ease surgical workflow. Methods: Data were collected from 822 patients diagnosed with histopathologically confirmed high-grade gliomas (HGG)—according to the WHO 2021 criteria—who underwent surgery at the Fondazione Policlinico Universitario Agostino Gemelli between January 2012 and January 2022. Results: From our large institutional experience, the learned technical pearls were grouped in five distinct domains: 1. Analysis of visualization, overall workflow, and technical recommendations to improve intraoperative set-up; 2. Techniques to reduce the risk of inadvertent residuals and failure to evocate fluorescence; 3. Analysis of specific surgical conditions favoring remnants; 4. Assessment of different degrees of fluorescence and their surgical meaning; 5. Analysis of false positive cases. Conclusions: With all the limitations of a qualitative and retrospective analysis, this paper was specifically conceived as a vademecum for educational purposes to promote and maximize 5-ALA employment. Full article
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13 pages, 3101 KiB  
Communication
Identification of Dysregulated microRNAs in Glioblastoma Stem-like Cells
by Lara Evers, Agnes Schäfer, Raffaella Pini, Kai Zhao, Susanne Stei, Christopher Nimsky and Jörg W. Bartsch
Brain Sci. 2023, 13(2), 350; https://doi.org/10.3390/brainsci13020350 - 18 Feb 2023
Cited by 2 | Viewed by 1702
Abstract
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite multimodal therapy, median survival is poor at 12–15 months. At the molecular level, radio-/chemoresistance and resulting tumor progression are attributed to a small fraction of tumor cells, termed glioblastoma [...] Read more.
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite multimodal therapy, median survival is poor at 12–15 months. At the molecular level, radio-/chemoresistance and resulting tumor progression are attributed to a small fraction of tumor cells, termed glioblastoma stem-like cells (GSCs). These CD133-expressing, self-renewing cells display the properties of multi-lineage differentiation, resulting in the heterogenous composition of GBM. MicroRNAs (miRNAs) as regulators of gene expression at the post-transcriptional level can alter many pathways pivotal to cancer stem cell fate. This study explored changes in the miRNA expression profiles in patient-derived GSCs altered on differentiation into glial fiber acid protein (GFAP)-expressing, astrocytic tumor cells using a polymerase chain reaction (PCR) array. Initially, 22 miRNAs showed higher expression in GSCs and 9 miRNAs in differentiated cells. The two most downregulated miRNAs in differentiated GSCs were miR-17-5p and miR-425-5p, whilst the most upregulated miRNAs were miR-223-3p and let-7-5p. Among those, miR-425-5p showed the highest consistency in an upregulation in all three GSCs. By transfection of a 425-5p miRNA mimic, we demonstrated downregulation of the GFAP protein in differentiated patient-derived GBM cells, providing potential evidence for direct regulation of miRNAs in the GSC/GBM cell transition. Full article
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19 pages, 16156 KiB  
Article
Single-Cell Sequencing Analysis Identified ASTN2 as a Migration Biomarker in Adult Glioblastoma
by Tangjun Guo, Aijun Bao, Yandong Xie, Jianting Qiu and Haozhe Piao
Brain Sci. 2022, 12(11), 1472; https://doi.org/10.3390/brainsci12111472 - 30 Oct 2022
Cited by 2 | Viewed by 1784
Abstract
Glioblastoma is the most common and aggressive primary central nervous system malignant tumors. With the development of targeted sequencing and proteomic profiling technology, some new tumor types have been established and a series of novel molecular markers have also been identified. The 2021 [...] Read more.
Glioblastoma is the most common and aggressive primary central nervous system malignant tumors. With the development of targeted sequencing and proteomic profiling technology, some new tumor types have been established and a series of novel molecular markers have also been identified. The 2021 updated World Health Organization classification of central nervous system tumors first mentioned the classification of adult glioma and pediatric glioma based on the molecular diagnosis. Thus, we used single-cell RNA sequencing analysis to explore the diversity and similarities in the occurrence and development of adult and pediatric types. ASTN2, which primarily encodes astrotactin, has been reported to be dysregulated in various neurodevelopmental disorders. Although some studies have demonstrated that ASTN2 plays an important role in glial-guided neuronal migration, there are no studies about its impact on glioblastoma cell migration. Subsequent single-cell RNA sequencing revealed ASTN2 to be a hub gene of a cell cluster which had a poor effect on clinical prognosis. Eventually, a western blot assay and a wound-healing assay first confirmed that ASTN2 expression in glioblastoma cell lines is higher than that in normal human astrocytes and affects the migration ability of glioblastoma cells, making it a potential therapeutic target. Full article
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Other

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41 pages, 2259 KiB  
Systematic Review
Molecular Targeted Therapies in Glioblastoma Multiforme: A Systematic Overview of Global Trends and Findings
by Emir Begagić, Ragib Pugonja, Hakija Bečulić, Amila Čeliković, Lejla Tandir Lihić, Samra Kadić Vukas, Lejla Čejvan, Rasim Skomorac, Edin Selimović, Belma Jaganjac, Fatima Juković-Bihorac, Aldin Jusić and Mirza Pojskić
Brain Sci. 2023, 13(11), 1602; https://doi.org/10.3390/brainsci13111602 - 17 Nov 2023
Cited by 5 | Viewed by 1598
Abstract
This systematic review assesses current molecular targeted therapies for glioblastoma multiforme (GBM), a challenging condition with limited treatment options. Using PRISMA methodology, 166 eligible studies, involving 2526 patients (61.49% male, 38.51% female, with a male-to-female ratio of 1.59/1), were analyzed. In laboratory studies, [...] Read more.
This systematic review assesses current molecular targeted therapies for glioblastoma multiforme (GBM), a challenging condition with limited treatment options. Using PRISMA methodology, 166 eligible studies, involving 2526 patients (61.49% male, 38.51% female, with a male-to-female ratio of 1.59/1), were analyzed. In laboratory studies, 52.52% primarily used human glioblastoma cell cultures (HCC), and 43.17% employed animal samples (mainly mice). Clinical participants ranged from 18 to 100 years, with 60.2% using combined therapies and 39.8% monotherapies. Mechanistic categories included Protein Kinase Phosphorylation (41.6%), Cell Cycle-Related Mechanisms (18.1%), Microenvironmental Targets (19.9%), Immunological Targets (4.2%), and Other Mechanisms (16.3%). Key molecular targets included Epidermal Growth Factor Receptor (EGFR) (10.8%), Mammalian Target of Rapamycin (mTOR) (7.2%), Vascular Endothelial Growth Factor (VEGF) (6.6%), and Mitogen-Activated Protein Kinase (MEK) (5.4%). This review provides a comprehensive assessment of molecular therapies for GBM, highlighting their varied efficacy in clinical and laboratory settings, ultimately impacting overall and progression-free survival in GBM management. Full article
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