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The Occurrence, Evolution and Treatment of Glioblastoma: Second Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 May 2025 | Viewed by 9987

Special Issue Editor

Dr. Antonella Mangraviti

E-Mail Website
Guest Editor
Department of Neuroscience, Mental Health and Sense Organs (NESMOS), Sapienza University of Rome, 00189 Rome, Italy
Interests: brain tumors; glioblastoma; drug delivery; nanobased delivery systems; neuroimaging; stem cells; antiangiogenetic drugs; preclinical animal models; cerebral blood flow imaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Of the 100,000 new cases of diffuse gliomas diagnosed every year worldwide, approximately 75% are glioblastoma(GBM). Novel therapeutics over the past couple of decades have only met with limited success, and median survival remains at 14 to 17 months. However, recent advances in gene profiling and proteomics have led to significant breakthroughs in the taxonomy, classification, and grading of both adults and pediatric brain gliomas. The aim of this Special Issue is to shed light on the molecular heterogeneity of this tumor in both adults and children, as well as to evaluate the benefits of multimodal treatment strategies involving surgery, radiotherapy, and chemotherapy. With new drug candidates now at different stages of clinical development, this approach takes full advantage of research on molecular and gene profiling to ensure ever more precise diagnoses as well as new promising treatments.

We welcome submissions, including original papers and reviews. Our Special Issue will focus on, but is not restricted to, the following:

  • Tumor signatures in primary vs. secondary gliomas;
  • The role of recently identified biomarkers in both the prognosis and treatment of pediatric gliomas;
  • Role of checkpoints inhibitors in low- and high-grade gliomas;
  • Mechanisms of recurrence of high-grade gliomas;
  • Molecular and radiological features in low-grade gliomas shifting into high-grade gliomas;
  • Role of re-surgery and re-radiation in recurrent GBMs;
  • New developments in the armamentarium of pre-, intra-, and post-operative tools for the treatment of newly diagnosed/recurrent GBMs;
  • Role of radiomics and neuroimaging in deep-seeded and multifocal gliomas for improved patient treatment and information;
  • Midbrain gliomas: management and prognosis.

Dr. Antonella Mangraviti
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • GBM
  • low-grade and high-grade
  • pediatric diffuse gliomas
  • signaling pathways in GBMs
  • recurrent gliomas
  • midbrain gliomas
  • radiomics in brain tumors
  • re-surgery and re-radiation in GBMs
  • immunotherapy
  • targeted therapies for GBMs

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Published Papers (6 papers)

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Research

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17 pages, 4583 KiB  
Article
The Immunomodulatory Effects of Vitamin D on COVID-19 Induced Glioblastoma Recurrence via the PI3K-AKT Signaling Pathway
by Bi-Tian Zhang, Ping-Chung Leung, Chun-Kwok Wong and Dong-Jie Wang
Int. J. Mol. Sci. 2024, 25(23), 12952; https://doi.org/10.3390/ijms252312952 - 2 Dec 2024
Cited by 1 | Viewed by 1304
Abstract
Glioma is a highly invasive brain cancer that is difficult to treat due to its complex molecular characteristics and poor prognosis. The COVID-19 pandemic has introduced additional clinical challenges for cancer patients, especially those with glioma. This study explored the molecular interactions between [...] Read more.
Glioma is a highly invasive brain cancer that is difficult to treat due to its complex molecular characteristics and poor prognosis. The COVID-19 pandemic has introduced additional clinical challenges for cancer patients, especially those with glioma. This study explored the molecular interactions between glioma and COVID-19 using integrated bioinformatics methods, including enrichment analysis, survival analysis, and molecular docking, focusing on the PI3K-Akt signaling pathway and the immunomodulatory role of vitamin D. From gene expression data of glioma and COVID-19, 203 common differentially expressed genes were identified, and six prognostic key genes—MYBL2, RBM6, VEPH1, AHNAK2, GNG10, and DUSP14—were further determined. After intersecting with vitamin D targets five prognostic key genes were determined—MYBL2, RBM6, VEPH1, AHNAK2 and GNG10. These genes play significant roles in the PI3K-Akt pathway and potentially interact with vitamin D. Molecular docking and single-cell RNA sequencing analyses suggest that vitamin D may improve the prognosis of glioma patients infected with COVID-19 by regulating these key genes and the PI3K-Akt pathway. The findings reveal molecular links between glioma and COVID-19, thereby providing new insights for developing targeted therapeutic strategies. Full article
(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma: Second Edition)
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17 pages, 3824 KiB  
Article
Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma
by Sonia Shinhmar, Judith Schaf, Katie Lloyd Jones, Olivier E. Pardo, Philip Beesley and Robin S. B. Williams
Int. J. Mol. Sci. 2024, 25(12), 6586; https://doi.org/10.3390/ijms25126586 - 14 Jun 2024
Viewed by 1392
Abstract
Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has [...] Read more.
Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system Dictyostelium discoideum and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In D. discoideum, T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn-) or MIOS (mios-). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the D. discoideum mios- cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified. Full article
(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma: Second Edition)
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17 pages, 1700 KiB  
Article
EGFRvIII Confers Sensitivity to Saracatinib in a STAT5-Dependent Manner in Glioblastoma
by Mylan R. Blomquist, Ryan Eghlimi, Angad Beniwal, Dustin Grief, David G. Nascari, Landon Inge, Christopher P. Sereduk, Serdar Tuncali, Alison Roos, Hannah Inforzato, Ritin Sharma, Patrick Pirrotte, Shwetal Mehta, Shannon P. Fortin Ensign, Joseph C. Loftus and Nhan L. Tran
Int. J. Mol. Sci. 2024, 25(11), 6279; https://doi.org/10.3390/ijms25116279 - 6 Jun 2024
Cited by 1 | Viewed by 1884
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 [...] Read more.
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival. Full article
(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma: Second Edition)
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Review

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20 pages, 750 KiB  
Review
Serendipity in Neuro-Oncology: The Evolution of Chemotherapeutic Agents
by Denise Nadora, Shawyon Ezzati, Brandon Bol and Orwa Aboud
Int. J. Mol. Sci. 2025, 26(7), 2955; https://doi.org/10.3390/ijms26072955 - 25 Mar 2025
Viewed by 431
Abstract
The development of novel therapeutics in neuro-oncology faces significant challenges, often marked by high costs and low success rates. Despite advances in molecular biology and genomics, targeted therapies have had limited impact on improving patient outcomes in brain tumors, particularly gliomas, due to [...] Read more.
The development of novel therapeutics in neuro-oncology faces significant challenges, often marked by high costs and low success rates. Despite advances in molecular biology and genomics, targeted therapies have had limited impact on improving patient outcomes in brain tumors, particularly gliomas, due to the complex, multigenic nature of these malignancies. While significant efforts have been made to design drugs that target specific signaling pathways and genetic mutations, the clinical success of these rational approaches remains sparse. This review critically examines the landscape of neuro-oncology drug discovery, highlighting instances where serendipity has led to significant breakthroughs, such as the unexpected efficacy of repurposed drugs and off-target effects that proved beneficial. By exploring historical and contemporary cases, we underscore the role of chance in the discovery of impactful therapies, arguing that embracing serendipity alongside rational drug design may enhance future success in neuro-oncology drug development. Full article
(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma: Second Edition)
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22 pages, 2243 KiB  
Review
Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme
by Corina Tamas, Flaviu Tamas, Attila Kovecsi, Alina Cehan and Adrian Balasa
Int. J. Mol. Sci. 2024, 25(10), 5482; https://doi.org/10.3390/ijms25105482 - 17 May 2024
Cited by 6 | Viewed by 2865
Abstract
The metabolism of glucose and lipids plays a crucial role in the normal homeostasis of the body. Although glucose is the main energy substrate, in its absence, lipid metabolism becomes the primary source of energy. The main means of fatty acid oxidation (FAO) [...] Read more.
The metabolism of glucose and lipids plays a crucial role in the normal homeostasis of the body. Although glucose is the main energy substrate, in its absence, lipid metabolism becomes the primary source of energy. The main means of fatty acid oxidation (FAO) takes place in the mitochondrial matrix through β-oxidation. Glioblastoma (GBM) is the most common form of primary malignant brain tumor (45.6%), with an incidence of 3.1 per 100,000. The metabolic changes found in GBM cells and in the surrounding microenvironment are associated with proliferation, migration, and resistance to treatment. Tumor cells show a remodeling of metabolism with the use of glycolysis at the expense of oxidative phosphorylation (OXPHOS), known as the Warburg effect. Specialized fatty acids (FAs) transporters such as FAT, FABP, or FATP from the tumor microenvironment are overexpressed in GBM and contribute to the absorption and storage of an increased amount of lipids that will provide sufficient energy used for tumor growth and invasion. This review provides an overview of the key enzymes, transporters, and main regulatory pathways of FAs and ketone bodies (KBs) in normal versus GBM cells, highlighting the need to develop new therapeutic strategies to improve treatment efficacy in patients with GBM. Full article
(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma: Second Edition)
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Other

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14 pages, 1518 KiB  
Brief Report
Investigating Expression Dynamics of miR-21 and miR-10b in Glioblastoma Cells In Vitro: Insights into Responses to Hypoxia and Secretion Mechanisms
by Hanna Charbit and Iris Lavon
Int. J. Mol. Sci. 2024, 25(14), 7984; https://doi.org/10.3390/ijms25147984 - 22 Jul 2024
Cited by 2 | Viewed by 1373
Abstract
Glioblastoma poses significant challenges in oncology, with bevacizumab showing promise as an antiangiogenic treatment but with limited efficacy. microRNAs (miRNAs) 10b and 21 have emerged as potential biomarkers for bevacizumab response in glioblastoma patients. This study delves into the expression dynamics of miR-21 [...] Read more.
Glioblastoma poses significant challenges in oncology, with bevacizumab showing promise as an antiangiogenic treatment but with limited efficacy. microRNAs (miRNAs) 10b and 21 have emerged as potential biomarkers for bevacizumab response in glioblastoma patients. This study delves into the expression dynamics of miR-21 and miR-10b in response to hypoxia and explores their circulation mechanisms. In vitro experiments exposed glioma cells (A172, U87MG, U251) and human umbilical vein endothelial cells (HUVEC) to hypoxic conditions (1% oxygen) for 24 h, revealing heightened levels of miR-10b and miR-21 in glioblastoma cells. Manipulating miR-10b expression in U87MG, demonstrating a significant decrease in VEGF alpha (VEGFA) following miR-10b overexpression under hypoxic conditions. Size exclusion chromatography illustrated a notable shift towards miR-21 and miR-10b exosomal packaging during hypoxia. A proposed model suggests that effective bevacizumab treatment reduces VEGFA levels, heightening hypoxia and subsequently upregulating miR-21 and miR-10b expression. These miRNAs, released via exosomes, might impact various cellular processes, with miR-10b notably contributing to VEGFA level reduction. However, post-treatment increases in miR-10b and miR-21 could potentially restore cells to normoxic conditions through the downregulation of VEGF. This study highlights the intricate feedback loop involving miR-10b, miR-21, and VEGFA in glioblastoma treatment, underscoring the necessity for personalized therapeutic strategies. Further research should explore clinical implications for personalized glioma treatments. Full article
(This article belongs to the Special Issue The Occurrence, Evolution and Treatment of Glioblastoma: Second Edition)
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