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Glioblastoma: Pathogenetic, Diagnostic and Therapeutic Perspectives

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: 31 March 2025 | Viewed by 7066

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Dr. Thi Thu Trang Nguyen

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Vagelos College of Physicians and Surgeons, New York, NY, USA
Interests: brain tumor

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Dear Colleagues,

Glioblastoma (GBM) is a highly aggressive and invasive tumor that targets the central nervous system (CNS), boasting the lowest survival rate among CNS tumors with a median survival time of only 12–15 months. Its treatment protocol involves surgical resection, followed by fractionated radiotherapy and concurrent/adjuvant chemotherapy using temozolomide. Despite these clinical interventions, recurrence is prevalent, occurring in over 80% of cases at the resection cavity's edge within months post-treatment. This high recurrence rate and the tumor's location underscore the pressing need for a deeper understanding of therapeutic strategies.

An enhanced comprehension of GBM's molecular and cellular heterogeneity can not only refine subgroup categorization for precise diagnosis but also pave the way for targeted therapy success. Targeting the Warburg effect presents a promising avenue for GBM treatment due to its metabolic adaptability. Moreover, employing various immunotherapeutic approaches such as checkpoint inhibitors, vaccines, CAR-modified NK or T cells, and oncolytic virotherapy aims to bolster the immune response against GBM. Additionally, efforts to breach the blood–brain barrier (BBB) using nanotherapies (targeting GB cellular receptors or opening the BBB) or non-ionizing energies (high/low-intensity focused ultrasounds) offer potential breakthroughs to overcome current therapy limitations.

This Special Issue aims to delve into the pathophysiological mechanisms driving glioblastoma, uncover potential therapeutic targets, and explore advanced methodologies that hold promise in combating this lethal disease.

Dr. Thi Thu Trang Nguyen
Guest Editor

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Keywords

drug delivery methods (TTFields, nanoparticles)
immunotherapy
oncolytic virotherapy
cell metabolism (glycolysis, OXPHOS, fatty acid oxidation)
epigenetic
biomarkers
gene therapy (CRISPR/Cas9)

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Research

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19 pages, 3840 KiB

Open AccessArticle

Hypoxia-Regulated CD44 and xCT Expression Contributes to Late Postoperative Epilepsy in Glioblastoma

by Kosuke Kusakabe, Akihiro Inoue, Takanori Ohnishi, Yawara Nakamura, Yoshihiro Ohtsuka, Masahiro Nishikawa, Hajime Yano, Mohammed E. Choudhury, Motoki Murata, Shirabe Matsumoto, Satoshi Suehiro, Daisuke Yamashita, Seiji Shigekawa, Hideaki Watanabe and Takeharu Kunieda

Biomedicines 2025, 13(2), 372; https://doi.org/10.3390/biomedicines13020372 - 5 Feb 2025

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Abstract

Background/Objectives: Late epilepsy occurring in the late stage after glioblastoma (GBM) resection is suggested to be caused by increased extracellular glutamate (Glu). To elucidate the mechanism underlying postoperative late epilepsy, the present study aimed to investigate the expressions and relations of molecules related to Glu metabolism in tumor tissues from GBM patients and cultured glioma stem-like cells (GSCs). Methods: Expressions of CD44, xCT and excitatory amino acid transporter (EAAT) 2 and extracellular Glu concentration in GBM patients with and without epilepsy were examined and their relationships were analyzed. For the study using GSCs, expressions and relationships of the same molecules were analyzed and the effects of CD44 knock-down on xCT, EAAT2, and Glu were investigated. In addition, the effects of hypoxia on the expressions of these molecules were investigated. Results: Tumor tissues highly expressed CD44 and xCT in the periphery of GBM with epilepsy, whereas no significant difference in EAAT2 expression was seen between groups with and without epilepsy. Extracellular Glu concentration was higher in patients with epilepsy than those without epilepsy. GSCs displayed reciprocal expressions of CD44 and xCT. Concentrations of extracellular Glu coincided with the degree of xCT expression, and CD44 knock-down elevated xCT expression and extracellular Glu concentrations. Hypoxia of 1% O₂ elevated expression of CD44, while 5% O₂ increased xCT and extracellular Glu concentration. Conclusions: Late epilepsy after GBM resection was related to extracellular Glu concentrations that were regulated by reciprocal expression of CD44 and xCT, which were stimulated by differential hypoxia for each molecule. Full article

(This article belongs to the Special Issue Glioblastoma: Pathogenetic, Diagnostic and Therapeutic Perspectives)

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17 pages, 15430 KiB

Open AccessArticle

CLIC4 Is a New Biomarker for Glioma Prognosis

by Zhichun Liu, Junhui Liu, Zhibiao Chen, Xiaonan Zhu, Rui Ding, Shulan Huang and Haitao Xu

Biomedicines 2024, 12(11), 2579; https://doi.org/10.3390/biomedicines12112579 - 11 Nov 2024

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Abstract

Background: Chloride Intracellular Channel 4 (CLIC4) plays a versatile role in cellular functions beyond its role in primary chloride ion transport. Notably, many studies found an association between CLIC4 expression and cancers. However, the correlation between CLIC4 and glioma remains to be uncovered. Methods: A total of 3162 samples from nine public datasets were analyzed to reveal the relationship between CLIC4 expression and glioma malignancy or prognosis. Immunohistochemistry (IHC) staining was performed to examine the results in an in-house cohort. A nomogram model was constructed to predict the prognosis. Functional enrichment analysis was employed to find CLIC4-associated differentially expressed genes in glioma. Immune infiltration analysis, correlation analysis, and IHC staining were employed, aiming to examine the correlation between CLIC4 expression, immune cell infiltration, and ECM (extracellular matrix)-related genes. Results: The expression level of CLIC4 was correlated with the malignancy of glioma and the prognosis of patients. More aggressive gliomas and mesenchymal GBM are associated with a high expression of CLIC4. Gliomas with IDH mutation or 1p19q codeletion express a low level of CLIC4, and a high expression of CLIC4 correlates with poor prognosis. The nomogram model shows a good predictive performance. The DEGs (differentially expressed genes) in gliomas with high and low CLIC4 expression are enriched in extracellular matrix and immune functions. On the one hand, gliomas with high CLIC4 expression have a greater presence of macrophages, neutrophils, and eosinophils; on the other hand, a high CLIC4 expression in gliomas is positively associated with ECM-related genes. Conclusions: Compared to glioma cells with low CLIC4 expression, gliomas with high CLIC4 expression exhibit greater malignancy and poorer prognosis. Our findings indicate that a high level of CLIC4 correlates with high expression of ECM-related genes and the infiltration of macrophages, neutrophils, and eosinophils within glioma tissues. Full article

(This article belongs to the Special Issue Glioblastoma: Pathogenetic, Diagnostic and Therapeutic Perspectives)

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17 pages, 288 KiB

Open AccessArticle

CDKN2A Homozygous Deletion Is a Stronger Predictor of Outcome than IDH1/2-Mutation in CNS WHO Grade 4 Gliomas

by Sang Hyuk Lee, Tae Gyu Kim, Kyeong Hwa Ryu, Seok Hyun Kim and Young Zoon Kim

Biomedicines 2024, 12(10), 2256; https://doi.org/10.3390/biomedicines12102256 - 4 Oct 2024

Cited by 1 | Viewed by 1455

Abstract

Background: We primarily investigated the prognostic role of CDKN2A homozygous deletion in CNS WHO grade 4 gliomas. Additionally, we plan to examine traditional prognostic factors for grade 4 gliomas and validate the findings. Materials: We conducted a retrospective analysis of the glioma cohorts at our institute. We reviewed medical records spanning a 15-year period and examined pathological slides for an updated diagnosis according to the 2021 WHO classification of CNS tumors. We examined the IDH1/2 mutation and CDKN2A deletion using NGS analysis with ONCOaccuPanel^®. Further, we examined traditional prognostic factors, including age, WHO performance status, extent of resection, and MGMT promoter methylation status. Results: The mean follow-up duration was 27.5 months (range: 4.1–43.5 months) and mean overall survival (OS) was 20.7 months (SD, ±1.759). After the exclusion of six patients with a poor status of pathologic samples, a total of 136 glioblastoma cases diagnosed by previous WHO classification criteria were newly classified into 29 (21.3%) astrocytoma, IDH-mutant, and CNS WHO grade 4 cases, and 107 (78.7%) glioblastoma, IDH-wildtype, and CNS WHO grade 4 cases. Among them, 61 (56.0%) had CDKN2A deletions. The high-risk group with CDKN2A deletion regardless of IDH1/2 mutation had a mean OS of 16.65 months (SD, ±1.554), the intermediate-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 21.85 months (SD, ±2.082), and the low-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 33.38 months (SD, ±2.946). Multifactor analysis showed that age (≥50 years vs. <50 years; HR 4.645), WHO performance (0, 1 vs. 2; HR 5.002), extent of resection (gross total resection vs. others; HR 5.528), MGMT promoter methylation, (methylated vs. unmethylated; HR 5.078), IDH1/2 mutation (mutant vs. wildtype; HR 6.352), and CDKN2A deletion (absence vs. presence; HR 13.454) were associated with OS independently. Conclusions: The present study suggests that CDKN2A deletion plays a powerful prognostic role in CNS WHO grade 4 gliomas. Even if CNS WHO grade 4 gliomas have mutant IDH1/2, they may have poor clinical outcomes because of CDKN2A deletion. Full article

(This article belongs to the Special Issue Glioblastoma: Pathogenetic, Diagnostic and Therapeutic Perspectives)

11 pages, 2028 KiB

Open AccessArticle

Epigenetic Characteristics in Primary and Recurrent Glioblastoma—Influence on the Clinical Course

by Alexander Quiring, Hannah Spielmann, Fritz Teping, Safwan Saffour, Fatemeh Khafaji, Walter Schulz-Schaeffer, Nathan Monfroy, Joachim Oertel, Stefan Linsler and Christoph Sippl

Biomedicines 2024, 12(9), 2078; https://doi.org/10.3390/biomedicines12092078 - 12 Sep 2024

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Abstract

Objective: Epigenetic tumor characteristics are in focus for glioblastoma prognosis. This raises the question if these characteristics present with stable expression during the progression of the disease, and if potential temporal instability might influence their prognostic value. Methods: A total of 44 patients suffering from glioblastoma who were treated for their primary and relapse tumors were included in the study. Tumor specimens from the initial and recurrent tumor resection were subjected to evaluation of MGMT, p15, and p16 methylation statuses. MiRNA-21, -24, -26a, and -181d expression was evaluated as well. The stability of these epigenetic markers during the progression of the disease was correlated with further clinical data. A Cancer Genome Atlas (TCGA) dataset of 224 glioblastoma patients was used as an independent cohort to validate the results. Results: Instability was observed in all examined epigenetic markers. MGMT methylation changed in 30% of patients, p15 methylation changed in 35%, and p16 methylation changed in 37.5% of cases. MiRNA expression in corresponding initial and relapse tumor specimens varied considerably in general, individual cases presented with a stable expression. Patients with a decreased expression of miRNA-21 in their recurrence tumor showed significantly longer overall survival. These results are supported by the data from TCGA indicating similar results. Conclusions: Epigenetic characteristics may change during the course of glioblastoma disease. This may influence the prognostic value of derived molecular markers. Full article

(This article belongs to the Special Issue Glioblastoma: Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Figure 1
Details of methylation analysis for each specimen. The cases are organized from left to right (1–40). The different methylation sites are indicated on the left, for the initial tumor and the relapse tumor. A methylated gene promoter is indicated in grey, a non-methylated one in white. The blue triangles indicate cases with a chance in methylation status between initial and relapse tumor tissue. The red tiles represent cases with no methylation result. Full article ">Figure 2
Details of miRNA analysis for each specimen. The cases are organized from left to right (1–40). The different analyzed miRNAs are shown on the left, for the initial tumor and the relapse tumor. The color of each tile represents the expression value for the respective tumor specimen. The scale of color ranges from green (lowest expression) to red (highest expression) for the indicated miRNA. Full article ">Figure 3
Mean miRNA expression in initial and relapse tumors. (A–D) indicate the expression of miRNA-21, miRNA-24, miRNA-26a, and miRNA-181d, respectively. The y-axis represents miRNA expression measured as relative expression level (REL). If a value is more than 1.5 standard deviations from the mean, it is considered a mild outlier and marked with a small circle (°). Extreme outliers, more than 3 standard deviations from the mean, are visualized with a star (*). Full article ">Figure 4
A comparison between the study collective (A) and the TCGA control group (B) regarding miRNA-21 expression and survival. Patients with a decrease in the miRNA-21 expression in their relapse tumor (red curve) showed a significantly longer survival in both cohorts. Full article ">

Review

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26 pages, 2875 KiB

Open AccessReview

Revolutionizing Brain Tumor Care: Emerging Technologies and Strategies

by Trang T. T. Nguyen, Lloyd A. Greene, Hayk Mnatsakanyan and Christian E. Badr

Biomedicines 2024, 12(6), 1376; https://doi.org/10.3390/biomedicines12061376 - 20 Jun 2024

Viewed by 2614

Abstract

Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain tumor, characterized by a daunting prognosis with a life expectancy hovering around 12–16 months. Despite a century of relentless research, only a select few drugs have received approval for brain tumor treatment, largely due to the formidable barrier posed by the blood–brain barrier. The current standard of care involves a multifaceted approach combining surgery, irradiation, and chemotherapy. However, recurrence often occurs within months despite these interventions. The formidable challenges of drug delivery to the brain and overcoming therapeutic resistance have become focal points in the treatment of brain tumors and are deemed essential to overcoming tumor recurrence. In recent years, a promising wave of advanced treatments has emerged, offering a glimpse of hope to overcome the limitations of existing therapies. This review aims to highlight cutting-edge technologies in the current and ongoing stages of development, providing patients with valuable insights to guide their choices in brain tumor treatment. Full article

(This article belongs to the Special Issue Glioblastoma: Pathogenetic, Diagnostic and Therapeutic Perspectives)

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Figure 1
Multimodal approaches to glioblastoma treatment encompass various strategies. Robotic-assisted procedures enhance the effectiveness and accessibility of brain tumor surgery by offering heightened precision and minimal invasiveness. Alongside this, external beam radiation therapy utilizes computer-controlled linear accelerators to administer precise radiation doses to targeted areas within the tumor. Additionally, chemotherapy plays a crucial role by utilizing potent drugs to eliminate rapidly dividing cancer cells, often administered orally or intravenously to complement other treatment modalities like surgery and radiation therapy. Moreover, innovative strategies, such as immunotherapy and oncolytic virus therapy, are being explored to harness the immune system’s capabilities and directly combat cancer cells. Full article ">Figure 2
Refining glioblastoma treatment involves employing methods for targeted therapy. Upper left: PARP inhibitors target an enzyme called poly ADP-ribose polymerase (PARP), which plays a key role in repairing damaged DNA. SSB: single strand break; DSB: double stand break; PARPi: PARP inhibitor. Upper right: HDAC inhibitors target enzymes known as histone deacetylases, which play a role in regulating gene expression. HDACi: HDAC inhibitor. Lower left: CDK4/6 inhibitors block the activities of cyclin-dependent kinases 4 and 6, which are involved in cell cycle progression. Cyclin-D-CDK4/6 complexes regulate the cell cycle by phosphorylating RB. Phosphorylated RB releases E2F, facilitating cell cycle progression from the G1 to S phase. CDK4/6i: CDK4/6 inhibitor; RB: Retinoblastoma tumor suppressor gene. Lower right: Bevacizumab blocks the action of vascular endothelial growth factor (VEGF) and inhibits angiogenesis, which is vital for tumor growth and metastasis. The figure was generated using BioRender. Full article ">Figure 3
Current treatment for a newly diagnosed brain tumor. Patients will receive maximal safe surgical resection, followed by radiation therapy and adjuvant treatments like temozolomide and TTFields. The figure was generated using BioRender. Full article ">

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