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Glioblastoma: Molecular Pathogenesis and Treatment
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Glioblastoma: Molecular Pathogenesis and Treatment

A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 November 2026 | Viewed by 9281

Editors

Dr. Maurizio Martini

E-Mail Website
Guest Editor
Anatomic Pathology Unit, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy
Interests: hematopathology; glial and central nervous system cancer; gastrointestinal tumor; lung cancer; thyroid cancer; genitourinary cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Vincenzo Fiorentino

E-Mail Website
Guest Editor
Anatomic Pathology Unit, Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, 98125 Messina, Italy
Interests: molecular biology; liquid biopsy; immunohistochemistry; predictive markers; endometrial carcinoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

Glioblastoma (GBM) remains one of the most devastating and challenging neoplasms to treat, with a poor prognosis despite the availability of aggressive multimodal therapy. This Special Issue delves into the complexities of this aggressive brain tumor, exploring both its underlying molecular mechanisms and the forefront of therapeutic advancements.

Recent breakthroughs in understanding the genomic, transcriptomic, and epigenetic landscapes of GBM have revealed a remarkable degree of heterogeneity and adaptability, contributing to treatment resistance. Our aim is compile research that highlights critical aspects of GBM biology, including the roles of key signaling pathways, the tumor microenvironment, immune evasion, and the evolving landscape of driver mutations. Furthermore, this Special Issue aims to showcase innovative therapeutic strategies, from targeted therapies and immunotherapies to novel drug delivery systems and emerging approaches such as gene editing. We wish to provide a comprehensive overview of the current state of GBM research and offer insights into avenues for future therapeutic development to finally improve patient outcomes.

Dr. Maurizio Martini
Dr. Vincenzo Fiorentino
Guest Editors

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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

  • glioblastoma
  • molecular therapy
  • pathogenesis
  • immunotherapy
  • brain tumor

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Published Papers (4 papers)

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Research

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17 pages, 514 KB  
Article
AMPK Pathway Activation Markers in GBM: Expression Patterns and Clinical Associations in a Real-World Study
by Federica Ferrarini, Paola Del Bianco, Martina Corrà, Tiziana Talienti, Matteo Mauceri, Daniele Boso, Giusi Romanazzi, Martina Bedeschi, Mario Caccese, Marta Padovan, Angela Guerriero, Giovanni Esposito, Isacco Desideri, Enrico Franceschi, Paola Gaviani, Michela Buglione di Monale e Bastia, Gian Luca De Salvo, Alba Fiorentino, Anna Tesei, Tommaso Mazza, Giuseppe Lombardi and Stefano Indraccoloadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2026, 27(17), 7789; https://doi.org/10.3390/ijms27177789 - 31 Aug 2026
Viewed by 163
Abstract
Phosphorylated ACC (pACC), a downstream effector of the LKB1/AMPK pathway, may support tumor bioenergetics and exert a tumor-promoting role in glioblastoma (GBM). In the randomized REGOMA trial, pACC expression was associated with improved overall survival (OS) in GBM patients treated with regorafenib, but [...] Read more.
Phosphorylated ACC (pACC), a downstream effector of the LKB1/AMPK pathway, may support tumor bioenergetics and exert a tumor-promoting role in glioblastoma (GBM). In the randomized REGOMA trial, pACC expression was associated with improved overall survival (OS) in GBM patients treated with regorafenib, but its validity in large cohorts is unclear. This study aimed to characterize pACC and phosphorylated AMPK (pAMPK) expression in a real-world GBM cohort and to assess their prognostic and predictive value in patients receiving second-line regorafenib or fotemustine/lomustine. In this retrospective, multicenter translational study, pACC and pAMPK were assessed by immunohistochemistry on FFPE tumor sections from 174 IDH-wild-type GBM patients treated with regorafenib (n = 84) or fotemustine/lomustine (n = 90). Staining was performed with a validated anti-pACC monoclonal antibody and quantified by digital pathology. Survival analyses included univariable and multivariable Cox proportional hazards models, with interaction testing. pACC and pAMPK were expressed in 85.6% and 95.4% of samples, respectively, with heterogeneous spatial patterns. Neither marker was significantly associated with OS in the univariable analyses, and neither retained independent prognostic value in multivariable analysis. Regorafenib was associated with significantly longer OS than alkylating agents (10.4 vs. 6.3 months; p = 0.0021). However, the treatment-by-pACC interaction test was not statistically significant (adjusted p = 0.610), providing no formal evidence of a differential treatment effect by pACC status. Although pACC-positive expression was enriched among patients experiencing longer overall survival under regorafenib, formal treatment-by-biomarker interaction was non-significant. These exploratory findings indicate that pACC is not an established predictive biomarker and warrant prospectively powered evaluation. Full article
(This article belongs to the Special Issue Glioblastoma: Molecular Pathogenesis and Treatment)
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18 pages, 1774 KB  
Article
Epstein–Barr Virus in Brain Cancer—Friend or Foe?
by Michał Brzozowski, Magdalena Góralczyk, Sylwester Bogacki and Małgorzata Polz-Dacewicz
Int. J. Mol. Sci. 2026, 27(11), 4812; https://doi.org/10.3390/ijms27114812 - 27 May 2026
Viewed by 720
Abstract
Recent research suggests a link between EBV and brain cancer, especially in high-grade gliomas, but its role has not been sufficiently elucidated. Therefore, we evaluated its occurrence in brain cancer. For this purpose, the EBV DNA and LMP-1 in tumor tissue, the level [...] Read more.
Recent research suggests a link between EBV and brain cancer, especially in high-grade gliomas, but its role has not been sufficiently elucidated. Therefore, we evaluated its occurrence in brain cancer. For this purpose, the EBV DNA and LMP-1 in tumor tissue, the level of viral load in the cerebrospinal fluid (CSF), and the serological status of patients were analyzed. We detected EBV DNA in 28.9% (42/145) of glioma samples, among which 28 were isolated from glioblastomas (GBs) and 14 from other gliomas. LMP-1 was detected in 26 (92.8%) GB samples and 5 (35.7%) samples from other gliomas. The EBV DNA load in the CSF was significantly higher in GB compared to other gliomas; anti-EBNA1, anti-EBVCA, anti-EA, and anti-Zta antibodies were detected in the serum of GB patients; and their concentration was higher in GB patients. Further research is needed to determine whether and to what extent EBV contributes to glioma development. Elucidating the role of latent EBV genes synthesized in glioblastoma is important for understanding the role of viral infection in cancer development and progression in this hitherto poorly studied area. Full article
(This article belongs to the Special Issue Glioblastoma: Molecular Pathogenesis and Treatment)
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Review

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16 pages, 4707 KB  
Review
Beyond Oligodendroglioma: An Integrated Diagnostic Approach to CNS Tumors with Oligodendroglioma-like Morphology, with a Focus on Morphological Pitfalls, Immunoprofiles, and Molecular Signatures
by Giulio Attanasio, Rosario Caltabiano, Francesca Amato, Giuseppe Maria Vincenzo Barbagallo, Francesco Certo, Durmus Ayan, Valeria Barresi and Giuseppe Broggi
Int. J. Mol. Sci. 2026, 27(16), 7163; https://doi.org/10.3390/ijms27167163 - 11 Aug 2026
Viewed by 455
Abstract
Oligodendroglioma-like morphology, classically recognized by round nuclei, optically clear cytoplasm, and perinuclear halos, is one of the most familiar patterns in neuropathology but also one of the most diagnostically misleading. Although historically associated with oligodendroglioma, this phenotype is now recognized across a wide [...] Read more.
Oligodendroglioma-like morphology, classically recognized by round nuclei, optically clear cytoplasm, and perinuclear halos, is one of the most familiar patterns in neuropathology but also one of the most diagnostically misleading. Although historically associated with oligodendroglioma, this phenotype is now recognized across a wide spectrum of neoplastic and non-neoplastic central nervous system lesions, including adult-type diffuse gliomas, ependymal tumors, pediatric-type low-grade gliomas, glioneuronal and neurocytic tumors, metastatic clear-cell neoplasms, demyelinating disease, and subacute infarcts. The 2021 WHO Classification of CNS Tumors has consolidated a diagnostic framework in which histology remains indispensable, but no longer sufficient, for tumor classification. In this setting, oligodendroglioma-like morphology should be interpreted as a morphological clue that prompts a differential diagnosis and guides ancillary testing rather than as a definitive diagnostic category. This review provides a practical integrated approach to CNS tumors and tumor-like lesions with oligodendroglioma-like or clear-cell morphology. We summarize the major diagnostic mimics of oligodendroglioma, highlighting first-line immunohistochemical panels, and proposing a tiered molecular workflow to identify the conditions in which genome-wide DNA methylation profiling becomes essential. Particular emphasis is placed on clinico-pathological correlation and on red flags that should prompt reconsideration of a conventional oligodendroglioma diagnosis. Full article
(This article belongs to the Special Issue Glioblastoma: Molecular Pathogenesis and Treatment)
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47 pages, 2976 KB  
Review
Epigenetic Alterations in Glioblastoma Multiforme as Novel Therapeutic Targets: A Scoping Review
by Marco Meleiro and Rui Henrique
Int. J. Mol. Sci. 2025, 26(12), 5634; https://doi.org/10.3390/ijms26125634 - 12 Jun 2025
Cited by 25 | Viewed by 7014
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a dismal prognosis despite advances in multimodal treatment. Conventional therapies fail to achieve durable responses due to GBM’s molecular heterogeneity and capacity to evade therapeutic pressures. Epigenetic alterations have emerged as critical [...] Read more.
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a dismal prognosis despite advances in multimodal treatment. Conventional therapies fail to achieve durable responses due to GBM’s molecular heterogeneity and capacity to evade therapeutic pressures. Epigenetic alterations have emerged as critical contributors to GBM pathobiology, including aberrant DNA methylation, histone modifications, and non-coding RNA (ncRNA) dysregulation. These mechanisms drive oncogenesis, therapy resistance, and immune evasion. This scoping review evaluates the current state of knowledge on epigenetic modifications in GBM, synthesizing findings from original articles and preclinical and clinical trials published over the last decade. Particular attention is given to MGMT promoter hypermethylation status as a biomarker for temozolomide (TMZ) sensitivity, histone deacetylation and methylation as modulators of chromatin structure, and microRNAs as regulators of pathways such as apoptosis and angiogenesis. Therapeutically, epigenetic drugs, like DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis), appear as promising approaches in preclinical models and early trials. Emerging RNA-based therapies targeting dysregulated ncRNAs represent a novel approach to reprogram the tumor epigenome. Combination therapies, pairing epigenetic agents with immune checkpoint inhibitors or chemotherapy, are explored for their potential to enhance treatment response. Despite these advancements, challenges such as tumor heterogeneity, the blood–brain barrier (BBB), and off-target effects remain significant. Future directions emphasize integrative omics approaches to identify patient-specific targets and refine therapies. This article thus highlights the potential of epigenetics in reshaping GBM treatment paradigms. Full article
(This article belongs to the Special Issue Glioblastoma: Molecular Pathogenesis and Treatment)
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