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Brain Tumors: From Molecular Basis to Therapy

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuro-oncology".

Deadline for manuscript submissions: closed (30 January 2026) | Viewed by 14275

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Dr. Paolo Tini

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Radiation Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Bracci 16, 53100 Siena, Italy
Interests: neuro-oncology; radiotherapy in CNS cancers; radiosurgery; bio-molecular prognostic factors
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Dr. Giuseppe Minniti

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Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy. IRCCS Neuromed, Pozzilli IS, Italy.
Interests: neuro-oncology; radiotherapy in CNS cancers; radiosurgery
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Special Issue Information

Dear Colleagues,

The landscape of brain tumor research is rapidly evolving, driven by the urgent need to improve diagnosis, treatment and patient outcomes. Brain tumors, ranging from benign to highly malignant, present significant clinical challenges due to their complex biology and the critical nature of their location. Despite advances in medical research, many aspects of brain tumor pathology, genetics and therapeutic response remain poorly understood. This Special Issue aims to address these gaps by fostering a deeper understanding of the molecular underpinnings of brain tumors and translating these insights into innovative therapeutic strategies. By tackling core problems such as tumor heterogeneity, resistance to conventional therapies and the blood–brain barrier's limiting effects on drug delivery, we strive to pave the way for breakthroughs that can transform patient care. To advance our knowledge and develop effective treatments, this Special Issue will encompass a wide range of topics, including, but not limited to, the following:

Molecular and Genetic Basis of Brain Tumors: Investigations into the genetic mutations, signaling pathways and molecular mechanisms driving tumor initiation and progression.
Innovative Diagnostic Techniques: Development and validation of novel biomarkers, imaging technologies and diagnostic tools that enhance the early detection and accurate classification of brain tumors.
Therapeutic Advances: Exploration of cutting-edge treatments, including targeted therapies, immunotherapies and personalized medicine approaches tailored to individual tumor profiles.
Overcoming Therapeutic Resistance: Studies addressing the mechanisms behind resistance to current treatments and strategies to overcome these barriers.
Drug Delivery Systems: Innovations in delivering therapeutic agents across the blood–brain barrier, enhancing the efficacy and safety of brain tumor treatments.
Clinical Trials and Translational Research: Reports on clinical trials, case studies and translational research that bridge the gap between laboratory findings and clinical application.

We invite researchers, clinicians and scholars from across the globe to contribute their original research, review articles and case studies to this Special Issue. Your expertise and insights are crucial in advancing our understanding of brain tumors and developing effective therapies. By participating in this Special Issue, you will join a collaborative effort to address some of the most pressing challenges in brain tumor research and treatment.

Dr. Paolo Tini
Dr. Giuseppe Minniti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). 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

brain tumors
molecular pathways
targeted therapy
diagnostic biomarkers
predictive biomarkers
therapeutic resistance

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Related Special Issue

Brain Tumors: From Molecular Basis to Therapy: 2nd Edition in Brain Sciences

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15 pages, 3365 KB

Open AccessArticle

Reduced Clinical Target Volume Margins in Glioblastoma: Exploratory Evidence Supporting Further Margin Reduction Independent of MGMT Status

by Flavio Donnini, Giuseppe Minniti, Salvatore Chibbaro, Giulio Bagnacci, Armando Perrella, Giuseppe Battaglia, Giovanni Rubino, Pierpaolo Pastina, Tommaso Carfagno, Marta Vannini, Maria Antonietta Mazzei, Alfonso Cerase and Paolo Tini

Brain Sci. 2026, 16(5), 458; https://doi.org/10.3390/brainsci16050458 - 24 Apr 2026

Viewed by 187

Abstract

Background: Clinical target volume (CTV) delineation in glioblastoma remains debated, particularly in the era of modern chemoradiation and image-guided radiotherapy. Whether reduced CTV margins can preserve oncological outcomes without increasing marginal or out-of-field failures remains uncertain. We evaluated the association of the gross tumor volume (GTV)-to-CTV margin with survival, patterns of failure, and its interaction with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Materials and Methods: We retrospectively analyzed a single-center cohort of patients with glioblastoma treated with conventionally fractionated chemoradiation (58–60 Gy in 29–33 fractions). Patients were categorized into two predefined margin groups: <1.5 cm and 1.5 cm. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and patterns of failure. Survival was assessed using Kaplan–Meier estimates and Cox regression, including an interaction term with MGMT status. Results: Among 102 eligible patients, 95 were included in the margin-based OS analysis. Reduced margins (<1.5 cm; applied range 1.0–1.4 cm) were not associated with worse OS, either overall or within MGMT subgroups. No significant differences were observed in PFS or recurrence patterns, with overlapping distributions and no increase in marginal or out-of-field recurrences. MGMT methylation and gross total resection were independently associated with improved survival, while no statistically significant interaction between margin and MGMT status was detected. Conclusions: In this retrospective exploratory cohort, reduced GTV-to-CTV margins were not associated with a clear signal of worse survival or less favorable recurrence patterns. These findings are consistent with the oncological adequacy of margins around 15 mm and justify cautious prospective evaluation of whether further reduction can be achieved safely, including formal assessment of toxicity, neurocognitive outcomes, and quality of life. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

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17 pages, 3525 KB

Open AccessArticle

Arsenic Trioxide and the MNK1 Inhibitor AUM001 Exert Synergistic Anti-Glioblastoma Effects by Modulating Key Translational, Cell Cycle, and Transmembrane Transport Pathways

by Yue Hao, Charles Shaffer, Nanyun Tang, Valerie DeLuca, Angela Baker and Michael E. Berens

Brain Sci. 2026, 16(2), 121; https://doi.org/10.3390/brainsci16020121 - 23 Jan 2026

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Background: The profound heterogeneity of glioblastoma and the often-limited efficacy of conventional treatments, including arsenic trioxide (ATO), underscore the urgent and critical demand for innovative combination strategies specifically designed to overcome treatment resistance. Methods: We evaluated the therapeutic effects of ATO as a single agent and in combination with the MNK1 inhibitor AUM001 across patient-derived xenograft (PDX) models and investigated molecular determinants of sensitivity and synergy. Our results demonstrated that GBM models resistant to ATO, particularly those of the mesenchymal subtype, are more likely to show synergistic cytotoxicity when AUM001 is added. The combination significantly reduces the frequency of glioblastoma stem cells (GSCs) compared to either drug alone, especially in ATO-resistant models. Results: These observations suggest that targeting the MNK1 pathway in conjunction with ATO is a promising strategy to specifically eradicate GSCs, which are major drivers of GBM recurrence and therapeutic failure. Transcriptomic analyses revealed that ATO sensitivity correlated with activated translation-related pathways and cell cycle processes, while synergistic responses to the combination were driven by distinct molecular signatures in different GBM subtypes. Overall, synergistic response to the combination therapy is more associated with cellular organization, amino acid transmembrane transporter activity, ion channels, extracellular matrix organization and collagen formation. Conclusions: Our findings highlight that specific molecular pathways and their activities, including those involving translation, cell cycle and ion transport, appear to modulate the synergistic efficacy of the ATO and AUM001 combination, thereby offering potential biomarkers for improved patient stratification in future GBM clinical trials of such ATO-based treatments. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

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12 pages, 794 KB

Open AccessArticle

Biomolecular Predictors of Recurrence Patterns and Survival in IDH-Wild-Type Glioblastoma: A Retrospective Analysis of Patients Treated with Radiotherapy and Temozolomide

by Paolo Tini, Flavio Donnini, Francesco Marampon, Marta Vannini, Tommaso Carfagno, Pierpaolo Pastina, Giovanni Rubino, Salvatore Chibbaro, Alfonso Cerase, Giulio Bagnacci, Armando Perrella, Maria Antonietta Mazzei, Alessandra Pascucci, Vincenzo D’Alonzo, Anna Maria Di Giacomo and Giuseppe Minniti

Brain Sci. 2025, 15(7), 713; https://doi.org/10.3390/brainsci15070713 - 2 Jul 2025

Cited by 3 | Viewed by 2157

Abstract

Background and Aim: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with poor prognosis despite maximal surgical resection, radiotherapy (RT), and temozolomide (TMZ) per the Stupp protocol. IDH-wild-type GBM, the predominant molecular subtype, frequently harbors EGFR amplification and is resistant to therapy, while MGMT promoter methylation predicts improved TMZ response. This study aimed to assess the prognostic impact of EGFR and MGMT status on survival and recurrence patterns in IDH-wild-type GBM. Materials and Methods: We retrospectively analyzed 218 patients with IDH-wild-type GBM treated at the Azienda Ospedaliero-Universitaria Senese (2016–2024). All patients underwent maximal safe surgical resection whenever feasible. The cohort includes patients who received gross total resection (GTR), subtotal resection (STR), or biopsy only, depending on tumor location and clinical condition, followed by intensity-modulated RT (59.4–60 Gy) with concurrent and adjuvant TMZ. EGFR amplification was assessed via FISH/NGS and immunohistochemistry; MGMT promoter methylation was determined using methylation-specific PCR. Progression-free survival (PFS), overall survival (OS), and recurrence patterns (in-field, marginal, out-field) were evaluated using Kaplan–Meier, Cox regression, and logistic regression analyses. Results: Among patients (64.7% male; mean age 61.8), 58.7% had EGFR amplification and 49.1% showed MGMT methylation. Median OS and PFS were 14 and 8 months, respectively. EGFR non-amplified/MGMT methylated tumors had the best outcomes (OS: 22.0 months, PFS: 10.5 months), while EGFR-amplified/MGMT unmethylated tumors fared worst (OS: 10.0 months, PFS: 5.0 months; p < 0.001). MGMT methylation was an independent positive prognostic factor (HR: 0.48, p < 0.001), while EGFR amplification predicted worse survival (HR: 1.57, p = 0.02) and higher marginal recurrence (OR: 2.42, p = 0.01). Conclusions: EGFR amplification and MGMT methylation significantly influence survival and recurrence dynamics in IDH-wild-type GBM. Incorporating these biomarkers into treatment planning may enable tailored therapeutic strategies, potentially improving outcomes in this challenging disease. Prospective studies are needed to validate biomolecularly guided management approaches. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

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12 pages, 1606 KB

Open AccessArticle

Prognostic Biomarkers in Isocitrate Dehydrogenase Wild-Type Glioblastoma: A Focus on B7-H3

by Ramazan Oğuz Yüceer, Seyhmus Kaya, Sema Nur Balcı, Hatice Reyhan Eğilmez, Mukaddes Yılmaz and Eda Erdıs

Brain Sci. 2025, 15(2), 212; https://doi.org/10.3390/brainsci15020212 - 19 Feb 2025

Cited by 8 | Viewed by 2654

Abstract

Background: Isocitrate dehydrogenase (IDH) wild-type (wt) glioblastoma is an aggressive malignancy associated with poor clinical outcomes, marked by high heterogeneity and resistance to treatment. This study aims to investigate the prognostic significance of B7-H3 expression in IDH wt glioblastoma and its potential association with clinical outcomes, including overall survival (OS) and progression-free survival (PFS). Additionally, the relationship between B7-H3 and PD-L1 expression was explored. Methods: A retrospective cohort of 86 IDH wt glioblastoma patients, all of whom underwent surgery, radiotherapy, and temozolomide treatment, was analyzed. B7-H3 expression was quantified using an immunoreactivity score (IRS), classifying samples as low (IRS ≤ 4) or high (IRS > 4). PD-L1 expression was evaluated based on tumor and immune cell staining, with >5% positivity indicating significant expression. Results: High B7-H3 expression was significantly associated with poorer OS and PFS. Co-expression of B7-H3 and PD-L1 was prevalent, particularly among younger male patients with unifocal tumors; however, PD-L1 expression did not show a significant correlation with clinical outcomes. Conclusions: B7-H3 appears to be a promising prognostic biomarker in IDH wt glioblastoma and may serve as a target for developing combination therapies, integrating B7-H3-targeting treatments with immune checkpoint inhibitors. Further prospective studies are necessary to validate these findings and to explore potential therapeutic strategies. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

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17 pages, 1523 KB

Open AccessArticle

Prognostic Role of Invasion-Related Extracellular Matrix Molecules in Diffusely Infiltrating Grade 2 and 3 Astrocytomas

by László Szivos, József Virga, Zoltán Mészár, Melinda Rostás, Andrea Bakó, Gábor Zahuczki, Tibor Hortobágyi and Álmos Klekner

Brain Sci. 2024, 14(11), 1157; https://doi.org/10.3390/brainsci14111157 - 20 Nov 2024

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Abstract

Background: Astrocytoma, an IDH-mutant is a common primary brain tumor. Total surgical resection is not feasible due to peritumoral infiltration mediated by extracellular matrix (ECM) molecules. Methods: This study aimed at determining the expression pattern of ECM molecules in different prognostic groups of WHO grade 2 and grade 3 patients and identifying the effect of onco-radiotherapy on tumor cell invasion of grade 3 patients. Gene and protein expression of ECM molecules was determined by qRT-PCR and immunohistochemistry, respectively. Results: In the different prognostic groups of grade 2 tumors HMMR, IDH-1, MKI-67, PDGF-A and versican, in grade 3 tumors integrin α-3, and in both groups integrin α-3 and IDH-1 mRNA expression was significantly different. Regarding protein expression, only integrin αV expression changed significantly in the prognostic groups of grade 2 tumors. Conclusions: Based on the invasion spectrum determined by this joint gene and protein expression analysis, there was a sensitivity of 87.5% and a negative predictive value of 88.9% regarding the different prognostic groups of grade 2 astrocytoma. For grade 3 tumors, the applied standard oncotherapeutic modalities apparently lacked significant anti-invasive effects. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

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12 pages, 1009 KB

Open AccessArticle

The Systemic Inflammation Response Index Efficiently Discriminates between the Failure Patterns of Patients with Isocitrate Dehydrogenase Wild-Type Glioblastoma Following Radiochemotherapy with FLAIR-Based Gross Tumor Volume Delineation

by Sukran Senyurek, Murat Serhat Aygun, Nulifer Kilic Durankus, Eyub Yasar Akdemir, Duygu Sezen, Erkan Topkan, Yasemin Bolukbasi and Ugur Selek

Brain Sci. 2024, 14(9), 922; https://doi.org/10.3390/brainsci14090922 - 15 Sep 2024

Cited by 1 | Viewed by 1865

Abstract

Background/Objectives: The objective of this study was to assess the connection between the systemic inflammation response index (SIRI) values and failure patterns of patients with IDH wild-type glioblastoma (GB) who underwent radiotherapy (RT) with FLAIR-based gross tumor volume (GTV) delineation. Methods: Seventy-one patients who received RT at a dose of 60 Gy to the GTV and 50 Gy to the clinical target volume (CTV) and had documented recurrence were retrospectively analyzed. Each patient’s maximum distance of recurrence (MDR) from the GTV was documented in whichever plane it extended the farthest. The failure patterns were described as intra-GTV, in-CTV/out-GTV, distant, and intra-GTV and distant. For analytical purposes, the failure pattern was categorized into two groups, namely Group 1, intra-GTV or in-CTV/out-GTV, and Group 2, distant or intra-GTV and distant. The SIRI was calculated before surgery and corticosteroid administration. A receiver operating characteristic (ROC) curve analysis was used to determine the optimal SIRI cut-off that distinguishes between the different failure patterns. Results: Failure occurred as follows: intra-GTV in 40 (56.3%), in-CTV/out-GTV in 4 (5.6%), distant in 18 (25.4%), and intra-GTV + distant in 9 (12.7%) patients. The mean MDR was 13.5 mm, and recurrent lesions extended beyond 15 mm in only seven patients. Patients with an SIRI score ≥ 3 demonstrated a significantly higher incidence of Group 1 failure patterns than their counterparts with an SIRI score < 3 (74.3% vs. 50.0%; p = 0.035). Conclusions: The present results show that using the SIRI with a cut-off value of ≥3 significantly predicts failure patterns. Additionally, the margin for the GTV can be safely reduced to 15 mm when using FLAIR-based target delineation in patients with GB. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

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Review

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14 pages, 256 KB

Open AccessReview

Natural Source of Drugs Targeting Central Nervous System Tumors—Focus on NAD(P)H Oxidoreductase 1 (NQO1) Activity

by Nikola M. Stojanovic, Milica Mitić, Jovan Ilić, Milica Radić, Miša Radisavljević, Marko Baralić and Miljan Krstić

Brain Sci. 2025, 15(2), 132; https://doi.org/10.3390/brainsci15020132 - 29 Jan 2025

Cited by 4 | Viewed by 2175

Abstract

Central nervous system (CNS) tumors involve a large and diverse group of malignancies that arise from various cell types within the brain tissue. Although there are advances in treatments, CNS tumors still remain challenging, due to their complex biology and the delicate nature of the surrounding tissue. NAD(P)H O=oxidoreductase 1 (NQO1) is an enzyme that plays a critical role in the detoxification of quinones, protecting cells from oxidative stress. In CNS tumors this enzyme is often overexpressed, which contributes to the resistance of tumor cells to chemotherapy by enhancing their antioxidant defenses. NQO1 influences the progression of CNS tumors by affecting downstream signaling pathways, such as those involving the transcription factor SNAIL, as well as others that are associated with tumor behavior. Plants represent a valuable source of numerous constituents with different chemical structures known to affect different molecular signaling pathways associated with different pathologies. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

Other

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13 pages, 3582 KB

Open AccessCase Report

Adult-Onset Diffuse Midline Glioma, H3K27-Altered: A Genomics-Guided, Individualized, Multimodal Treatment Approach

by Abdussamet Çelebi, Bilal Yıldırım, Emine Yıldırım, Selver Işık, Ezgi Çoban, Erhan Bıyıklı, Osman Köstek, İbrahim Vedat Bayoğlu and Murat Sarı

Brain Sci. 2026, 16(1), 97; https://doi.org/10.3390/brainsci16010097 - 16 Jan 2026

Viewed by 1862

Abstract

Background: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive central nervous system malignancy with limited therapeutic options and poor prognosis. Precision medicine strategies that integrate molecular profiling with individualized treatment selection represent a critical avenue for improving outcomes. Case presentation: We describe a 31-year-old woman with H3K27-altered DMG who, after standard chemoradiotherapy, was treated with a personalized, mechanism-guided combination regimen based on her tumor’s molecular profile. Next-generation sequencing identified pathogenic alterations in ATRX, H3F3A, and NF1, with a high NF1 mutation allelic fraction indicating RAS/MAPK pathway activation. Immunohistochemistry demonstrated elevated phosphorylated mTOR consistent with PI3K/AKT/mTOR pathway upregulation. The individualized regimen comprised trametinib and everolimus for dual pathway inhibition, the tissue-agnostic agent dordaviprone (ONC201), metabolic modulation with 2-deoxy-D-glucose, and electric field-based therapy. At seven months, MRI showed approximately a 60% volumetric reduction in the enhancing tumor component, accompanied by marked T2-weighted signal regression. Clinically, the patient remained neurologically intact with a Karnofsky Performance Score of 100%. Conclusions: This case illustrates the potential clinical value of a genomics-guided, multimodal treatment strategy in H3K27-altered DMG. The systematic integration of comprehensive molecular profiling with mechanistically rational treatment selection may contribute to meaningful radiological and clinical benefit in this otherwise uniformly fatal disease. These observations support further investigation of individualized, pathway-targeted approaches in prospective studies and N-of-1 trial frameworks. Full article

(This article belongs to the Special Issue Brain Tumors: From Molecular Basis to Therapy)

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