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Current Developments in Glioblastoma Research and Therapy

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

Deadline for manuscript submissions: closed (20 December 2024) | Viewed by 18249

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Dr. Aleksandra Majchrzak-Celińska

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Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 60-806 Poznan, Poland
Interests: brain tumors; glioblastoma; epigenetics; pharmacoepigenetics; biomarkers; Wnt/β-catenin pathway; phytocompounds
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Dear Colleagues,

Glioblastoma remains one of the most aggressive and incurable malignancies. Even after the standard treatment, consisting of surgery, radiotherapy, and chemotherapy, tumor recurrence is only a matter of time and the prognosis for glioblastoma patients is still very poor. Therefore, rapid progress in developing a better understanding of glioblastoma pathogenesis and recurrence is needed and novel ways to improve patient outcomes are desperately required.

Fortunately, glioblastoma research is thriving, and new approaches towards the more precise diagnosis and effective therapy of this deadly disease are constantly being evaluated. The implementation of combinatorial therapies, immunotherapy, and nanomedicine are several of the examples of strategies tested in order to surpass the current obstacles in glioblastoma treatment.

The aim of this Special Issue is to collect the most recent discoveries regarding glioblastoma research, ranging from molecular mechanisms to therapeutic approaches. All advancements in characterizing GBM pathogenesis, including genomic, epigenomic, transcriptomic, and proteomic analyses of GBM cells, are of interest in this Special Issue. Moreover, we welcome the evaluation of innovative therapeutic agents and new treatment approaches.

We invite authors to submit original preclinical, translational, and clinical works, as well as review articles regarding the above-mentioned cutting-edge topics, to this Special Issue of International Journal of Molecular Sciences.

We are looking forward to your contributions.

Dr. Aleksandra Majchrzak-Celińska
Guest Editor

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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.

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Keywords

diagnostic, prognostic and predictive biomarkers of glioblastoma
ways to target glioma stem cells
targeting glioblastoma-related signaling pathways
epigenetics of glioblastoma
treatment resistance mechanisms
novel treatment options for glioblastoma
combinatorial therapies
immunotherapy
nanotherapy
the application of CRISPR/Cas9 in glioma research
molecular testing of long-term glioblastoma survivors

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Current Developments in Glioblastoma Research and Therapy: 2nd Edition in International Journal of Molecular Sciences

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Research

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15 pages, 5403 KiB

Open AccessArticle

Tinostamustine (EDO-S101) and Its Combination with Celecoxib or Temozolomide as a Therapeutic Option for Adult-Type Diffuse Gliomas

by Wiktoria Pawlak and Aleksandra Majchrzak-Celińska

Int. J. Mol. Sci. 2025, 26(2), 661; https://doi.org/10.3390/ijms26020661 - 14 Jan 2025

Viewed by 794

Abstract

Adult-type diffuse gliomas are characterized by inevitable recurrence and very poor prognosis. Novel treatment options, including multimodal drugs or effective drug combinations, are therefore eagerly awaited. Tinostamustine is an alkylating and histone deacetylase inhibiting molecule with great potential in cancer treatment. Thus, the aim of this study was to investigate its effects on glioma cells. In this context, tinostamustine was evaluated in monotherapy and as a combination therapy, with either celecoxib or temozolomide; additionally, the results were compared to the golden glioma chemotherapy standard—temozolomide. Our experiments, conducted on both temozolomide-sensitive U-87 MG astrocytoma and temozolomide-resistant U-138 MG glioblastoma cells revealed that tinostamustine and its combination with either celecoxib or temozolomide exert dose-dependent cytotoxicity, cause cell cycle arrest, induce oxidative stress-mediated apoptosis of malignant glioma cells, and mitigate their migratory potential. Astrocytoma cells were more susceptible to the tested treatments than glioblastoma cells, and, generally, those dual therapies were superior in anti-glioma efficacy compared to temozolomide. Overall, our study provides evidence that tinostamustine and the combination therapies consisting of tinostamustine and celecoxib or tinostamustine and temozolomide may represent a new approach for the effective treatment of malignant gliomas. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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17 pages, 12603 KiB

Open AccessArticle

Targeting Metabolic and Epigenetic Vulnerabilities in Glioblastoma with SN-38 and Rabusertib Combination Therapy

by Jennifer Chiou, Valeria Impedovo, Yen Bao Huynh, Ruggiero Gorgoglione, Luiz O. F. Penalva, Alessia Lodi, Andrew J. Brenner and Stefano Tiziani

Int. J. Mol. Sci. 2025, 26(2), 474; https://doi.org/10.3390/ijms26020474 - 8 Jan 2025

Viewed by 1183

Abstract

Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O⁶-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. This underscores the need for novel, more targeted therapies. Our study investigates the metabolic–epigenetic impact of combining SN-38, a novel topoisomerase inhibitor inducing DNA double-strand breaks, with rabusertib, a checkpoint kinase 1 inhibitor. We identified this synergistic combination through high-throughput drug screening across a panel of GBM cell lines using a cancer drug library combined with SN-38. A secondary metabolic screening with the PEDS algorithm demonstrated a synergistic modulation of purine, one-carbon, and redox metabolism. Furthermore, the combined treatment led to the significant depletion of epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O⁶-methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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26 pages, 3816 KiB

Open AccessArticle

Genomic Profiling in Glioma Patients to Explore Clinically Relevant Markers

by Viacheslav Varachev, Olga Susova, Alexei Mitrofanov, David Naskhletashvili, George Krasnov, Anna Ikonnikova, Svetlana Bezhanova, Vera Semenova, Nadezhda Sevyan, Evgenii Prozorenko, Yulia Ammour, Ali Bekyashev and Tatiana Nasedkina

Int. J. Mol. Sci. 2024, 25(23), 13004; https://doi.org/10.3390/ijms252313004 - 3 Dec 2024

Cited by 1 | Viewed by 1679

Abstract

Gliomas are a heterogeneous group of brain tumors, among which the most aggressive subtype is glioblastoma, accounting for 60% of cases in adults. Available systemic treatment options are few and ineffective, so new approaches to therapies for glioblastoma are in high demand. In total, 131 patients with diffuse glioma were studied. Paired tumor–normal samples were sequenced on the Illumina platform; the panel included 812 genes associated with cancer development. Molecular profiles in clinically distinct groups were investigated. In low-grade glioma (LGG) patients (n = 18), the most common mutations were IDH1/2 (78%), ATRX (33%), TP53 (33%), PIK3CA (17%), and co-deletion 1p/19q (22%). In high-grade glioma (HGG) patients (n = 113), more frequently affected genes were CDKN2A/B (33%), TERTp (71%), PTEN (60%), TP53 (27%), and EGFR (40%). The independent predictors of better prognosis were tumor grade and IDH1/2 mutations. In IDH—wildtype glioblastoma patients, a history of other precedent cancer was associated with worse overall survival (OS), while re-operation and bevacizumab therapy increased OS. Also, among genetic alterations, TERTp mutation and PTEN deletion were markers of poor prognosis. Nine patients received molecular targeted therapy, and the results were evaluated. The search for molecular changes associated with tumor growth and progression is important for diagnosis and choice of therapy. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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22 pages, 16518 KiB

Open AccessArticle

Intratumoral Cell Heterogeneity in Patient-Derived Glioblastoma Cell Lines Revealed by Single-Cell RNA-Sequencing

by Mikhail Arbatskiy, Dmitriy Balandin, Alexey Churov, Vyacheslav Varachev, Eugenia Nikolaeva, Alexei Mitrofanov, Ali Bekyashev, Olga Tkacheva, Olga Susova and Tatiana Nasedkina

Int. J. Mol. Sci. 2024, 25(15), 8472; https://doi.org/10.3390/ijms25158472 - 2 Aug 2024

Cited by 3 | Viewed by 1868

Abstract

Glioblastoma cell lines derived from different patients are widely used in tumor biology research and drug screening. A key feature of glioblastoma is the high level of inter- and intratumor heterogeneity that accounts for treatment resistance. Our aim was to investigate whether intratumor heterogeneity is maintained in cell models. Single-cell RNA sequencing was used to investigate the cellular composition of a tumor sample and six patient-derived glioblastoma cell lines. Three cell lines preserved the mutational profile of the original tumor, whereas three others differed from their precursors. Copy-number variation analysis showed significantly rearranged genomes in all the cell lines and in the tumor sample. The tumor had the most complex cell composition, including cancer cells and microenvironmental cells. Cell lines with a conserved genome had less diverse cellularity, and during cultivation, a relative increase in the stem-cell-derived progenitors was noticed. Cell lines with genomes different from those of the primary tumors mainly contained neural progenitor cells and microenvironmental cells. The establishment of cell lines without the driver mutations that are intrinsic to the original tumors may be related to the selection of clones or cell populations during cultivation. Thus, patient-derived glioblastoma cell lines differ substantially in their cellular profile, which should be taken into account in translational studies. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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19 pages, 10685 KiB

Open AccessArticle

Evaluation of Microvascular Density in Glioblastomas in Relation to p53 and Ki67 Immunoexpression

by Tamás-Csaba Sipos, Attila Kövecsi, Lóránd Kocsis, Monica Nagy-Bota and Zsuzsánna Pap

Int. J. Mol. Sci. 2024, 25(12), 6810; https://doi.org/10.3390/ijms25126810 - 20 Jun 2024

Cited by 5 | Viewed by 1395

Abstract

Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and invasion, although there are controversial results in the specialized literature regarding its impact on survival. This study aims to correlate the immunoexpression of angiogenesis markers (CD34, CD105) with the proliferation index Ki67 and p53 in primary and secondary glioblastomas. This retrospective study included 54 patients diagnosed with glioblastoma at the Pathology Department of County Emergency Clinical Hospital Târgu Mureș. Microvascular density was determined using CD34 and CD105 antibodies, and the results were correlated with the immunoexpression of p53, IDH1, ATRX and Ki67. The number of neoformed blood vessels varied among cases, characterized by different shapes and calibers, with endothelial cells showing modified morphology and moderate to marked pleomorphism. Neovessels with a glomeruloid aspect, associated with intense positivity for CD34 or CD105 in endothelial cells, were observed, characteristic of glioblastomas. Mean microvascular density values were higher for the CD34 marker in all cases, though there were no statistically significant differences compared to CD105. Mutant IDH1 and ATRX glioblastomas, wild-type p53 glioblastomas, and those with a Ki67 index above 20% showed a more abundant microvascular density, with statistical correlations not reaching significance. This study highlighted a variety of percentage intervals of microvascular density in primary and secondary glioblastomas using immunohistochemical markers CD34 and CD105, respectively, with no statistically significant correlation between evaluated microvascular density and p53 or Ki67. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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14 pages, 1652 KiB

Open AccessArticle

Profiling of Tumor-Infiltrating Immune Cells and Their Impact on Survival in Glioblastoma Patients Undergoing Immunotherapy with Dendritic Cells

by Nataly Peres, Guilherme A. Lepski, Carla S. Fogolin, Gabriela C. M. Evangelista, Elizabeth A. Flatow, Jaqueline V. de Oliveira, Mariana P. Pinho, Patricia C. Bergami-Santos and José A. M. Barbuto

Int. J. Mol. Sci. 2024, 25(10), 5275; https://doi.org/10.3390/ijms25105275 - 12 May 2024

Cited by 3 | Viewed by 3695

Abstract

Glioblastomas (GBM) are the most common primary malignant brain tumors, comprising 2% of all cancers in adults. Their location and cellular and molecular heterogeneity, along with their highly infiltrative nature, make their treatment challenging. Recently, our research group reported promising results from a prospective phase II clinical trial involving allogeneic vaccination with dendritic cells (DCs). To date, six out of the thirty-seven reported cases remain alive without tumor recurrence. In this study, we focused on the characterization of infiltrating immune cells observed at the time of surgical resection. An analytical model employing a neural network-based predictive algorithm was used to ascertain the potential prognostic implications of immunological variables on patients’ overall survival. Counterintuitively, immune phenotyping of tumor-associated macrophages (TAMs) has revealed the extracellular marker PD-L1 to be a positive predictor of overall survival. In contrast, the elevated expression of CD86 within this cellular subset emerged as a negative prognostic indicator. Fundamentally, the neural network algorithm outlined here allows a prediction of the responsiveness of patients undergoing dendritic cell vaccination in terms of overall survival based on clinical parameters and the profile of infiltrated TAMs observed at the time of tumor excision. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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Review

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23 pages, 1672 KiB

Open AccessReview

The Clinical Role of miRNAs in the Development and Treatment of Glioblastoma

by Samantha Epistolio, Paolo Spina, Ismail Zaed, Andrea Cardia, Francesco Marchi and Milo Frattini

Int. J. Mol. Sci. 2025, 26(6), 2723; https://doi.org/10.3390/ijms26062723 - 18 Mar 2025

Viewed by 365

Abstract

Glioblastoma multiforme (GBM) is the most common brain tumor and one of the most aggressive, with a median overall survival (OS) of only 15–18 months. These characteristics make it necessary to identify new targets for the improvement of prognosis and better prediction of response to therapies currently available for GBM patients. One possible candidate target could be the evaluation of miRNAs. miRNAs are small non-coding RNAs that play important roles in post-transcriptional gene regulation. Due to their functions, miRNAs also control biological processes underlying the development of GBM and may be considered possible targets with a clinical role. This narrative review introduces the concept of miRNAs in GBM from a clinical and a molecular perspective and then addresses the specific miRNAs that are most described in the literature as relevant for the development, the prognosis, and the response to therapies for patients affected by GBM. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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42 pages, 2949 KiB

Open AccessReview

Nanotherapy of Glioblastoma—Where Hope Grows

by Jan Grzegorzewski, Maciej Michalak, Maria Wołoszczuk, Magdalena Bulicz and Aleksandra Majchrzak-Celińska

Int. J. Mol. Sci. 2025, 26(5), 1814; https://doi.org/10.3390/ijms26051814 - 20 Feb 2025

Viewed by 1062

Abstract

Localization in the central nervous system, diffuse growth, the presence of stem cells, and numerous resistance mechanisms, all make glioblastoma (GBM) an incurable tumor. The standard treatment of GBM consisting of surgery; radio- and chemotherapy with temozolomide provides insufficient therapeutic benefit and needs to be updated with effective modern solutions. One of the most promising and intensively explored therapeutic approaches against GBM is the use of nanotherapy. The first, and so far only, nanoparticle-based therapy approved for GBM treatment is NanoTherm^TM. It is based on iron oxide nanoparticles and the thermal ablation of the tumor with a magnetic field. Numerous other types of nanotherapies are being evaluated, including polymer and lipid-based nanoformulations, nanodiscs, dendrimers, and metallic, silica, or bioderived nanoparticles, among others. The advantages of these nanoscale drug carriers include improved penetration across the blood–brain barrier, targeted drug delivery, biocompatibility, and lower systemic toxicity, while major problems with their implementation involve scaling up their production and high costs. Nevertheless, taking all the impressive benefits of nanotherapies into consideration, it seems obvious that the combined effort of the scientific world will need to be taken to tackle these challenges and implement these novel therapies into clinics, giving hope that the battle against GBM can finally be won. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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28 pages, 427 KiB

Open AccessReview

Review of Novel Surgical, Radiation, and Systemic Therapies and Clinical Trials in Glioblastoma

by Allison R. Valerius, Lauren M. Webb, Anna Thomsen, Eric J. Lehrer, William G. Breen, Jian L. Campian, Cecile Riviere-Cazaux, Terry C. Burns and Ugur Sener

Int. J. Mol. Sci. 2024, 25(19), 10570; https://doi.org/10.3390/ijms251910570 - 30 Sep 2024

Cited by 5 | Viewed by 2779

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite an established standard of care including surgical resection, radiation therapy, and chemotherapy, GBM unfortunately is associated with a dismal prognosis. Therefore, researchers are extensively evaluating avenues to expand GBM therapy and improve outcomes in patients with GBM. In this review, we provide a broad overview of novel GBM therapies that have recently completed or are actively undergoing study in clinical trials. These therapies expand across medical, surgical, and radiation clinical trials. We additionally review methods for improving clinical trial design in GBM. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

19 pages, 851 KiB

Open AccessReview

Molecular Profile as an Outcome Predictor in Glioblastoma along with MRI Features and Surgical Resection: A Scoping Review

by Serban Iancu Papacocea, Daniela Vrinceanu, Mihai Dumitru, Felicia Manole, Crenguta Serboiu and Marius Toma Papacocea

Int. J. Mol. Sci. 2024, 25(17), 9714; https://doi.org/10.3390/ijms25179714 - 8 Sep 2024

Cited by 4 | Viewed by 1922

Abstract

Glioblastoma (GBM) is one of the most aggressive malignant tumors of the brain. We queried PubMed for articles about molecular predictor markers in GBM. This scoping review aims to analyze the most important outcome predictors in patients with GBM and to compare these factors in terms of absolute months of survival benefit and percentages. Performing a gross total resection for patients with GBM undergoing optimal chemo- and radiotherapy provides a significant benefit in overall survival compared to those patients who received a subtotal or partial resection. However, compared to IDH-Wildtype GBMs, patients with IDH-Mutant 1/2 GBMs have an increased survival. MGMT promoter methylation status is another strong outcome predictor for patients with GBM. In the reviewed literature, patients with methylated MGMT promoter lived approximately 50% to 90% longer than those with an unmethylated MGMT gene promoter. Moreover, KPS is an important predictor of survival and quality of life, demonstrating that we should refrain from aggressive surgery in important brain areas. As new therapies (such as TTFs) emerge, we are optimistic that the overall median survival will increase, even for IDH-Wildtype GBMs. In conclusion, molecular profiles are stronger outcome predictors than the extent of neurosurgical resection for GBM. Full article

(This article belongs to the Special Issue Current Developments in Glioblastoma Research and Therapy)

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