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Molecular Targeted Therapeutic Strategies for Glioblastoma
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Molecular Targeted Therapeutic Strategies for Glioblastoma

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 7012

Special Issue Editor

Dr. Frank Eckerdt

E-Mail Website
Guest Editor
1. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA
2 Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA
Interests: glioma; glioblastoma; medulloblastoma; brain cancer stem cells; kinase signaling; phosphorylation; kinase inhibitors; therapy resistance

Special Issue Information

Dear Colleagues,

This Special Issue is devoted to the diagnostic and therapeutic role of molecular markers and signaling pathways in glioblastoma (GBM). GBM, classified as WHO grade 4 glioma, is the most common malignant primary brain tumor and ranks among the most lethal of human cancers. Extensive efforts in the molecular characterization of GBM revealed remarkable intratumoral cellular heterogeneity and plasticity. GBM tumors contain diverse neoplastic populations among which glioma stem cells (GSCs) have been attributed key roles in plasticity and therapy resistance. Recent advances in molecular and genetic techniques have improved our understanding of GBM complexity and may help anticipate molecular adaptations and subtype transitions that promote disease recurrence and contribute to therapy resistance. This Special Issue will compile new data and concepts regarding targeted strategies for GBM that include, but are not limited to, targeting signaling pathways, immunotherapeutic approaches and strategies for drug delivery through the blood-brain barrier (BBB).

Dr. Frank Eckerdt
Guest Editor

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 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • glioblastoma (GBM)
  • glioma stem cells
  • therapeutic target
  • gBM subtypes
  • tumor heterogeneity and plasticity
  • therapy resistance
  • tinase inhibitor
  • signaling pathways

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Published Papers (3 papers)

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Research

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21 pages, 6768 KiB  
Article
NADPH Oxidase Subunit CYBB Confers Chemotherapy and Ferroptosis Resistance in Mesenchymal Glioblastoma via Nrf2/SOD2 Modulation
by I-Chang Su, Yu-Kai Su, Syahru Agung Setiawan, Vijesh Kumar Yadav, Iat-Hang Fong, Chi-Tai Yeh, Chien-Min Lin and Heng-Wei Liu
Int. J. Mol. Sci. 2023, 24(9), 7706; https://doi.org/10.3390/ijms24097706 - 22 Apr 2023
Cited by 9 | Viewed by 2623
Abstract
Glioblastoma multiforme (GBM) is a highly heterogeneous disease with a mesenchymal subtype tending to exhibit more aggressive and multitherapy-resistant features. Glioblastoma stem-cells derived from mesenchymal cells are reliant on iron supply, accumulated with high reactive oxygen species (ROS), and susceptible to ferroptosis. Temozolomide [...] Read more.
Glioblastoma multiforme (GBM) is a highly heterogeneous disease with a mesenchymal subtype tending to exhibit more aggressive and multitherapy-resistant features. Glioblastoma stem-cells derived from mesenchymal cells are reliant on iron supply, accumulated with high reactive oxygen species (ROS), and susceptible to ferroptosis. Temozolomide (TMZ) treatment is the mainstay drug for GBM despite the rapid development of resistance in mesenchymal GBM. The main interconnection between mesenchymal features, TMZ resistance, and ferroptosis are poorly understood. Herein, we demonstrated that a subunit of NADPH oxidase, CYBB, orchestrated mesenchymal shift and promoted TMZ resistance by modulating the anti-ferroptosis circuitry Nrf2/SOD2 axis. Public transcriptomic data re-analysis found that CYBB and SOD2 were highly upregulated in the mesenchymal subtype of GBM. Accordingly, our GBM cohort confirmed a high expression of CYBB in the GBM tumor and was associated with mesenchymal features and poor clinical outcome. An in vitro study demonstrated that TMZ-resistant GBM cells displayed mesenchymal and stemness features while remaining resilient to erastin-mediated ferroptosis by activating the CYBB/Nrf2/SOD2 axis. The CYBB maintained a high ROS state to sustain the mesenchymal phenotype, TMZ resistance, and reduced erastin sensitivity. Mechanistically, CYBB interacted with Nrf2 and consequently regulated SOD2 transcription. Compensatory antioxidant SOD2 essentially protected against the deleterious effect of high ROS while attenuating ferroptosis in TMZ-resistant cells. An animal study highlighted the protective role of SOD2 to mitigate erastin-triggered ferroptosis and tolerate oxidative stress burden in mice harboring TMZ-resistant GBM cell xenografts. Therefore, CYBB captured ferroptosis resilience in mesenchymal GBM. The downstream compensatory activity of CYBB via the Nrf2/SOD2 axis is exploitable through erastin-induced ferroptosis to overcome TMZ resistance. Full article
(This article belongs to the Special Issue Molecular Targeted Therapeutic Strategies for Glioblastoma)
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14 pages, 2952 KiB  
Article
Expanding the Disease Network of Glioblastoma Multiforme via Topological Analysis
by Apurva Badkas, Sébastien De Landtsheer and Thomas Sauter
Int. J. Mol. Sci. 2023, 24(4), 3075; https://doi.org/10.3390/ijms24043075 - 4 Feb 2023
Viewed by 1416
Abstract
Glioblastoma multiforme (GBM), a grade IV glioma, is a challenging disease for patients and clinicians, with an extremely poor prognosis. These tumours manifest a high molecular heterogeneity, with limited therapeutic options for patients. Since GBM is a rare disease, sufficient statistically strong evidence [...] Read more.
Glioblastoma multiforme (GBM), a grade IV glioma, is a challenging disease for patients and clinicians, with an extremely poor prognosis. These tumours manifest a high molecular heterogeneity, with limited therapeutic options for patients. Since GBM is a rare disease, sufficient statistically strong evidence is often not available to explore the roles of lesser-known GBM proteins. We present a network-based approach using centrality measures to explore some key, topologically strategic proteins for the analysis of GBM. Since network-based analyses are sensitive to changes in network topology, we analysed nine different GBM networks, and show that small but well-curated networks consistently highlight a set of proteins, indicating their likely involvement in the disease. We propose 18 novel candidates which, based on differential expression, mutation analysis, and survival analysis, indicate that they may play a role in GBM progression. These should be investigated further for their functional roles in GBM, their clinical prognostic relevance, and their potential as therapeutic targets. Full article
(This article belongs to the Special Issue Molecular Targeted Therapeutic Strategies for Glioblastoma)
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Review

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21 pages, 771 KiB  
Review
A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance
by Aniruddha S. Karve, Janki M. Desai, Sidharth N. Gadgil, Nimita Dave, Trisha M. Wise-Draper, Gary A. Gudelsky, Timothy N. Phoenix, Biplab DasGupta, Lalanthica Yogendran, Soma Sengupta, David R. Plas and Pankaj B. Desai
Int. J. Mol. Sci. 2024, 25(6), 3217; https://doi.org/10.3390/ijms25063217 - 12 Mar 2024
Cited by 5 | Viewed by 2324
Abstract
A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating [...] Read more.
A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to the limited therapeutic benefit, TMZ also causes debilitating adverse events (AEs) that significantly impact the quality of life of GBM patients. Some of the most common AEs include hematologic (e.g., thrombocytopenia, neutropenia, anemia) and non-hematologic (e.g., nausea, vomiting, constipation, dizziness) toxicities. Recurrent GBMs are often resistant to TMZ and other DNA-damaging agents. Thus, there is an urgent need to devise strategies to potentiate TMZ activity, to overcome drug resistance, and to reduce dose-dependent AEs. Here, we analyze major mechanisms of the TMZ resistance-mediated intracellular signaling activation of DNA repair pathways and the overexpression of drug transporters. We review some of the approaches investigated to counteract these mechanisms of resistance to TMZ, including the use of chemosensitizers and drug delivery strategies to enhance tumoral drug exposure. Full article
(This article belongs to the Special Issue Molecular Targeted Therapeutic Strategies for Glioblastoma)
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