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Cancers
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Mechanisms of Therapeutic Resistance in Glioblastoma
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Mechanisms of Therapeutic Resistance in Glioblastoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 8418

Special Issue Editors

Dr. Manish K. Aghi

E-Mail Website
Guest Editor
Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA
Interests: neurosurgery; brain tumor; glioblastoma
Dr. Saket Jain

E-Mail Website
Guest Editor
Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA
Interests: gene expression; cancer biology; immunofluorescence; immunohistochemistry

Special Issue Information

Dear Colleagues,

Glioblastoma is an aggressive brain cancer with a dismal prognosis. Despite aggressive treatment including surgery followed by radiotherapy and adjuvant chemotherapy, the median survival remains less than two years.  The causes of treatment failure are multifactorial and can be attributed to perturbations in tumor cells themselves or in the complex interactions between the tumor and the cells of the tumor microenvironment. Single-cell sequencing approaches in the past decade have revealed the transcriptomic and epigenetic changes driving tumor evolution during treatment, providing insights for treatment resistance. Immunotherapies have been successful in other solid malignancies but have had limited success in GBM due to several resistance mechanisms leading to a pro-tumoral microenvironment. Anti-angiogenic therapies show modest benefits but ultimately lead to treatment resistance through the adaptation of tumor cells. This Special Issue aims to address the advances in our understanding of how the biology of GBM tumor cells and the interactions between these tumors cells and the tumor microenvironment drive therapeutic resistance. We will also describe possible approaches to overcoming this resistance in order to improve patient outcomes.

In this Special Issue, original research articles and reviews are welcome. The research areas may include (but are not limited to) the following:

  1. The mechanisms of resistance to immune-cell-based therapies;
  2. The role of epigenetic alterations in glioblastoma stem cells in therapeutic resistance;
  3. Immunotherapeutic approaches targeting GBM stem cells;
  4. Strategies to overcome the blood–brain barrier in GBM treatment;
  5. The role of GBM stem cells in therapeutic resistance;
  6. Resistance to anti-angiogenic therapy in GBM;
  7. Using single-cell sequencing to define resistance mediators in GBM;
  8. Strategies to overcome the blood–brain barrier in GBM treatment;
  9. The mechanisms of radiation resistance in glioblastoma;
  10. The role of abnormal tumor metabolism in GBM therapeutic resistance;
  11. The role of oxidative stress in therapeutic resistance in GBM;
  12. The mathematical modeling of drug resistance in glioblastoma;
  13. The use of liquid biomarkers to monitor for GBM recurrence;
  14. The mechanisms of resistance to oncolytic viral therapies;
  15. The patterns of the epigenetic changes associated with GBM recurrence;
  16. The role of chromatin remodeling in therapeutic resistance;
  17. The role of the germline and somatic genomic landscape on therapeutic resistance in GBM;
  18. The role of GBM–neuron interactions in therapeutic resistance;
  19. The role of the innate immune response in resistance to GBM immunotherapy;
  20. DNA-damage-repair mechanisms in stem cells as a mechanism of radiation resistance in GBM;
  21. The mechanisms of the response to therapy-induced DNA alkylation damage in glioblastoma;
  22. Repurposing drugs to address therapeutic resistance in glioblastoma;
  23. Resistance to anti-angiogenic therapy in glioblastoma;
  24. Single-cell sequencing as a tool for defining the resistance mechanisms in glioblastoma.

We look forward to receiving your contributions.

Dr. Manish K. Aghi
Dr. Saket Jain
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 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.

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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

  • GBM microenvironment
  • therapeutic resistance
  • immunotherapy
  • anti-angiogenic therapy
  • tumor evolution
  • single-cell genomics

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Published Papers (3 papers)

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Research

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14 pages, 1892 KiB  
Article
Therapy Resistance of Glioblastoma in Relation to the Subventricular Zone: What Is the Role of Radiotherapy?
by Ekin Ermiş, Alexander Althaus, Marcela Blatti, Emre Uysal, Dominic Leiser, Shokoufe Norouzi, Elena Riggenbach, Hossein Hemmatazad, Uzeyir Ahmadli and Franca Wagner
Cancers 2023, 15(6), 1677; https://doi.org/10.3390/cancers15061677 - 9 Mar 2023
Cited by 1 | Viewed by 2147
Abstract
Glioblastoma is a highly heterogeneous primary malignant brain tumor with marked inter-/intratumoral diversity and a poor prognosis. It may contain a population of neural stem cells (NSC) and glioblastoma stem cells that have the capacity for migration, self-renewal and differentiation. While both may [...] Read more.
Glioblastoma is a highly heterogeneous primary malignant brain tumor with marked inter-/intratumoral diversity and a poor prognosis. It may contain a population of neural stem cells (NSC) and glioblastoma stem cells that have the capacity for migration, self-renewal and differentiation. While both may contribute to resistance to therapy, NSCs may also play a role in brain tissue repair. The subventricular zone (SVZ) is the main reservoir of NSCs. This study investigated the impact of bilateral SVZ radiation doses on patient outcomes. We included 147 patients. SVZs were delineated and the dose administered was extracted from dose–volume histograms. Tumors were classified based on their spatial relationship to the SVZ. The dose and outcome correlations were analyzed using the Kaplan–Meier and Cox proportional hazards regression methods. Median progression-free survival (PFS) was 7 months (range: 4–11 months) and median overall survival (OS) was 14 months (range: 9–23 months). Patients with an ipsilateral SVZ who received ≥50 Gy showed significantly better PFS (8 versus 6 months; p < 0.001) and OS (16 versus 11 months; p < 0.001). Furthermore, lower doses (<32 Gy) to the contralateral SVZ were associated with improved PFS (8 versus 6 months; p = 0.030) and OS (15 versus 11 months; p = 0.001). Targeting the potential tumorigenic cells in the ipsilateral SVZ while sparing contralateral NSCs correlated with an improved outcome. Further studies should address the optimization of dose distribution with modern radiotherapy techniques for the areas surrounding infiltrated and healthy SVZs. Full article
(This article belongs to the Special Issue Mechanisms of Therapeutic Resistance in Glioblastoma)
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20 pages, 6120 KiB  
Article
Senescence Is the Main Trait Induced by Temozolomide in Glioblastoma Cells
by Lea Beltzig, Christian Schwarzenbach, Petra Leukel, Katrin B. M. Frauenknecht, Clemens Sommer, Alessandro Tancredi, Monika E. Hegi, Markus Christmann and Bernd Kaina
Cancers 2022, 14(9), 2233; https://doi.org/10.3390/cancers14092233 - 29 Apr 2022
Cited by 26 | Viewed by 3068
Abstract
First-line drug in the treatment of glioblastoma, the most severe brain cancer, is temozolomide (TMZ), a DNA-methylating agent that induces the critical damage O6-methylguanine (O6MeG). This lesion is cytotoxic through the generation of mismatch repair-mediated DNA double-strand breaks (DSBs), [...] Read more.
First-line drug in the treatment of glioblastoma, the most severe brain cancer, is temozolomide (TMZ), a DNA-methylating agent that induces the critical damage O6-methylguanine (O6MeG). This lesion is cytotoxic through the generation of mismatch repair-mediated DNA double-strand breaks (DSBs), which trigger apoptotic pathways. Previously, we showed that O6MeG also induces cellular senescence (CSEN). Here, we show that TMZ-induced CSEN is a late response which has similar kinetics to apoptosis, but at a fourfold higher level. CSEN cells show a high amount of DSBs, which are located outside of telomeres, a high level of ROS and oxidized DNA damage (8-oxo-guanine), and sustained activation of the DNA damage response and histone methylation. Despite the presence of DSBs, CSEN cells are capable of repairing radiation-induced DSBs. Glioblastoma cells that acquired resistance to TMZ became simultaneously resistant to TMZ-induced CSEN. Using a Tet-On glioblastoma cell system, we show that upregulation of MGMT immediately after TMZ completely abrogated apoptosis and CSEN, while induction of MGMT long-term (>72 h) after TMZ did not reduce apoptosis and CSEN. Furthermore, upregulation of MGMT in the senescent cell population had no impact on the survival of senescent cells, indicating that O6MeG is required for induction, but not for maintenance of the senescent state. We further show that, in recurrent GBM specimens, a significantly higher level of DSBs and CSEN-associated histone H3K27me3 was observed than in the corresponding primary tumors. Overall, the data indicate that CSEN is a key node induced in GBM following chemotherapy. Full article
(This article belongs to the Special Issue Mechanisms of Therapeutic Resistance in Glioblastoma)
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Review

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18 pages, 1304 KiB  
Review
Roles of Chromatin Remodelling and Molecular Heterogeneity in Therapy Resistance in Glioblastoma
by Huey-Miin Chen, Ana Nikolic, Divya Singhal and Marco Gallo
Cancers 2022, 14(19), 4942; https://doi.org/10.3390/cancers14194942 - 9 Oct 2022
Cited by 5 | Viewed by 2594
Abstract
Cancer stem cells (CSCs) represent a therapy-resistant reservoir in glioblastoma (GBM). It is now becoming clear that epigenetic and chromatin remodelling programs link the stemlike behaviour of CSCs to their treatment resistance. New evidence indicates that the epigenome of GBM cells is shaped [...] Read more.
Cancer stem cells (CSCs) represent a therapy-resistant reservoir in glioblastoma (GBM). It is now becoming clear that epigenetic and chromatin remodelling programs link the stemlike behaviour of CSCs to their treatment resistance. New evidence indicates that the epigenome of GBM cells is shaped by intrinsic and extrinsic factors, including their genetic makeup, their interactions and communication with other neoplastic and non-neoplastic cells, including immune cells, and their metabolic niche. In this review, we explore how all these factors contribute to epigenomic heterogeneity in a tumour and the selection of therapy-resistant cells. Lastly, we discuss current and emerging experimental platforms aimed at precisely understanding the epigenetic mechanisms of therapy resistance that ultimately lead to tumour relapse. Given the growing arsenal of drugs that target epigenetic enzymes, our review addresses promising preclinical and clinical applications of epidrugs to treat GBM, and possible mechanisms of resistance that need to be overcome. Full article
(This article belongs to the Special Issue Mechanisms of Therapeutic Resistance in Glioblastoma)
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