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Biomedicines
Special Issues
Principal Challenges in the Adjuvant Treatment of Glioblastoma
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Principal Challenges in the Adjuvant Treatment of Glioblastoma

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 36654

Special Issue Editors

Prof. Marc-Eric Halatsch

E-Mail Website
Guest Editor
Ulm University Hospital, Department of Neurosurgery, Ulm, Germany
Interests: Neuro-oncology; glioblastoma; translational research; targeted therapy; multi-targeting; drug-repurposingn
Dr. Tim Heiland

E-Mail Website
Guest Editor
Ulm University Hospital, Department of Neurosurgery, Ulm, Germany
Interests: neuro-oncology; glioblastoma; translational research; targeted therapy; multi-targeting; drug-repurposing

Special Issue Information

Dear Colleagues,

Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably incurable. Roughly 3 in 100 000 people develop this tumor each year. The course of the disease is characterized by a high symptom burden; early progression or recurrence; and, overall, a poor prognosis. New and promising treatment strategies, such as immunotherapy, photodynamic therapy, or pharmacological combination therapy, are arising to complement the mainstays of surgery, radiation, and traditional antineoplastic agents.

The current standard of care is maximally safe surgical resection followed by radiochemotherapy and adjuvant chemotherapy with temozolomide. Most patients experience tumor progression or recurrence within the first nine months after initial treatment. Second- and third-line therapies are usually less effective. Current conventional research and treatment strategies have so far failed to break ground. Even though we increasingly document the geno- and phenotypic heterogeneity of glioblastoma, successful translation of this knowledge into better clinical outcomes is largely lacking. In their respective areas, a couple of beacon studies showed promising results. In addition to the challenging molecular biology of the tumor, the established structure of many neuro-oncological clinical trials imposes scientific and legal obstacles for individual and patient-centered care and continuous research.

Because biomarkers for disease monitoring have not yet become a clinical routine, the main pillar of disease monitoring is radiological imaging. The use of high-resolution magnetic resonance tomography and positron emission tomography significantly increased diagnostic and bioptic accuracy and enabled some correlation of imaging and molecular tumor characteristics. Despite this progress, the differentiation of progression and pseudoprogression remains challenging.

To delineate the borders of up-to-date glioblastoma research and treatment today and to define challenges and, even more so, formidable problems we are just beginning to understand, we invite the most innovative, high-profile, front-line researchers and investigators in their respective areas to submit both original research and review articles regarding the following topics:

(a) Progression versus pseudoprogression;
(b) Radiogenomics;
(c) The potential of photodynamic therapy;
(d) The role of (re-) irradiation and radiosurgery;
(e) Driver versus passenger gene mutations/TCGA;
(f) Bioinformatic approaches in target gene identification;
(g) Deep machine learning in oncology—the chances for targeted therapy;
(h) The potential and limits of targeted therapy;
(i) Adaptive clinical trials—pros and cons;
(j) The chances and limitations of immunotherapy;
(k) The guidance of adjuvant personalized glioblastoma therapy by serial liquid biopsies—the potential of detecting circulating tumor DNA in plasma and cerebrospinal fluid.

Prof. Marc-Eric Halatsch
Dr. Tim Heiland
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 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. Biomedicines 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 2600 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

  • Neuro-oncology
  • Glioblastoma
  • Translational research
  • Targeted therapy
  • Multi-targeting
  • Drug-repurposing

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 168 KiB  
Editorial
Special Issue: Principal Challenges in the Adjuvant Treatment of Glioblastoma
by Marc-Eric Halatsch
Biomedicines 2023, 11(7), 1881; https://doi.org/10.3390/biomedicines11071881 - 3 Jul 2023
Viewed by 965
Abstract
Despite advances in local treatments, such as supramaximal resection (even in eloquent locations [...] Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)

Research

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12 pages, 9670 KiB  
Article
Haloperidol Induced Cell Cycle Arrest and Apoptosis in Glioblastoma Cells
by Fotios Papadopoulos, Rafaela Isihou, George A. Alexiou, Thomas Tsalios, Evrysthenis Vartholomatos, Georgios S. Markopoulos, Chrissa Sioka, Pericles Tsekeris, Athanasios P. Kyritsis and Vasiliki Galani
Biomedicines 2020, 8(12), 595; https://doi.org/10.3390/biomedicines8120595 - 11 Dec 2020
Cited by 24 | Viewed by 3761
Abstract
Although several antipsychotic drugs have been shown to possess anticancer activities, haloperidol, a “first-generation” antipsychotic drug, has not been extensively evaluated for potential antineoplastic properties. The aim of this study was to investigate the antitumoral effects of haloperidol in glioblastoma (GBM) U87, U251 [...] Read more.
Although several antipsychotic drugs have been shown to possess anticancer activities, haloperidol, a “first-generation” antipsychotic drug, has not been extensively evaluated for potential antineoplastic properties. The aim of this study was to investigate the antitumoral effects of haloperidol in glioblastoma (GBM) U87, U251 and T98 cell lines, and the effects of combined treatment with temozolomide (TMZ) and/or radiotherapy, using 4 Gy of irradiation. The viability and proliferation of the cells were evaluated with trypan blue exclusion assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis, using the annexin-propidium iodide (PI), and cell cycle, cluster of differentiation (CD) expression and caspase-8 activation were measured using flow cytometry. Treatment with haloperidol significantly reduced cell viability in U87, U251 and T98 GBM cell lines. Haloperidol induced apoptosis in a dose-dependent manner, inhibited cell migration and produced an alteration in the expression of CD24/CD44. The additional effect of haloperidol, combined with temozolomide and radiation therapy, increased tumor cell death. Haloperidol was observed to induce apoptosis and to increase caspase-8 activation. In conclusion, haloperidol may represent an innovative strategy for the treatment of GBM and further studies are warranted in glioma xenograft models and other malignancies. Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
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Review

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29 pages, 1440 KiB  
Review
Considering the Experimental Use of Temozolomide in Glioblastoma Research
by Verena J. Herbener, Timo Burster, Alicia Goreth, Maximilian Pruss, Hélène von Bandemer, Tim Baisch, Rahel Fitzel, Markus D. Siegelin, Georg Karpel-Massler, Klaus-Michael Debatin, Mike-Andrew Westhoff and Hannah Strobel
Biomedicines 2020, 8(6), 151; https://doi.org/10.3390/biomedicines8060151 - 4 Jun 2020
Cited by 30 | Viewed by 8673
Abstract
Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage [...] Read more.
Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage and thus—ultimately—cell death, a recent debate has been initiated to re-evaluate the therapeutic role of TMZ in GB. Here, we discuss the experimental use of TMZ and highlight how it differs from its clinical role. Four areas could be identified in which the experimental data is particularly limited in its translational potential: 1. transferring clinical dosing and scheduling to an experimental system and vice versa; 2. the different use of (non-inert) solvent in clinic and laboratory; 3. the limitations of established GB cell lines which only poorly mimic GB tumours; and 4. the limitations of animal models lacking an immune response. Discussing these limitations in a broader biomedical context, we offer suggestions as to how to improve transferability of data. Finally, we highlight an underexplored function of TMZ in modulating the immune system, as an example of where the aforementioned limitations impede the progression of our knowledge. Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
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17 pages, 993 KiB  
Review
Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
by Hannah Strobel, Tim Baisch, Rahel Fitzel, Katharina Schilberg, Markus D. Siegelin, Georg Karpel-Massler, Klaus-Michael Debatin and Mike-Andrew Westhoff
Biomedicines 2019, 7(3), 69; https://doi.org/10.3390/biomedicines7030069 - 9 Sep 2019
Cited by 155 | Viewed by 10688
Abstract
The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around [...] Read more.
The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk—or at least of the invading cells—by the blood brain barrier (BBB). TMZ crosses the BBB, but—unlike classic chemotherapeutics—does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences. Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
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Other

3 pages, 182 KiB  
Reply
Comment in Response to “Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy etc. by B. Kaina”
by Mike-Andrew Westhoff, Tim Baisch, Verena J. Herbener, Georg Karpel-Massler, Klaus-Michael Debatin and Hannah Strobel
Biomedicines 2020, 8(4), 93; https://doi.org/10.3390/biomedicines8040093 - 20 Apr 2020
Cited by 6 | Viewed by 2563
Abstract
It is with great pleasure that we acknowledge the fact that our review on Temozolomide (TMZ) has initiated a discussion [...] Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
5 pages, 186 KiB  
Letter
On the Critical Issues in Temozolomide Research in Glioblastoma: Clinically Relevant Concentrations and MGMT-independent Resistance
by Aleksei A. Stepanenko and Vladimir P. Chekhonin
Biomedicines 2019, 7(4), 92; https://doi.org/10.3390/biomedicines7040092 - 27 Nov 2019
Cited by 17 | Viewed by 3577
Abstract
The current standard first-line treatment for adult patients with newly diagnosed glioblastoma includes concurrent radiotherapy and daily oral temozolomide (TMZ), followed by adjuvant TMZ. As a prodrug, TMZ undergoes spontaneous hydrolysis generating a methylating agent. O6-methylguanine is considered the most preponderant [...] Read more.
The current standard first-line treatment for adult patients with newly diagnosed glioblastoma includes concurrent radiotherapy and daily oral temozolomide (TMZ), followed by adjuvant TMZ. As a prodrug, TMZ undergoes spontaneous hydrolysis generating a methylating agent. O6-methylguanine is considered the most preponderant toxic damage mechanism at therapeutically relevant TMZ doses, whereas MGMT, which encodes the O6-methylguanine-DNA methyltransferase DNA repair enzyme, is the most relevant resistance mechanism. Speculations on clinically relevant TMZ concentrations, cytotoxic and cytostatic effects of TMZ, and resistance mechanisms exist in the literature. Here, we raise the following principal issues: What are the clinically relevant TMZ concentrations in glioma patients, and which TMZ-induced molecular lesion(s) and corresponding resistance mechanism(s) are important for TMZ therapeutic effects at clinically relevant concentrations? According to clinical data from patients with glioblastoma, the mean peak TMZ concentrations in the peritumoral tissue might be much lower (around 5 µM) than usually used in in vitro research, and may represent only 20% of systemic drug levels. According to in vitro reports, single-dose TMZ at concentrations around 5 µM have minimal, if any, effect on apoptosis and/or senescence of glioblastoma cell lines. However, the clinically relevant concentrations of TMZ are sufficient to radiosensitize both MGMT-positive and -negative cell lines in vitro. It is speculated that a single DNA repair protein, MGMT, is highly efficient in protecting cells against TMZ toxicity. However, an endogenous level of MGMT protein expression is not universally correlated with TMZ responsiveness, and MGMT-independent mechanisms of TMZ resistance exist. Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
5 pages, 545 KiB  
Comment
Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69
by Bernd Kaina
Biomedicines 2019, 7(4), 90; https://doi.org/10.3390/biomedicines7040090 - 11 Nov 2019
Cited by 31 | Viewed by 5846
Abstract
Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called SN1 alkylating agent is well described, including the types of induced DNA damage triggering the DNA damage response and survival [...] Read more.
Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called SN1 alkylating agent is well described, including the types of induced DNA damage triggering the DNA damage response and survival and death pathways, some researchers expressed doubt that data mostly obtained by in vitro models can be translated into the in vivo situation. In experimental settings, high doses of the agent are often used, which are likely to activate responses triggered by base N-alkylations instead of O6-methylguanine (O6MeG), which is the primary cytotoxic lesion induced by low doses of temozolomide and other methylating drugs in O6-methylguanine-DNA methyltransferase (MGMT) repair incompetent cells. However, numerous studies provided compelling evidence that O6MeG is not only a mutagenic, but also a powerful toxic lesion inducing DNA double-strand breaks, apoptosis, autophagy and cellular senescence. MGMT, repairing the lesion through methyl group transfer, is a key node in protecting cells against all these effects and has a significant impact on patient’s survival following temozolomide therapy, supporting the notion that findings obtained on a molecular and cellular level can be translated to the therapeutic setting in vivo. This comment summarizes the current knowledge on O6MeG-triggered pathways, including dose dependence and the question of thresholds, and comes up with the conclusion that data obtained on cell lines using low dose protocols are relevant and apoptosis, autophagy and senescence are therapeutically important endpoints. Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
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