Malignant Glioma: Novel Therapeutic Strategies

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 January 2022) | Viewed by 23247

Special Issue Editors

Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, 89081 Ulm, Germany
Interests: glioblastoma; combination therapy; apoptosis; temozolomide
Department of Neurological Surgery, Ulm University | UULM, Ulm, Germany
Interests: tumor cell metabolism; intelligent intracerebral implants; drug repurposing
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Special Issue Information

Dear Colleagues,

Malignant gliomas are a group of hard-to-treat brain tumors. Glioblastoma is among the most aggressive forms of these primary brain tumors, and is associated for most patients with an overall survival of less than 18 months. This is despite an intensive treatment regime of maximal safe tumor resection, followed by radiotherapy and treatment with the alkylating agent temozolomide.

While novel treatment strategies are obviously in dire need, glioma come with a unique set of difficulties that need to be overcome, such as the blood–brain barrier, which prevents access of many drugs to the tumor, or at least to the invading cells that have left the tumor bulk. Furthermore, glioblastoma cells have invariably spread throughout the brain upon presentation, necessitating a treatment approach that is brain systemic.

With these particular features of brain tumors, it is difficult to successfully implement strategies that have shown promise in other cancer entities. However, in recent years novel promising treatment approaches have been put forward that take the specific features of gliomas into account.

The journal Pharmaceuticals invites both reviews and original articles shedding light on the challenges and opportunities specific to glioma. Topics include drug repurposing, the roles of the immune system and the tumor metabolism, as well as improving our understanding of already implemented strategies. The collection of manuscripts will be published as a Special Issue of the journal.  

Dr. Mike-Andrew Westhoff
Prof. Georg Karpel-Massler
Guest Editors

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Keywords

  • glioma
  • glioblastoma
  • temozolomide
  • metabolism
  • cell death
  • drug repurposing
  • immunomodulation

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Published Papers (7 papers)

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Research

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15 pages, 3949 KiB  
Article
In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
Pharmaceuticals 2021, 14(12), 1241; https://doi.org/10.3390/ph14121241 - 29 Nov 2021
Cited by 8 | Viewed by 2185
Abstract
Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, [...] Read more.
Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. Methods: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. Results: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells’ migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. Conclusions: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378). Full article
(This article belongs to the Special Issue Malignant Glioma: Novel Therapeutic Strategies)
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13 pages, 2463 KiB  
Article
Inhibition of Intercellular Cytosolic Traffic via Gap Junctions Reinforces Lomustine-Induced Toxicity in Glioblastoma Independent of MGMT Promoter Methylation Status
Pharmaceuticals 2021, 14(3), 195; https://doi.org/10.3390/ph14030195 - 27 Feb 2021
Cited by 8 | Viewed by 2370
Abstract
Glioblastoma is a malignant brain tumor and one of the most lethal cancers in human. Temozolomide constitutes the standard chemotherapeutic agent, but only shows limited efficacy in glioblastoma patients with unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter status. Recently, it has been shown that glioblastoma [...] Read more.
Glioblastoma is a malignant brain tumor and one of the most lethal cancers in human. Temozolomide constitutes the standard chemotherapeutic agent, but only shows limited efficacy in glioblastoma patients with unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter status. Recently, it has been shown that glioblastoma cells communicate via particular ion-channels—so-called gap junctions. Interestingly, inhibition of these ion channels has been reported to render MGMT promoter-methylated glioblastoma cells more susceptible for a therapy with temozolomide. However, given the percentage of about 65% of glioblastoma patients with an unmethylated MGMT promoter methylation status, this treatment strategy is limited to only a minority of glioblastoma patients. In the present study we show that—in contrast to temozolomide—pharmacological inhibition of intercellular cytosolic traffic via gap junctions reinforces the antitumoral effects of chemotherapeutic agent lomustine, independent of MGMT promoter methylation status. In view of the growing interest of lomustine in glioblastoma first and second line therapy, these findings might provide a clinically-feasible way to profoundly augment chemotherapeutic effects for all glioblastoma patients. Full article
(This article belongs to the Special Issue Malignant Glioma: Novel Therapeutic Strategies)
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22 pages, 2931 KiB  
Article
Heat Shock Protein Inhibitor 17-Allyamino-17-Demethoxygeldanamycin, a Potent Inductor of Apoptosis in Human Glioma Tumor Cell Lines, Is a Weak Substrate for ABCB1 and ABCG2 Transporters
Pharmaceuticals 2021, 14(2), 107; https://doi.org/10.3390/ph14020107 - 29 Jan 2021
Cited by 4 | Viewed by 2162
Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and has a poor prognosis. Complex genetic alterations and the protective effect of the blood–brain barrier (BBB) have so far hampered effective treatment. Here, we investigated the cytotoxic effects of heat [...] Read more.
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and has a poor prognosis. Complex genetic alterations and the protective effect of the blood–brain barrier (BBB) have so far hampered effective treatment. Here, we investigated the cytotoxic effects of heat shock protein 90 (HSP90) inhibitors, geldanamycin (GDN) and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), in a panel of glioma tumor cell lines with various genetic alterations. We also assessed the ability of the main drug transporters, ABCB1 and ABCG2, to efflux GDN and 17-AAG. We found that GDN and 17-AAG induced extensive cell death with the morphological and biochemical hallmarks of apoptosis in all studied glioma cell lines at sub-micro-molar and nanomolar concentrations. Moderate efflux efficacy of GDN and 17-AAG mediated by ABCB1 was observed. There was an insignificant and low efflux efficacy of GDN and 17-AAG mediated by ABCG2. Conclusion: GDN and 17-AAG, in particular, exhibited strong proapoptotic effects in glioma tumor cell lines irrespective of genetic alterations. GDN and 17-AAG appeared to be weak substrates of ABCB1 and ABCG2. Therefore, the BBB would compromise their cytotoxic effects only partially. We hypothesize that GBM patients may benefit from 17-AAG either as a single agent or in combination with other drugs. Full article
(This article belongs to the Special Issue Malignant Glioma: Novel Therapeutic Strategies)
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15 pages, 756 KiB  
Review
Regulation of MHC I Molecules in Glioblastoma Cells and the Sensitizing of NK Cells
Pharmaceuticals 2021, 14(3), 236; https://doi.org/10.3390/ph14030236 - 08 Mar 2021
Cited by 15 | Viewed by 2631
Abstract
Immunotherapy has been established as an important area in the therapy of malignant diseases. Immunogenicity sufficient for immune recognition and subsequent elimination can be bypassed by tumors through altered and/or reduced expression levels of major histocompatibility complex class I (MHC I) molecules. Natural [...] Read more.
Immunotherapy has been established as an important area in the therapy of malignant diseases. Immunogenicity sufficient for immune recognition and subsequent elimination can be bypassed by tumors through altered and/or reduced expression levels of major histocompatibility complex class I (MHC I) molecules. Natural killer (NK) cells can eliminate tumor cells in a MHC I antigen presentation-independent manner by an array of activating and inhibitory receptors, which are promising candidates for immunotherapy. Here we summarize the latest findings in recognizing and regulating MHC I molecules that affect NK cell surveillance of glioblastoma cells. Full article
(This article belongs to the Special Issue Malignant Glioma: Novel Therapeutic Strategies)
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15 pages, 995 KiB  
Review
Reuse of Molecules for Glioblastoma Therapy
Pharmaceuticals 2021, 14(2), 99; https://doi.org/10.3390/ph14020099 - 28 Jan 2021
Cited by 3 | Viewed by 3793
Abstract
Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal [...] Read more.
Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal 12–18 months. New and emerging treatments include the application of a physical device, non-invasive ‘tumor treating fields’ (TTFs), including its concomitant use with standard of care; and varied vaccines and immunotherapeutics being trialed. Some of these approaches have extended life by a few months over standard of care, but in some cases are only available for a minority of GBM patients. Extensive activity is also underway to repurpose and reposition therapeutics for GBM, either alone or in combination with the standard of care. In this review, we present select molecules that target different pathways and are at various stages of clinical translation as case studies to illustrate the rationale for their repurposing-repositioning and potential clinical use. Full article
(This article belongs to the Special Issue Malignant Glioma: Novel Therapeutic Strategies)
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20 pages, 346 KiB  
Review
Update on Chemotherapeutic Approaches and Management of Bevacizumab Usage for Glioblastoma
Pharmaceuticals 2020, 13(12), 470; https://doi.org/10.3390/ph13120470 - 16 Dec 2020
Cited by 8 | Viewed by 2404
Abstract
Glioblastoma, the most common primary brain tumor in adults, has one of the most dismal prognoses in cancer. In 2009, bevacizumab was approved for recurrent glioblastoma in the USA. To evaluate the clinical impact of bevacizumab as a first-line drug for glioblastoma, two [...] Read more.
Glioblastoma, the most common primary brain tumor in adults, has one of the most dismal prognoses in cancer. In 2009, bevacizumab was approved for recurrent glioblastoma in the USA. To evaluate the clinical impact of bevacizumab as a first-line drug for glioblastoma, two randomized clinical trials, AVAglio and RTOG 0825, were performed. Bevacizumab was found to improve progression-free survival (PFS) and was reported to be beneficial for maintaining patient performance status as an initial treatment. These outcomes led to bevacizumab approval in Japan in 2013 as an insurance-covered first-line drug for glioblastoma concurrently with its second-line application. However, prolongation of overall survival was not evinced in these clinical trials; hence, the clinical benefit of bevacizumab for newly diagnosed glioblastomas remains controversial. A recent meta-analysis of randomized controlled trials of bevacizumab combined with temozolomide in recurrent glioblastoma also showed an effect only on PFS, and the benefit of bevacizumab even for recurrent glioblastoma is controversial. Here, we discuss the clinical impact of bevacizumab for glioblastoma treatment by reviewing previous clinical trials and real-world evidence by focusing on Japanese experiences. Moreover, the efficacy and safety of bevacizumab are summarized, and we provide suggestions for updating the approaches and management of bevacizumab. Full article
(This article belongs to the Special Issue Malignant Glioma: Novel Therapeutic Strategies)
26 pages, 1850 KiB  
Review
The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions
Pharmaceuticals 2020, 13(11), 389; https://doi.org/10.3390/ph13110389 - 14 Nov 2020
Cited by 32 | Viewed by 6385
Abstract
Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address [...] Read more.
Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments. Full article
(This article belongs to the Special Issue Malignant Glioma: Novel Therapeutic Strategies)
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