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Cancers
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Novel Treatment Strategies for Glioblastoma
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Novel Treatment Strategies for Glioblastoma

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

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 47919

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Stanley Stylli

E-Mail Website1 Website2
Guest Editor
Department of Neurosurgery, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC 3050, Australia. Department of Surgery, University of Melbourne, Parkville, Victoria 3010, Australia.
Interests: glioma; glioblastoma; invadopodia; invasion; exosomes; extracellular vesicles; drug repurposing; personalized medicine

Special Issue Information

Dear Colleagues,

Gliomas are among the deadliest and most invasive types of brain cancer, accounting for the majority of all brain-related malignancies. Glioblastoma is the most common malignant primary brain tumour and despite the current treatment approach combining surgery, radiotherapy, and chemotherapy, median survival has remained relatively unchanged since 2005 at approximately 15 months, as the tumour inevitably recurs and is invariably fatal. It is a neurologically destructive cancer with features such as intra/intertumoral heterogeneity, uncontrolled tumor cell proliferation, multifaceted resistance mechanisms leading to treatment resistance, an immunosuppressive microenvironment, and enhanced migration and invasive capabilities that provide therapeutic challenges to combating the disease.

In 2016, the World Health Organization updated the histological classification of brain tumours with the introduction of molecular markers. In conjunction with advances in techniques involving next-generation sequencing and high throughput technologies, efforts are being made to understand the pathology of the disease through the integration of molecular and immunological signatures and coupling these with clinical information with a view to providing precision oncology with a targeted approach to treatment.

This Special Issue will cover all aspects of exploring novel and strategic approaches for the treatment of glioblastoma, involving original research and comprehensive reviews including but not limited to investigational therapies with chemotherapy or immunotherapy based targeted agents in a pre-clinical or clinical setting (combined with conventional therapies or as a monotherapy), molecular mechanisms of treatment response or design strategies, and the use of robust prognostic or predictive biomarkers. We aim to provide an update on the current status and the future directions of this exciting field of research that is aiming to improve glioblastoma patient outcome.

Dr. Stanley Stylli
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.

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

  • glioblastoma
  • invasion
  • drug repurposing
  • immunotherapy
  • treatment resistance
  • targeted therapy
  • precision medicine
  • biomarkers

Published Papers (16 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 181 KiB  
Editorial
Novel Treatment Strategies for Glioblastoma—A Summary
by Stanley S. Stylli
Cancers 2021, 13(22), 5868; https://doi.org/10.3390/cancers13225868 - 22 Nov 2021
Cited by 5 | Viewed by 1501
Abstract
Glioblastoma (GBM) is the most common primary central nervous system tumor in adults, accounting for approximately 80% of all brain-related malignancies [...] Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
11 pages, 222 KiB  
Editorial
Novel Treatment Strategies for Glioblastoma
by Stanley S. Stylli
Cancers 2020, 12(10), 2883; https://doi.org/10.3390/cancers12102883 - 8 Oct 2020
Cited by 41 | Viewed by 4287
Abstract
Glioblastoma (GBM) is the most common primary central nervous system tumor in adults. It is a highly invasive disease, making it difficult to achieve a complete surgical resection, resulting in poor prognosis with a median survival of 12–15 months after diagnosis, and less [...] Read more.
Glioblastoma (GBM) is the most common primary central nervous system tumor in adults. It is a highly invasive disease, making it difficult to achieve a complete surgical resection, resulting in poor prognosis with a median survival of 12–15 months after diagnosis, and less than 5% of patients survive more than 5 years. Surgical, instrument technology, diagnostic and radio/chemotherapeutic strategies have slowly evolved over time, but this has not translated into significant increases in patient survival. The current standard of care for GBM patients involving surgery, radiotherapy, and concomitant chemotherapy temozolomide (known as the Stupp protocol), has only provided a modest increase of 2.5 months in median survival, since the landmark publication in 2005. There has been considerable effort in recent years to increase our knowledge of the molecular landscape of GBM through advances in technology such as next-generation sequencing, which has led to the stratification of the disease into several genetic subtypes. Current treatments are far from satisfactory, and studies investigating acquired/inherent resistance to current therapies, restricted drug delivery, inter/intra-tumoral heterogeneity, drug repurposing and a tumor immune-evasive environment have been the focus of intense research over recent years. While the clinical advancement of GBM therapeutics has seen limited progression compared to other cancers, developments in novel treatment strategies that are being investigated are displaying encouraging signs for combating this disease. This aim of this editorial is to provide a brief overview of a select number of these novel therapeutic approaches. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)

Research

Jump to: Editorial, Review, Other

18 pages, 7863 KiB  
Article
Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics
by Laura Guarnaccia, Stefania E. Navone, Matteo M. Masseroli, Melissa Balsamo, Manuela Caroli, Silvia Valtorta, Rosa M. Moresco, Rolando Campanella, Luigi Schisano, Giorgio Fiore, Valentina Galiano, Emanuele Garzia, Giuseppe C. Appiani, Marco Locatelli, Laura Riboni and Giovanni Marfia
Cancers 2022, 14(6), 1412; https://doi.org/10.3390/cancers14061412 - 10 Mar 2022
Cited by 7 | Viewed by 2134
Abstract
Background: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects [...] Read more.
Background: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. Methods: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. Results: Data resulting revealed a time- and μ-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. Conclusions: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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35 pages, 7108 KiB  
Article
Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells
by Vladimir Shapovalov, Liliya Kopanitsa, Lavinia-Lorena Pruteanu, Graham Ladds and David S. Bailey
Cancers 2021, 13(15), 3780; https://doi.org/10.3390/cancers13153780 - 27 Jul 2021
Cited by 5 | Viewed by 3898
Abstract
We have used three established human glioblastoma (GBM) cell lines—U87MG, A172, and T98G—as cellular systems to examine the plasticity of the drug-induced GBM cell phenotype, focusing on two clinical drugs, the phosphodiesterase PDE10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib, using genome-wide drug-induced [...] Read more.
We have used three established human glioblastoma (GBM) cell lines—U87MG, A172, and T98G—as cellular systems to examine the plasticity of the drug-induced GBM cell phenotype, focusing on two clinical drugs, the phosphodiesterase PDE10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib, using genome-wide drug-induced gene expression (DIGEX) to examine the drug response. Both drugs upregulate genes encoding specific growth factors, transcription factors, cellular signaling molecules, and cell surface proteins, while downregulating a broad range of targetable cell cycle and apoptosis-associated genes. A few upregulated genes encode therapeutic targets already addressed by FDA approved drugs, but the majority encode targets for which there are no approved drugs. Amongst the latter, we identify many novel druggable targets that could qualify for chemistry-led drug discovery campaigns. We also observe several highly upregulated transmembrane proteins suitable for combined drug, immunotherapy, and RNA vaccine approaches. DIGEX is a powerful way of visualizing the complex drug response networks emerging during GBM drug treatment, defining a phenotypic landscape which offers many new diagnostic and therapeutic opportunities. Nevertheless, the extreme heterogeneity we observe within drug-treated cells using this technique suggests that effective pan-GBM drug treatment will remain a significant challenge for many years to come. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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18 pages, 5445 KiB  
Article
KYP-2047, an Inhibitor of Prolyl-Oligopeptidase, Reduces GlioBlastoma Proliferation through Angiogenesis and Apoptosis Modulation
by Sarah Adriana Scuderi, Giovanna Casili, Alessio Ardizzone, Stefano Forte, Lorenzo Colarossi, Serena Sava, Irene Paterniti, Emanuela Esposito, Salvatore Cuzzocrea and Michela Campolo
Cancers 2021, 13(14), 3444; https://doi.org/10.3390/cancers13143444 - 9 Jul 2021
Cited by 17 | Viewed by 2525
Abstract
Glioblastoma (GB) is the most aggressive tumor of the central nervous system (CNS), characterized by excessive proliferation, necrosis and invasiveness. The survival rate for patients with GB still remains low. Angiogenesis and apoptosis play a key role in the development of GB. Thus, [...] Read more.
Glioblastoma (GB) is the most aggressive tumor of the central nervous system (CNS), characterized by excessive proliferation, necrosis and invasiveness. The survival rate for patients with GB still remains low. Angiogenesis and apoptosis play a key role in the development of GB. Thus, the modulation of angiogenesis and apoptosis processes represent a possible strategy to counteract GB progression. This study aimed to investigate the potential effect of KYP-2047, an inhibitor of the prolyl-oligopeptidase (POP), known to modulate angiogenesis, in an in vivo U87-xenograft model and in an in vitro study on human GB cells. Our results showed that KYP-2047 at doses of 2.5 mg/kg and 5 mg/kg was able to reduce tumor burden in the xenograft-model. Moreover, KYP-2047 significantly reduced vascular endothelial-growth-factor (VEGF), angiopoietins (Ang) and endothelial-nitric-oxide synthase (eNOS) expression. In vitro study revealed that KYP-2047 at different concentrations reduced GB cells’ viability. Additionally, KYP-2047 at the concentrations of 50 µM and 100 µM was able to increase the pro-apoptotic protein Bax, p53 and caspase-3 expression whereas Bcl-2 expression was reduced. Thus, KYP-2047 could represent a potential therapeutic treatment to counteract or reduce GB progression, thanks its abilities to modulate angiogenesis and apoptosis pathways. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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0 pages, 3889 KiB  
Article
RETRACTED: Anti-Cancer Activities of Thyrointegrin αvβ3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma
by Kavitha Godugu, Mehdi Rajabi and Shaker A. Mousa
Cancers 2021, 13(11), 2780; https://doi.org/10.3390/cancers13112780 - 3 Jun 2021
Cited by 5 | Viewed by 2313 | Correction | Retraction
Abstract
Integrin αvβ3 receptors are overexpressed in different tumors and their associated neovascularization and hence, represent a potential cancer target. We previously synthesized a high affinity thyrointegrin αvβ3, P4000-bi-TAT (tetrac derivative), with potent anticancer properties. However, the long polydisperse PEG conjugate showed [...] Read more.
Integrin αvβ3 receptors are overexpressed in different tumors and their associated neovascularization and hence, represent a potential cancer target. We previously synthesized a high affinity thyrointegrin αvβ3, P4000-bi-TAT (tetrac derivative), with potent anticancer properties. However, the long polydisperse PEG conjugate showed large scaleup and analytical/bioanalytical issues. Hence, in the present study, we synthesized a mono versus bi-triazole tetrac with discrete monodisperse PEG, which provided improvement in scaleup and bioanalysis. In the present study, we compared binding affinity and anticancer activates with a smaller PEG size (P1600-bi-TAT, Compound 2) and the removal of one TAT molecule (P1600-m-TAT, Compound 3) versus P4000-bi-TAT, Compound 1. The results of the selectivity and affinity of TATs showed greater affinity to integrin αvβ3. The xenograft weights and tumor cell viabilities were decreased by >90% at all doses compared to the control (ON Treatment, *** p < 0.001) in cells treated with Compounds 1, 2, and 3 in U87-Luc-treated mice. The in vivo luminescent signals of U87-luc cells reflect the proliferation and distribution of tumor cells in the animals and the maximum intensity corresponding to the maximum tumor cells that the animals could tolerate. We found that the three thyrointegrin αvβ3 antagonists exhibited optimal therapeutic efficacy against U87 or primary glioblastoma cells. Biological studies showed that decreasing the PEG linker size (1600 vs. 4000) or having mono-TAT or bi-TAT had no significant impact on their αvβ3 binding affinity, anti-angiogenesis, or overall anti-cancer efficacy. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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17 pages, 6574 KiB  
Article
CK2 Activity Mediates the Aggressive Molecular Signature of Glioblastoma Multiforme by Inducing Nerve/Glial Antigen (NG)2 Expression
by Beate M. Schmitt, Anne S. Boewe, Claudia Götz, Stephan E. Philipp, Steffi Urbschat, Joachim Oertel, Michael D. Menger, Matthias W. Laschke and Emmanuel Ampofo
Cancers 2021, 13(7), 1678; https://doi.org/10.3390/cancers13071678 - 2 Apr 2021
Cited by 12 | Viewed by 2175
Abstract
Nerve/glial antigen (NG)2 expression crucially determines the aggressiveness of glioblastoma multiforme (GBM). Recent evidence suggests that protein kinase CK2 regulates NG2 expression. Therefore, we investigated in the present study whether CK2 inhibition suppresses proliferation and migration of NG2-positive GBM cells. For this purpose, [...] Read more.
Nerve/glial antigen (NG)2 expression crucially determines the aggressiveness of glioblastoma multiforme (GBM). Recent evidence suggests that protein kinase CK2 regulates NG2 expression. Therefore, we investigated in the present study whether CK2 inhibition suppresses proliferation and migration of NG2-positive GBM cells. For this purpose, CK2 activity was suppressed in the NG2-positive cell lines A1207 and U87 by the pharmacological inhibitor CX-4945 and CRISPR/Cas9-mediated knockout of CK2α. As shown by quantitative real-time PCR, luciferase-reporter assays, flow cytometry and western blot, this significantly reduced NG2 gene and protein expression when compared to vehicle-treated and wild type controls. In addition, CK2 inhibition markedly reduced NG2-dependent A1207 and U87 cell proliferation and migration. The Cancer Genome Atlas (TCGA)-based data further revealed not only a high expression of both NG2 and CK2 in GBM but also a positive correlation between the mRNA expression of the two proteins. Finally, we verified a decreased NG2 expression after CX-4945 treatment in patient-derived GBM cells. These findings indicate that the inhibition of CK2 represents a promising approach to suppress the aggressive molecular signature of NG2-positive GBM cells. Therefore, CX-4945 may be a suitable drug for the future treatment of NG2-positive GBM. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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21 pages, 4546 KiB  
Article
Inhibition of Radiation and Temozolomide-Induced Glioblastoma Invadopodia Activity Using Ion Channel Drugs
by Marija Dinevska, Natalia Gazibegovic, Andrew P. Morokoff, Andrew H. Kaye, Katharine J. Drummond, Theo Mantamadiotis and Stanley S. Stylli
Cancers 2020, 12(10), 2888; https://doi.org/10.3390/cancers12102888 - 8 Oct 2020
Cited by 9 | Viewed by 2837
Abstract
Glioblastoma (GBM) is the most prevalent and malignant type of primary brain cancer. The rapid invasion and dissemination of tumor cells into the surrounding normal brain is a major driver of tumor recurrence, and long-term survival of GBM patients is extremely rare. Actin-rich [...] Read more.
Glioblastoma (GBM) is the most prevalent and malignant type of primary brain cancer. The rapid invasion and dissemination of tumor cells into the surrounding normal brain is a major driver of tumor recurrence, and long-term survival of GBM patients is extremely rare. Actin-rich cell membrane protrusions known as invadopodia can facilitate the highly invasive properties of GBM cells. Ion channels have been proposed to contribute to a pro-invasive phenotype in cancer cells and may also be involved in the invadopodia activity of GBM cells. GBM cell cytotoxicity screening of several ion channel drugs identified three drugs with potent cell killing efficacy: flunarizine dihydrochloride, econazole nitrate, and quinine hydrochloride dihydrate. These drugs demonstrated a reduction in GBM cell invadopodia activity and matrix metalloproteinase-2 (MMP-2) secretion. Importantly, the treatment of GBM cells with these drugs led to a significant reduction in radiation/temozolomide-induced invadopodia activity. The dual cytotoxic and anti-invasive efficacy of these agents merits further research into targeting ion channels to reduce GBM malignancy, with a potential for future clinical translation in combination with the standard therapy. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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Review

Jump to: Editorial, Research, Other

17 pages, 1279 KiB  
Review
The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma
by Michael O’Rawe, Ethan J. Kilmister, Theo Mantamadiotis, Andrew H. Kaye, Swee T. Tan and Agadha C. Wickremesekera
Cancers 2021, 13(16), 4004; https://doi.org/10.3390/cancers13164004 - 9 Aug 2021
Cited by 11 | Viewed by 3998
Abstract
Glioblastoma (GB) is an aggressive primary brain tumor. Despite intensive research over the past 50 years, little advance has been made to improve the poor outcome, with an overall median survival of 14.6 months following standard treatment. Local recurrence is inevitable due to [...] Read more.
Glioblastoma (GB) is an aggressive primary brain tumor. Despite intensive research over the past 50 years, little advance has been made to improve the poor outcome, with an overall median survival of 14.6 months following standard treatment. Local recurrence is inevitable due to the quiescent cancer stem cells (CSCs) in GB that co-express stemness-associated markers and components of the renin–angiotensin system (RAS). The dynamic and heterogeneous tumor microenvironment (TME) plays a fundamental role in tumor development, progression, invasiveness, and therapy resistance. There is increasing evidence showing the critical role of the RAS in the TME influencing CSCs via its upstream and downstream pathways. Drugs that alter the hallmarks of cancer by modulating the RAS present a potential new therapeutic alternative or adjunct to conventional treatment of GB. Cerebral and GB organoids may offer a cost-effective method for evaluating the efficacy of RAS-modulating drugs on GB. We review the nexus between the GB TME, CSC niche, and the RAS, and propose re-purposed RAS-modulating drugs as a potential therapeutic alternative or adjunct to current standard therapy for GB. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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18 pages, 601 KiB  
Review
Glioblastoma: Emerging Treatments and Novel Trial Designs
by Vincenzo Di Nunno, Enrico Franceschi, Alicia Tosoni, Lidia Gatto, Raffaele Lodi, Stefania Bartolini and Alba Ariela Brandes
Cancers 2021, 13(15), 3750; https://doi.org/10.3390/cancers13153750 - 26 Jul 2021
Cited by 19 | Viewed by 2856
Abstract
Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The [...] Read more.
Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The expanding availability of innovative compounds requires the design of a new generation of clinical trials, testing experimental compounds in a short time and tailoring the sample cohort based on molecular and clinical behaviors. In this review, we focused our attention on the assessment of promising novel treatment approaches, discussing novel trial design and possible future fields of development in this setting. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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22 pages, 688 KiB  
Review
Advances in Immunotherapy for Adult Glioblastoma
by Chirayu R. Chokshi, Benjamin A. Brakel, Nazanin Tatari, Neil Savage, Sabra K. Salim, Chitra Venugopal and Sheila K. Singh
Cancers 2021, 13(14), 3400; https://doi.org/10.3390/cancers13143400 - 7 Jul 2021
Cited by 9 | Viewed by 3944
Abstract
Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent [...] Read more.
Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent clinical and preclinical efforts to evaluate vaccination strategies, immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells. Although these modalities have shown long-term tumor regression in subsets of treated patients, the underlying biology that may predict efficacy and inform therapy development is being actively investigated. Common to all therapeutic modalities are fundamental mechanisms of therapy evasion by tumor cells, including immense intratumoral heterogeneity, suppression of the tumor immune microenvironment and low mutational burden. These insights have led efforts to design rational combinatorial therapies that can reignite the anti-tumor immune response, effectively and specifically target tumor cells and reliably decrease tumor burden for GBM patients. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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14 pages, 467 KiB  
Review
One-Carbon Metabolism Associated Vulnerabilities in Glioblastoma: A Review
by Kimia Ghannad-Zadeh and Sunit Das
Cancers 2021, 13(12), 3067; https://doi.org/10.3390/cancers13123067 - 19 Jun 2021
Cited by 6 | Viewed by 2590
Abstract
Altered cell metabolism is a hallmark of cancer cell biology, and the adaptive metabolic strategies of cancer cells have been of recent interest to many groups. Metabolic reprogramming has been identified as a critical step in glial cell transformation, and the use of [...] Read more.
Altered cell metabolism is a hallmark of cancer cell biology, and the adaptive metabolic strategies of cancer cells have been of recent interest to many groups. Metabolic reprogramming has been identified as a critical step in glial cell transformation, and the use of antimetabolites against glioblastoma has been investigated. One-carbon (1-C) metabolism and its associated biosynthetic pathways, particularly purine nucleotide synthesis, are critical for rapid proliferation and are altered in many cancers. Purine metabolism has also been identified as essential for glioma tumourigenesis. Additionally, alterations of 1-C-mediated purine synthesis have been identified as commonly present in brain tumour initiating cells (BTICs) and could serve as a phenotypic marker of cells responsible for tumour recurrence. Further research is required to elucidate mechanisms through which metabolic vulnerabilities may arise in BTICs and potential ways to therapeutically target these metabolic processes. This review aims to summarize the role of 1-C metabolism-associated vulnerabilities in glioblastoma tumourigenesis and progression and investigate the therapeutic potential of targeting this pathway in conjunction with other treatment strategies. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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28 pages, 8081 KiB  
Review
FAM72, Glioblastoma Multiforme (GBM) and Beyond
by Nguyen Thi Thanh Ho, Chinmay Satish Rahane, Subrata Pramanik, Pok-Son Kim, Arne Kutzner and Klaus Heese
Cancers 2021, 13(5), 1025; https://doi.org/10.3390/cancers13051025 - 1 Mar 2021
Cited by 9 | Viewed by 3736
Abstract
Neural stem cells (NSCs) offer great potential for regenerative medicine due to their excellent ability to differentiate into various specialized cell types of the brain. In the central nervous system (CNS), NSC renewal and differentiation are under strict control by the regulation of [...] Read more.
Neural stem cells (NSCs) offer great potential for regenerative medicine due to their excellent ability to differentiate into various specialized cell types of the brain. In the central nervous system (CNS), NSC renewal and differentiation are under strict control by the regulation of the pivotal SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2)—Family with sequence similarity 72 (FAM72) master gene (i.e., |-SRGAP2–FAM72-|) via a divergent gene transcription activation mechanism. If the gene transcription control unit (i.e., the intergenic region of the two sub-gene units, SRGAP2 and FAM72) gets out of control, NSCs may transform into cancer stem cells and generate brain tumor cells responsible for brain cancer such as glioblastoma multiforme (GBM). Here, we discuss the surveillance of this |-SRGAP2–FAM72-| master gene and its role in GBM, and also in light of FAM72 for diagnosing various types of cancers outside of the CNS. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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17 pages, 1858 KiB  
Review
Nanomedicine: A Useful Tool against Glioma Stem Cells
by Elia Bozzato, Chiara Bastiancich and Véronique Préat
Cancers 2021, 13(1), 9; https://doi.org/10.3390/cancers13010009 - 22 Dec 2020
Cited by 20 | Viewed by 2919
Abstract
The standard of care therapy of glioblastoma (GBM) includes invasive surgical resection, followed by radiotherapy and concomitant chemotherapy. However, this therapy has limited success, and the prognosis for GBM patients is very poor. Although many factors may contribute to the failure of current [...] Read more.
The standard of care therapy of glioblastoma (GBM) includes invasive surgical resection, followed by radiotherapy and concomitant chemotherapy. However, this therapy has limited success, and the prognosis for GBM patients is very poor. Although many factors may contribute to the failure of current treatments, one of the main causes of GBM recurrences are glioma stem cells (GSCs). This review focuses on nanomedicine strategies that have been developed to eliminate GSCs and the benefits that they have brought to the fight against cancer. The first section describes the characteristics of GSCs and the chemotherapeutic strategies that have been used to selectively kill them. The second section outlines the nano-based delivery systems that have been developed to act against GSCs by dividing them into nontargeted and targeted nanocarriers. We also highlight the advantages of nanomedicine compared to conventional chemotherapy and examine the different targeting strategies that have been employed. The results achieved thus far are encouraging for the pursuit of effective strategies for the eradication of GSCs. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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Graphical abstract

23 pages, 1700 KiB  
Review
Viral Vectors as Gene Therapy Agents for Treatment of Glioblastoma
by Oleg Mozhei, Anja G. Teschemacher and Sergey Kasparov
Cancers 2020, 12(12), 3724; https://doi.org/10.3390/cancers12123724 - 11 Dec 2020
Cited by 14 | Viewed by 3471
Abstract
In this review, we scrutinize the idea of using viral vectors either as cytotoxic agents or gene delivery tools for treatment of glioblastoma multiforme (GBM) in light of the experience that our laboratory has accumulated over ~20 years when using similar vectors in [...] Read more.
In this review, we scrutinize the idea of using viral vectors either as cytotoxic agents or gene delivery tools for treatment of glioblastoma multiforme (GBM) in light of the experience that our laboratory has accumulated over ~20 years when using similar vectors in experimental neuroscience. We review molecular strategies and current clinical trials and argue that approaches which are based on targeting a specific biochemical pathway or a characteristic mutation are inherently prone to failure because of the high genomic instability and clonal selection characteristics of GBM. For the same reasons, attempts to develop a viral system which selectively transduces only GBM cells are also unlikely to be universally successful. One of the common gene therapy approaches is to use cytotoxic viruses which replicate and cause preferential lysis of the GBM cells. This strategy, in addition to its reliance on the specific biochemical makeup of the GBM cells, bears a risk of necrotic cell death accompanied by release of large quantities of pro-inflammatory molecules. On the other hand, engaging the immune system in the anti-GBM response seems to be a potential avenue to explore further. We suggest that a plausible strategy is to focus on viral vectors which efficiently transduce brain cells via a non-selective, ubiquitous mechanism and which target (ideally irreversibly) processes that are critical only for dividing tumor cells and are dispensable for quiescent brain cells. Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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Other

1 pages, 551 KiB  
Correction
Correction: Godugu et al. Anti-Cancer Activities of Thyrointegrin αvβ3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma. Cancers 2021, 13, 2780
by Kavitha Godugu, Mehdi Rajabi and Shaker A. Mousa
Cancers 2022, 14(21), 5371; https://doi.org/10.3390/cancers14215371 - 31 Oct 2022
Cited by 1 | Viewed by 850
Abstract
In the original publication [...] Full article
(This article belongs to the Special Issue Novel Treatment Strategies for Glioblastoma)
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