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Glioblastoma: Recent Advances and Challenges
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Glioblastoma: Recent Advances and Challenges

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

Deadline for manuscript submissions: closed (30 September 2024) | Viewed by 8888

Special Issue Editor

Dr. P. Leia Nghiemphu

E-Mail Website
Guest Editor
UCLA Neuro-Oncology Program, Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
Interests: brain cancer; gliomas; neurofibromatosis

Special Issue Information

Dear Colleagues,

Glioblastoma (GBM) is the most common and most malignant of all primary tumors of the brain and nervous system. To date, treatments with standard radiation and chemotherapy have provided little additional survival benefits to patients with GBM. Unlike other cancers, there are limited FDA-approved treatments for GBM, and different treatment modalities with proven success in preclinical settings have not been successfully translated to the clinic.Overall, more treatments options are critically needed specifically to target GBM. Various treatment options for GBM that have been tested still have significant limitations regarding brain tumor penetration and the heterogeneity of this cancer. New cancer therapeutics such as immunotherapies are still being evaluated for the treatment of GBM. Better understanding in GBM cancer biology and tumor microenvironment would considerably improve new treatments for GBM.

In this Special Issue, advances in the treatment of GBM will highlight needed areas of studies to enhance treatment options for patients with GBM from a basic and clinical standpoint. 

Dr. P. Leia Nghiemphu
Guest Editor

Manuscript Submission Information

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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
  • cancer immunotherapy
  • brain tumor microenvironment
  • molecular targeted therapy
  • GBM

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Published Papers (5 papers)

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Research

10 pages, 1573 KiB  
Article
Metabolic Risk Factors and Survival in Patients with Glioblastoma
by John Paul Aboubechara and Orwa Aboud
Cancers 2024, 16(21), 3666; https://doi.org/10.3390/cancers16213666 - 30 Oct 2024
Viewed by 416
Abstract
Background: Metabolic syndrome increases the risk of developing various systemic cancers. The prevalence of metabolic syndrome in newly diagnosed glioblastoma patients is unknown. Further, there have been contradictory reports about how metabolic syndrome affects clinical outcomes. Therefore, the purpose of this study is [...] Read more.
Background: Metabolic syndrome increases the risk of developing various systemic cancers. The prevalence of metabolic syndrome in newly diagnosed glioblastoma patients is unknown. Further, there have been contradictory reports about how metabolic syndrome affects clinical outcomes. Therefore, the purpose of this study is to test the hypothesis that metabolic syndrome is associated with an increased prevalence of glioblastoma and worsened survival outcomes. Methods: This retrospective cohort study examines seventy-three patients with isocitrate dehydrogenase (IDH)-wild-type glioblastoma as it provides a relatively homogeneous population to examine. Patient characteristics, vital signs, lab results, tumor molecular markers, and overall survival were analyzed. Patients with metabolic syndrome and individual risk factors were identified, and survival outcomes were examined. Results: Our results demonstrate that there is a higher prevalence of metabolic syndrome in our cohort of patients with glioblastoma than in the general population (41% vs. 33%), though this effect is confounded by older age. We also demonstrate that after correction for confounding variables, metabolic syndrome is not significantly associated with overall survival (p = 0.1). When analyzing individual metabolic risk factors, we demonstrate that there is a significant association between the accumulation of metabolic risk factors and decreased survival (p = 0.03), and hyperglycemia emerges as a significant independent risk factor for decreased survival (p = 0.05). Conclusions: These results suggest that metabolic risk factors can affect survival in patients with glioblastoma, which can have significant implications for clinical practice. These findings need to be further explored through further clinical and mechanistic studies. Full article
(This article belongs to the Special Issue Glioblastoma: Recent Advances and Challenges)
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19 pages, 4681 KiB  
Article
Efficacy and Low Toxicity of Normo-Fractionated Re-Irradiation with Combined Chemotherapy for Recurrent Glioblastoma—An Analysis of Treatment Response and Failure
by Niklas Benedikt Pepper, Nicholas Grischa Prange, Fabian Martin Troschel, Kai Kröger, Michael Oertel, Tanja Kuhlmann, Michael Müther, Oliver Grauer, Walter Stummer and Hans Theodor Eich
Cancers 2024, 16(21), 3652; https://doi.org/10.3390/cancers16213652 - 29 Oct 2024
Viewed by 634
Abstract
Background: Glioblastoma is the most common malignant brain tumor in adults. Even after maximal safe resection and adjuvant chemoradiotherapy, patients normally relapse after a few years or even months. Standard treatment for recurrent glioblastoma is not yet defined, with re-resection, re-irradiation, and systemic [...] Read more.
Background: Glioblastoma is the most common malignant brain tumor in adults. Even after maximal safe resection and adjuvant chemoradiotherapy, patients normally relapse after a few years or even months. Standard treatment for recurrent glioblastoma is not yet defined, with re-resection, re-irradiation, and systemic therapy playing key roles. Usually, re-irradiation is combined with concurrent chemotherapy, harnessing the radiosensitizing effects of alkylating agents. Methods: A retrospective analysis of 101 patients with recurrent glioblastoma treated with re-irradiation was conducted, evaluating the survival impact of concurrent chemotherapy regimens, as well as prior resection. Patients were subcategorized according to concurrent chemotherapy (temozolomide vs. CCNU vs. combination of both vs. none) and details are given regarding treatment toxicity and patterns of relapse after first- and second-line treatment. Results: Patients were treated with normo-fractionated re-irradiation (with prescription dose of ~40 Gy to the PTV), resulting in a moderate cumulative EQD2 (~100 Gy). The mean overall survival was 11.3 months (33.5 months from initial diagnosis) and mean progression free survival was 9.5 months. Prior resection resulted in increased survival (p < 0.001), especially when gross total resection was achieved. Patients who received concurrent chemotherapy had significantly longer survival vs. no chemotherapy (p < 0.01), with the combination of CCNU and TMZ achieving the best results. Overall survival was significantly better in patients who received the CCNU + TMZ combination at any time during treatment (first or second line) vs. monotherapy only. The treatment of larger volumes (mean PTV size = 112.7 cm3) was safe and did not result in worse prognosis or increased demand for corticosteroids. Overall, the incidence of high-grade toxicity or sequential radionecrosis (5%) was reasonably low and treatment was tolerated well. While second-line chemotherapy did not seem to influence patterns of relapse, patients who received TMZ + CCNU as first-line treatment had a tendency towards better local control with more out-field recurrence. Conclusions: Normo-fractionated re-irradiation appears to be safe and is accompanied by good survival outcomes, even when applied to larger treatment volumes. Patients amenable to undergo re-resection and achieving concurrent systemic therapy with alkylating agents had better OS, especially when gross total resection was possible. Based on existing data and experiences reflected in this analysis, we advocate for a multimodal approach to recurrent glioblastoma with maximal safe re-resection and adjuvant second chemoradiation. The combination of TMZ and CCNU for patients with methylated MGMT promoter yielded the best results in the primary and recurrent situation (together with re-RT). Normo-fractionated RT enables the use of more generous margins and is tolerated well. Full article
(This article belongs to the Special Issue Glioblastoma: Recent Advances and Challenges)
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20 pages, 11248 KiB  
Article
Novel Function of Cancer Stem Cell Marker ALDH1A3 in Glioblastoma: Pro-Angiogenesis through Paracrine PAI-1 and IL-8
by Zhen Chen, Rainer Will, Su Na Kim, Maike Anna Busch, Nicole Dünker, Philipp Dammann, Ulrich Sure and Yuan Zhu
Cancers 2023, 15(17), 4422; https://doi.org/10.3390/cancers15174422 - 4 Sep 2023
Cited by 3 | Viewed by 2010
Abstract
Hyper-angiogenesis is a typical feature of glioblastoma (GBM), the most aggressive brain tumor. We have reported the expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in proliferating vasculature in GBM patients. We hypothesized that ALDH1A3 may act as an angiogenesis promoter in GBM. Two GBM [...] Read more.
Hyper-angiogenesis is a typical feature of glioblastoma (GBM), the most aggressive brain tumor. We have reported the expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in proliferating vasculature in GBM patients. We hypothesized that ALDH1A3 may act as an angiogenesis promoter in GBM. Two GBM cell lines were lentivirally transduced with either ALDH1A3 (ox) or an empty vector (ev). The angiogenesis phenotype was studied in indirect and direct co-culture of endothelial cells (ECs) with oxGBM cells (oxGBMs) and in an angiogenesis model in vivo. Angiogenesis array was performed in oxGBMs. RT2-PCR, Western blot, and double-immunofluorescence staining were performed to confirm the expression of targets identified from the array. A significantly activated angiogenesis phenotype was observed in ECs indirectly and directly co-cultured with oxGBMs and in vivo. Overexpression of ALDH1A3 (oxALDH1A3) led to a marked upregulation of PAI-1 and IL-8 mRNA and protein and a consequential increased release of both proteins. Moreover, oxALDH1A3-induced angiogenesis was abolished by the treatment of the specific inhibitors, respectively, of PAI-1 and IL-8 receptors, CXCR1/2. This study defined ALDH1A3 as a novel angiogenesis promoter. oxALDH1A3 in GBM cells stimulated EC angiogenesis via paracrine upregulation of PAI-1 and IL-8, suggesting ALDH1A3-PAI-1/IL-8 as a novel signaling for future anti-angiogenesis therapy in GBM. Full article
(This article belongs to the Special Issue Glioblastoma: Recent Advances and Challenges)
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15 pages, 8837 KiB  
Article
Vasculogenic Mimicry Occurs at Low Levels in Primary and Recurrent Glioblastoma
by Kelsey Maddison, Sam Faulkner, Moira C. Graves, Michael Fay, Nikola A. Bowden and Paul A. Tooney
Cancers 2023, 15(15), 3922; https://doi.org/10.3390/cancers15153922 - 1 Aug 2023
Cited by 1 | Viewed by 1585
Abstract
Vasculogenic mimicry (VM), the ability of tumour cells to form functional microvasculature without an endothelial lining, may contribute to anti-angiogenic treatment resistance in glioblastoma. We aimed to assess the extent of VM formation in primary and recurrent glioblastomas and to determine whether VM [...] Read more.
Vasculogenic mimicry (VM), the ability of tumour cells to form functional microvasculature without an endothelial lining, may contribute to anti-angiogenic treatment resistance in glioblastoma. We aimed to assess the extent of VM formation in primary and recurrent glioblastomas and to determine whether VM vessels also express prostate-specific membrane antigen (PSMA), a pathological vessel marker. Formalin-fixed paraffin-embedded tissue from 35 matched pairs of primary and recurrent glioblastoma was immunohistochemically labelled for PSMA and CD34 and stained with periodic acid–Schiff (PAS). Vascular structures were categorised as endothelial vessels (CD34+/PAS+) or VM (CD34−/PAS+). Most blood vessels in both primary and recurrent tumours were endothelial vessels, and these significantly decreased in recurrent tumours (p < 0.001). PSMA was expressed by endothelial vessels, and its expression was also decreased in recurrent tumours (p = 0.027). VM was observed in 42.86% of primary tumours and 28.57% of recurrent tumours. VM accounted for only a small proportion of the tumour vasculature and VM density did not differ between primary and recurrent tumours (p = 0.266). The functional contribution of VM and its potential as a treatment target in glioblastoma require further investigation. Full article
(This article belongs to the Special Issue Glioblastoma: Recent Advances and Challenges)
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14 pages, 2481 KiB  
Article
Anti-Vimentin Nanobody Decreases Glioblastoma Cell Invasion In Vitro and In Vivo
by Alja Zottel, Metka Novak, Neja Šamec, Bernarda Majc, Sara Colja, Mojca Katrašnik, Miloš Vittori, Barbara Hrastar, Ana Rotter, Andrej Porčnik, Tamara Lah Turnšek, Radovan Komel, Barbara Breznik and Ivana Jovčevska
Cancers 2023, 15(3), 573; https://doi.org/10.3390/cancers15030573 - 17 Jan 2023
Cited by 5 | Viewed by 2999
Abstract
Purpose: Glioblastoma (GBM) is the most common primary brain tumour and one of the deadliest cancers. In addition to late diagnosis and inadequate treatment, the extremely low survival rate is also due to the lack of appropriate therapeutic biomarkers and corresponding therapeutic agents. [...] Read more.
Purpose: Glioblastoma (GBM) is the most common primary brain tumour and one of the deadliest cancers. In addition to late diagnosis and inadequate treatment, the extremely low survival rate is also due to the lack of appropriate therapeutic biomarkers and corresponding therapeutic agents. One of the potential therapeutic biomarkers is the intermediate filament vimentin, which is associated with epithelial-mesenchymal transition (EMT). The purpose of this study was to analyse the effect of the anti-vimentin nanobody Nb79 on cell invasion in vitro and in vivo. To further our understanding of the mechanism of action, we investigated the association between Nb79 and EMT in GBM and GBM stem cells by analysing the expression levels of key EMT-related proteins. Methods: The expression of vimentin in glioma tissues and cells was determined by RT-qPCR. An invasion assay was performed on differentiated glioblastoma cell line U-87 MG and stem cell line NCH421k in vitro as well as in vivo in zebrafish embryos. The effect of Nb79 on expression of EMT biomarkers beta-catenin, vimentin, ZEB-1 and ZO1 was determined by Western blot and immunocytochemistry. Results: Our study shows that vimentin is upregulated in glioblastoma tissue compared to lower grade glioma and non-tumour brain tissue. We demonstrated that treatment with Nb79 reduced glioblastoma cell invasion by up to 64% in vitro and up to 21% in vivo. In addition, we found that the tight junction protein ZO-1 had higher expression on the cell membrane, when treated with inhibitory anti-vimentin Nb79 compared to control. Conclusion: In conclusion, our results suggest that anti-vimentin nanobody Nb79 is a promising tool to target glioblastoma cell invasion. Full article
(This article belongs to the Special Issue Glioblastoma: Recent Advances and Challenges)
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