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Biomedicines
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Glioblastoma: Current Status and Future Prospects
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Glioblastoma: Current Status and Future Prospects

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 July 2024) | Viewed by 7504

Special Issue Editor

Dr. Jason K. Sa

E-Mail Website
Guest Editor
Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
Interests: cancer biology and therapeutic section; molecular genetics and genetic disease section; pharmacogenomic and personalized medicine section potential topics: cancer genomics; tumor evolution; glioblastoma

Special Issue Information

Dear Colleagues,

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Despite aggressive treatment modality, the current standard treatment regimen only provides palliation with a median survival of less than 15 months and a 5-year survival rate of 5% after initial diagnosis. However, in recent years, there has been an emergence of large interest in the development of targeted therapies for glioblastoma owing to its profound levels of genomic aberrations. Major molecular-mediated therapeutic approaches consist of targeting various oncogenic pathway-encoding molecules, including EGFR, PI3K/AKT/mTOR, VEGF, MET, FGFR, BRAF, cell cycle, and TGFb. On the other hand, immunotherapies focus on the disruption of immune checkpoint molecules that are expressed in T cells or tumor cells, such as PD-1, PD-L1, CTLA-4, LAG-3, TIM3, and TIGIT. Given the complexity of genomic architecture and microenvironment composition in GBM, future target-mediated investigations could open up new opportunities for innovative treatments.

Dr. Jason K. Sa
Guest Editor

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Keywords

  • glioblastoma
  • targeted therapy
  • immunotherapy
  • precision medicine
  • genomics
  • pharmacogenoics
  • tumor evolution
  • tumor microenvrionment

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Published Papers (5 papers)

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Research

17 pages, 2617 KiB  
Article
Iloperidone and Temozolomide Synergistically Inhibit Growth, Migration and Enhance Apoptosis in Glioblastoma Cells
by Sahar Mubeen, Iffat Raza, Badaruddin Ujjan, Bushra Wasim, Lubna Khan, Nadia Naeem, Syed Ather Enam and Farina Hanif
Biomedicines 2024, 12(6), 1134; https://doi.org/10.3390/biomedicines12061134 - 21 May 2024
Viewed by 1275
Abstract
Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address the concerns in a timely and cost-effective manner. Epidemiological studies have shown that patients with schizophrenic using anti-psychotics have a low incidence [...] Read more.
Glioblastoma (GBM) is a fatal astrocytic glioma with poor prognosis and treatment resistance. Repurposing potential FDA-approved drugs like anti-psychotics can address the concerns in a timely and cost-effective manner. Epidemiological studies have shown that patients with schizophrenic using anti-psychotics have a low incidence of GBM. Therefore, we aimed to investigate the therapeutic potential of atypical anti-psychotic Iloperidone (ILO) alone and in combination with Temozolomide (TMZ) against GBM. The study assessed the growth inhibitory effect of ILO, TMZ, and their combination (ILO + TMZ) on U-87MG and T-98G cell lines using an MTT assay. The drug interaction coefficient (CDI) was determined, and doses with synergistic effects were used for subsequent experiments, including migratory, invasion, and TUNEL assays. The expressions of DRD2, β-catenin, Dvl2, Twist, and Slug were assessed by RTq-PCR, whereas the β-catenin protein expression was also determined by immunocytochemistry. ILO (p < 0.05) and TMZ (p < 0.01) significantly inhibited the growth of U-87MG cells at all tested doses. The combination of 60 µM of both drugs showed synergistic activity with CDI < 1. The inhibition of migration and apoptosis was more pronounced in the case of combination treatment (p < 0.001). Inhibition of the invading cells was also found to be significant in ILO- and combination-treated groups (p < 0.001). ILO and combination treatment also significantly downregulated the expression of DRD2, while TMZ upregulated the expression (p < 0.001). The expressions of β-catenin (p < 0.001), Dvl2 (p < 0.001), Twist (p < 0.001), and Slug (p < 0.001) were also significantly downregulated in all treatment groups as compared to the vehicle control. The data suggest that ILO possesses strong growth inhibitory activity, possibly due to its effect on DRD2 and β-catenin expression and has the potential to be repurposed against GBM. Full article
(This article belongs to the Special Issue Glioblastoma: Current Status and Future Prospects)
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16 pages, 4959 KiB  
Article
Exploring the Impact of Irradiation on Glioblastoma Blood-Brain-Barrier Permeability: Insights from Dynamic-Contrast-Enhanced-MRI and Histological Analysis
by Jérôme Conq, Nicolas Joudiou, Véronique Préat and Bernard Gallez
Biomedicines 2024, 12(5), 1091; https://doi.org/10.3390/biomedicines12051091 - 14 May 2024
Cited by 1 | Viewed by 1117
Abstract
(1) Background: Glioblastoma (GB) presents a formidable challenge in neuro-oncology due to its aggressive nature, limited treatment options, and poor prognosis. The blood–brain barrier (BBB) complicates treatment by hindering drug delivery to the tumor site, particularly to the infiltrative cells in the margin [...] Read more.
(1) Background: Glioblastoma (GB) presents a formidable challenge in neuro-oncology due to its aggressive nature, limited treatment options, and poor prognosis. The blood–brain barrier (BBB) complicates treatment by hindering drug delivery to the tumor site, particularly to the infiltrative cells in the margin of the tumor, which are mainly responsible for tumor recurrence. Innovative strategies are therefore needed to enhance drug delivery in the margins of the tumor. This study explores whether irradiation can enhance BBB permeability by assessing hemodynamic changes and the distribution of contrast agents in the core and the margins of GB tumors. (2) Methods: Mice grafted with U-87MG cells were exposed to increasing irradiation doses. The distribution of contrast agents and hemodynamic parameters was evaluated using both non-invasive magnetic resonance imaging (MRI) techniques with gadolinium–DOTA as a contrast agent and invasive histological analysis with Evans blue, a fluorescent vascular leakage marker. Diffusion–MRI was also used to assess cytotoxic effects. (3) Results: The histological study revealed a complex dose-dependent effect of irradiation on BBB integrity, with increased vascular leakage at 5 Gy but reduced leakage at higher doses (10 and 15 Gy). However, there was no significant increase in the diffusion of Gd-DOTA outside the tumor area by MRI. (4) Conclusions: The increase in BBB permeability could be an interesting approach to enhance drug delivery in glioblastoma margins for low irradiation doses. In this model, DCE-MRI analysis was of limited value in assessing the BBB opening in glioblastoma after irradiation. Full article
(This article belongs to the Special Issue Glioblastoma: Current Status and Future Prospects)
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12 pages, 7271 KiB  
Article
Isocitrate Dehydrogenase 1/2 Wildtype Adult Astrocytoma with WHO Grade 2/3 Histological Features: Molecular Re-Classification, Prognostic Factors, Clinical Outcomes
by Meetakshi Gupta, Mustafa Anjari, Sebastian Brandner, Naomi Fersht, Elena Wilson, Steffi Thust and Michael Kosmin
Biomedicines 2024, 12(4), 901; https://doi.org/10.3390/biomedicines12040901 - 18 Apr 2024
Cited by 1 | Viewed by 1162
Abstract
Background: Isocitrate Dehydrogenase 1/2 (IDH 1/2)-wildtype (WT) astrocytomas constitute a heterogeneous group of tumors and have undergone a series of diagnostic reclassifications over time. This study aimed to investigate molecular markers, clinical, imaging, and treatment factors predictive of outcomes in WHO grade 2/3 [...] Read more.
Background: Isocitrate Dehydrogenase 1/2 (IDH 1/2)-wildtype (WT) astrocytomas constitute a heterogeneous group of tumors and have undergone a series of diagnostic reclassifications over time. This study aimed to investigate molecular markers, clinical, imaging, and treatment factors predictive of outcomes in WHO grade 2/3 IDH-WT astrocytomas (‘early glioblastoma’). Methodology: Patients with WHO grade 2/3 IDH-WT astrocytomas were identified from the hospital archives. They were cross-referenced with the electronic medical records systems, including neuroimaging. The expert neuro-pathology team retrieved data on molecular markers—MGMT, TERT, IDH, and EGFR. Tumors with a TERT mutation and/or EGFR amplification were reclassified as glioblastoma. Results: Fifty-four patients were identified. Sixty-three percent of the patients could be conclusively reclassified as glioblastoma based on either TERT mutation, EGFR amplification, or both. On imaging, 65% showed gadolinium enhancement on MRI. Thirty-nine patients (72%) received long-course radiotherapy, of whom 64% received concurrent chemotherapy. The median follow-up of the group was 16 months (range: 2–90), and the median overall survival (OS) was 17.3 months. The 2-year OS of the whole cohort was 31%. On univariate analysis, older age, worse performance status (PS), and presence versus absence of contrast enhancement on diagnostic MRI were statistically significant for poorer OS. Conclusion: IDH-WT WHO grade 2/3 astrocytomas are a heterogeneous group of tumors with poor clinical outcomes. The majority can be reclassified as glioblastoma, based on current WHO classification criteria, but further understanding of the underlying biology of these tumors and the discovery of novel targeted agents are needed for better outcomes. Full article
(This article belongs to the Special Issue Glioblastoma: Current Status and Future Prospects)
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14 pages, 3135 KiB  
Article
Correlation between rCBV Delineation Similarity and Overall Survival in a Prospective Cohort of High-Grade Gliomas Patients: The Hidden Value of Multimodal MRI?
by Amina Latreche, Gurvan Dissaux, Solène Querellou, Doria Mazouz Fatmi, François Lucia, Anais Bordron, Alicia Vu, Ruben Touati, Victor Nguyen, Mohamed Hamya, Brieg Dissaux and Vincent Bourbonne
Biomedicines 2024, 12(4), 789; https://doi.org/10.3390/biomedicines12040789 - 3 Apr 2024
Cited by 1 | Viewed by 1345
Abstract
Purpose: The accuracy of target delineation in radiation treatment planning of high-grade gliomas (HGGs) is crucial to achieve high tumor control, while minimizing treatment-related toxicity. Magnetic resonance imaging (MRI) represents the standard imaging modality for delineation of gliomas with inherent limitations in accurately [...] Read more.
Purpose: The accuracy of target delineation in radiation treatment planning of high-grade gliomas (HGGs) is crucial to achieve high tumor control, while minimizing treatment-related toxicity. Magnetic resonance imaging (MRI) represents the standard imaging modality for delineation of gliomas with inherent limitations in accurately determining the microscopic extent of tumors. The purpose of this study was to assess the survival impact of multi-observer delineation variability of multiparametric MRI (mpMRI) and [18F]-FET PET/CT. Materials and Methods: Thirty prospectively included patients with histologically confirmed HGGs underwent a PET/CT and mpMRI including diffusion-weighted imaging (DWI: b0, b1000, ADC), contrast-enhanced T1-weighted imaging (T1-Gado), T2-weighted fluid-attenuated inversion recovery (T2Flair), and perfusion-weighted imaging with computation of relative cerebral blood volume (rCBV) and K2 maps. Nine radiation oncologists delineated the PET/CT and MRI sequences. Spatial similarity (Dice similarity coefficient: DSC) was calculated between the readers for each sequence. Impact of the DSC on progression-free survival (PFS) and overall survival (OS) was assessed using Kaplan–Meier curves and the log-rank test. Results: The highest DSC mean values were reached for morphological sequences, ranging from 0.71 +/− 0.18 to 0.84 +/− 0.09 for T2Flair and T1Gado, respectively, while metabolic volumes defined by PET/CT achieved a mean DSC of 0.75 +/− 0.11. rCBV variability (mean DSC0.32 +/− 0.20) significantly impacted PFS (p = 0.02) and OS (p = 0.002). Conclusions: Our data suggest that the T1-Gado and T2Flair sequences were the most reproducible sequences, followed by PET/CT. Reproducibility for functional sequences was low, but rCBV inter-reader similarity significantly impacted PFS and OS. Full article
(This article belongs to the Special Issue Glioblastoma: Current Status and Future Prospects)
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17 pages, 3877 KiB  
Article
Novel Brain-Penetrant, Small-Molecule Tubulin Destabilizers for the Treatment of Glioblastoma
by Lilian A. Patrón, Helen Yeoman, Sydney Wilson, Nanyun Tang, Michael E. Berens, Vijay Gokhale and Teri C. Suzuki
Biomedicines 2024, 12(2), 406; https://doi.org/10.3390/biomedicines12020406 - 9 Feb 2024
Viewed by 1764
Abstract
Glioblastoma (GB) is the most lethal brain cancer in adults, with a 5-year survival rate of 5%. The standard of care for GB includes maximally safe surgical resection, radiation, and temozolomide (TMZ) therapy, but tumor recurrence is inevitable in most GB patients. Here, [...] Read more.
Glioblastoma (GB) is the most lethal brain cancer in adults, with a 5-year survival rate of 5%. The standard of care for GB includes maximally safe surgical resection, radiation, and temozolomide (TMZ) therapy, but tumor recurrence is inevitable in most GB patients. Here, we describe the development of a blood–brain barrier (BBB)-penetrant tubulin destabilizer, RGN3067, for the treatment of GB. RGN3067 shows good oral bioavailability and achieves high concentrations in rodent brains after oral dosing (Cmax of 7807 ng/mL (20 μM), Tmax at 2 h). RGN3067 binds the colchicine binding site of tubulin and inhibits tubulin polymerization. The compound also suppresses the proliferation of the GB cell lines U87 and LN-18, with IC50s of 117 and 560 nM, respectively. In four patient-derived GB cell lines, the IC50 values for RGN3067 range from 148 to 616 nM. Finally, in a patient-derived xenograft (PDX) mouse model, RGN3067 reduces the rate of tumor growth compared to the control. Collectively, we show that RGN3067 is a BBB-penetrant small molecule that shows in vitro and in vivo efficacy and that its design addresses many of the physicochemical properties that prevent the use of microtubule destabilizers as treatments for GB and other brain cancers. Full article
(This article belongs to the Special Issue Glioblastoma: Current Status and Future Prospects)
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