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Molecular Mechanisms and Targeted Therapies for Glioblastoma
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Molecular Mechanisms and Targeted Therapies for Glioblastoma

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 7107

Special Issue Editor

Dr. Elvira V. Grigorieva

E-Mail Website
Guest Editor
Department of Molecular Biology and Biophysics Federal Research Center of Fundamental and Translational Medicine (FRC FTM)
Interests: glioblastoma; tumour microenvironment; extracellular matrix; glycosylation; proteoglycan; animal models; biomarker; chemotherapy; radiotherapy; targeted therapy; therapy-induced side-effects
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glioblastoma multiforme (GBM) is one of the most aggressive malignant tumors with a poor prognosis. Despite active adjuvant radiochemotherapy, in most cases recurrence of the disease develops, which leads to an unfavorable outcome. The search for new approaches to the treatment of GBM remains extremely relevant, and any discoveries in this area of research will improve the quality and life expectancy of GBM patients.

The solution to this problem is directly related to a deeper study of the molecular mechanisms of GBM development and the identification of key points that could serve as markers of disease prognosis and potential targets for the development of targeted therapies.

This Special Issue aims to collect latest findings and innovations in this research field. We are pleased to invite you to participate in this Special Issue by presenting original researches, clinical studies and reviews as well as new ideas and hypothesis on molecular mechanisms of GBM development and progression, identification of prognostic factors of the disease recurrence, development of new chemotherapeutic and other drugs, improvement of radiation therapy regimens, search for new molecular targets for targeted and personalised therapy of GBM patients.

Dr. Elvira V. Grigorieva
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • molecular mechanisms
  • biomarker
  • cell- and animal-based models
  • tumor microenvironment
  • extracellular matrix
  • glycosylation
  • proteoglycan
  • chemotherapy
  • radiotherapy
  • targeted therapy
  • combined therapy

Published Papers (4 papers)

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Research

14 pages, 1780 KiB  
Article
Dexamethasone Inhibits Heparan Sulfate Biosynthetic System and Decreases Heparan Sulfate Content in Orthotopic Glioblastoma Tumors in Mice
by Dmitry K. Sokolov, Oleg B. Shevelev, Anna S. Khotskina, Alexandra Y. Tsidulko, Anastasia V. Strokotova, Galina M. Kazanskaya, Alexander M. Volkov, Evgenii E. Kliver, Svetlana V. Aidagulova, Evgenii L. Zavjalov and Elvira V. Grigorieva
Int. J. Mol. Sci. 2023, 24(12), 10243; https://doi.org/10.3390/ijms241210243 - 16 Jun 2023
Cited by 2 | Viewed by 1223
Abstract
Glioblastoma (GB) is an aggressive cancer with a high probability of recurrence, despite active chemoradiotherapy with temozolomide (TMZ) and dexamethasone (DXM). These systemic drugs affect the glycosylated components of brain tissue involved in GB development; however, their effects on heparan sulfate (HS) remain [...] Read more.
Glioblastoma (GB) is an aggressive cancer with a high probability of recurrence, despite active chemoradiotherapy with temozolomide (TMZ) and dexamethasone (DXM). These systemic drugs affect the glycosylated components of brain tissue involved in GB development; however, their effects on heparan sulfate (HS) remain unknown. Here, we used an animal model of GB relapse in which SCID mice first received TMZ and/or DXM (simulating postoperative treatment) with a subsequent inoculation of U87 human GB cells. Control, peritumor and U87 xenograft tissues were investigated for HS content, HS biosynthetic system and glucocorticoid receptor (GR, Nr3c1). In normal and peritumor brain tissues, TMZ/DXM administration decreased HS content (5–6-fold) but did not affect HS biosynthetic system or GR expression. However, the xenograft GB tumors grown in the pre-treated animals demonstrated a number of molecular changes, despite the fact that they were not directly exposed to TMZ/DXM. The tumors from DXM pre-treated animals possessed decreased HS content (1.5–2-fold), the inhibition of HS biosynthetic system mainly due to the -3–3.5-fold down-regulation of N-deacetylase/N-sulfotransferases (Ndst1 and Ndst2) and sulfatase 2 (Sulf2) expression and a tendency toward a decreased expression of the GRalpha but not the GRbeta isoform. The GRalpha expression levels in tumors from DXM or TMZ pre-treated mice were positively correlated with the expression of a number of HS biosynthesis-involved genes (Ext1/2, Ndst1/2, Glce, Hs2st1, Hs6st1/2), unlike tumors that have grown in intact SCID mice. The obtained data show that DXM affects HS content in mouse brain tissues, and GB xenografts grown in DXM pre-treated animals demonstrate attenuated HS biosynthesis and decreased HS content. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies for Glioblastoma)
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17 pages, 4054 KiB  
Article
Aurora B Kinase Inhibition by AZD1152 Concomitant with Tumor Treating Fields Is Effective in the Treatment of Cultures from Primary and Recurrent Glioblastomas
by Dietmar Krex, Paula Bartmann, Doris Lachmann, Alexander Hagstotz, Willi Jugel, Rosa S. Schneiderman, Karnit Gotlib, Yaara Porat, Katja Robel, Achim Temme, Moshe Giladi and Susanne Michen
Int. J. Mol. Sci. 2023, 24(5), 5016; https://doi.org/10.3390/ijms24055016 - 6 Mar 2023
Cited by 5 | Viewed by 1777
Abstract
Tumor Treating Fields (TTFields) were incorporated into the treatment of glioblastoma, the most malignant brain tumor, after showing an effect on progression-free and overall survival in a phase III clinical trial. The combination of TTFields and an antimitotic drug might further improve this [...] Read more.
Tumor Treating Fields (TTFields) were incorporated into the treatment of glioblastoma, the most malignant brain tumor, after showing an effect on progression-free and overall survival in a phase III clinical trial. The combination of TTFields and an antimitotic drug might further improve this approach. Here, we tested the combination of TTFields with AZD1152, an Aurora B kinase inhibitor, in primary cultures of newly diagnosed (ndGBM) and recurrent glioblastoma (rGBM). AZD1152 concentration was titrated for each cell line and 5–30 nM were used alone or in addition to TTFields (1.6 V/cm RMS; 200 kHz) applied for 72 h using the inovitro™ system. Cell morphological changes were visualized by conventional and confocal laser microscopy. The cytotoxic effects were determined by cell viability assays. Primary cultures of ndGBM and rGBM varied in p53 mutational status; ploidy; EGFR expression and MGMT-promoter methylation status. Nevertheless; in all primary cultures; a significant cytotoxic effect was found following TTFields treatment alone and in all but one, a significant effect after treatment with AZD1152 alone was also observed. Moreover, in all primary cultures the combined treatment had the most pronounced cytotoxic effect in parallel with morphological changes. The combined treatment of TTFields and AZD1152 led to a significant reduction in the number of ndGBM and rGBM cells compared to each treatment alone. Further evaluation of this approach, which has to be considered as a proof of concept, is warranted, before entering into early clinical trials. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies for Glioblastoma)
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10 pages, 1658 KiB  
Article
Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi8,Met(O2)11]-Substance P
by Janine Suthiram, Ané Pieters, Zulfiah Mohamed Moosa, Jan Rijn Zeevaart, Mike M. Sathekge, Thomas Ebenhan, Ross C. Anderson and Claire L. Newton
Int. J. Mol. Sci. 2023, 24(3), 2134; https://doi.org/10.3390/ijms24032134 - 21 Jan 2023
Viewed by 1697
Abstract
Radiopharmaceutical development hinges on the affinity and selectivity of the biological component for the intended target. An analogue of the neuropeptide Substance P (SP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8,Met(O2)11]-SP (DOTA-[Thi8,Met(O2)11]SP), in the theranostic pair [...] Read more.
Radiopharmaceutical development hinges on the affinity and selectivity of the biological component for the intended target. An analogue of the neuropeptide Substance P (SP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8,Met(O2)11]-SP (DOTA-[Thi8,Met(O2)11]SP), in the theranostic pair [68Ga]Ga-/ [213Bi]Bi-DOTA-[Thi8,Met(O2)11]SP has shown promising clinical results in the treatment of inoperable glioblastoma. As the theranostic targeting component, modifications to SP that affect the selectivity of the resulting analogue for the intended target (neurokinin-1 receptor [NK1R]) could be detrimental to its therapeutic potential. In addition to other closely related tachykinin receptors (neurokinin-2 receptor [NK2R] and neurokinin-3 receptor [NK3R]), SP can activate a mast cell expressed receptor Mas-related G protein-coupled receptor subtype 2 (MRGPRX2), which has been implicated in allergic-type reactions. Therefore, activation of these receptors by SP analogues has severe implications for their therapeutic potential. Here, the receptor selectivity of DOTA-[Thi8,Met(O2)11]SP was examined using inositol phosphate accumulation assay in HEK293-T cells expressing NK1R, NK2R, NK3R or MRGPRX2. DOTA-[Thi8,Met(O2)11]SP had similar efficacy and potency as native SP at NK1R, but displayed greater NK1R selectivity. DOTA-[Thi8,Met(O2)11]SP was unable to elicit significant activation of the other tachykinin receptors nor MRGPRX2 at high concentrations nor did it display antagonistic behaviour at these receptors. DOTA-[Thi8,Met(O2)11]SP, therefore has high potency and selectivity for NK1R, supporting its potential for targeted theranostic use in glioblastoma multiforme and other conditions characterised by NK1R overexpression. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies for Glioblastoma)
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17 pages, 3737 KiB  
Article
Preparation of Hydrogels Based on Modified Pectins by Tuning Their Properties for Anti-Glioma Therapy
by Andrei Belousov, Aleksandra Patlay, Vladimir Silant’ev, Valeri V. Kovalev and Vadim Kumeiko
Int. J. Mol. Sci. 2023, 24(1), 630; https://doi.org/10.3390/ijms24010630 - 30 Dec 2022
Cited by 2 | Viewed by 1852
Abstract
The extracellular matrix (ECM) of the central nervous system (CNS), characterized by low stiffness and predominance of carbohydrates on protein components, mediates limited cell proliferation and migration. Pectins are polysaccharides derived from plants and could be very promising for a tunable hydrogel design [...] Read more.
The extracellular matrix (ECM) of the central nervous system (CNS), characterized by low stiffness and predominance of carbohydrates on protein components, mediates limited cell proliferation and migration. Pectins are polysaccharides derived from plants and could be very promising for a tunable hydrogel design that mimics the neural ECM. Aiming to regulate gel structure and viscoelastic properties, we elaborated 10 variants of pectin-based hydrogels via tuning the concentration of the polymer and the number of free carboxyl groups expressed in the degree of esterification (DE). Viscoelastic properties of hydrogels varied in the range of 3 to 900 Pa for G′ and were chosen as the first criteria for the selection of variants suitable for CNS remodeling. For extended reciprocal characterization, two pairs of hydrogels were taken to test pectins with opposite DEs close to 0% and 50%, respectively, but with a similar rheology exceeding 100 Pa (G′), which was achieved by adjusting the concentration of pectin. Hydrogel swelling properties and in vitro stability, together with structure characterization using SEM and FTIR spectroscopy, displayed some differences that may sense for biomedical application. Bioassays on C6 and U87MG glioblastoma cultures testified the potential prospects of the anti-glioma activity of hydrogels developed by decreasing cell proliferation and modulating migration but supporting the high viability of neural cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Targeted Therapies for Glioblastoma)
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