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The Molecular Targeting of Glioblastoma: Drug Discovery and Therapies
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The Molecular Targeting of Glioblastoma: Drug Discovery and Therapies

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (25 July 2021) | Viewed by 10344

Special Issue Editor

Dr. Mayra Paolillo

E-Mail Website
Guest Editor
Department of Drug Sciences, University of Pavia, Pavia, Italy
Interests: cancer stem cells; metastasis; brain tumors; 3D models

Special Issue Information

Dear Colleagues,

Among the most lethal cancer types, glioblastoma still holds a prominent position and represents a tremendous challenge for physicians, patients and scientists. A number of therapeutic strategies have been developed, but results, in terms of life expectancy, are far from the desired objectives. For this reason, the research for new molecular targets is increasingly pressing. Gene amplification, mutation and methylation represent research fields in glioblastoma that continuously provide new perspectives for therapy. Additionally, molecular targeting by integrin receptors has, in recent years, given rise to new hopes. This Special Issue of the Journal of Personalized Medicine aims to cover the current most advanced therapies, with a particular focus on the discovery of new potential molecular targets and related forthcoming therapies. Special attention will be devoted to the experimental models currently used in drug discovery and to their potential application in glioblastoma research. The overall purpose of this Special Issue is to share the knowledge of different research fields and provide researchers and clinicians with new insights in order to fight this mortal enemy successfully.

Dr. Mayra Paolillo
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. Journal of Personalized Medicine is an international peer-reviewed open access monthly 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 2600 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

  • Glioma stem cells
  • Gene amplification
  • Methylation
  • Integrins
  • Extracellular vesicles
  • Proteasome
  • BRAF mutation
  • EGFR mutation
  • Brain surgery
  • Brain irradiation

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Published Papers (3 papers)

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Research

14 pages, 2893 KiB  
Article
Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response
by Justin Bo-Kai Hsu, Tzong-Yi Lee, Sho-Jen Cheng, Gilbert Aaron Lee, Yung-Chieh Chen, Nguyen Quoc Khanh Le, Shiu-Wen Huang, Duen-Pang Kuo, Yi-Tien Li, Tzu-Hao Chang and Cheng-Yu Chen
J. Pers. Med. 2021, 11(11), 1047; https://doi.org/10.3390/jpm11111047 - 20 Oct 2021
Cited by 11 | Viewed by 3919
Abstract
The molecular heterogeneity of gene expression profiles of glioblastoma multiforme (GBM) are the most important prognostic factors for tumor recurrence and drug resistance. Thus, the aim of this study was to identify potential target genes related to temozolomide (TMZ) resistance and GBM recurrence. [...] Read more.
The molecular heterogeneity of gene expression profiles of glioblastoma multiforme (GBM) are the most important prognostic factors for tumor recurrence and drug resistance. Thus, the aim of this study was to identify potential target genes related to temozolomide (TMZ) resistance and GBM recurrence. The genomic data of patients with GBM from The Cancer Genome Atlas (TCGA; 154 primary and 13 recurrent tumors) and a local cohort (29 primary and 4 recurrent tumors), samples from different tumor regions from a local cohort (29 tumor and 25 peritumoral regions), and Gene Expression Omnibus data (GSE84465, single-cell RNA sequencing; 3589 cells) were included in this study. Critical gene signatures were identified based an analysis of differentially expressed genes (DEGs). DEGs were further used to evaluate gene enrichment levels among primary and recurrent GBMs and different tumor regions through gene set enrichment analysis. Protein–protein interactions (PPIs) were incorporated into gene regulatory networks to identify the affected metabolic pathways. The enrichment levels of 135 genes were identified in the peritumoral regions as being risk signatures for tumor recurrence. Fourteen genes (DVL1, PRKACB, ARRB1, APC, MAPK9, CAMK2A, PRKCB, CACNA1A, ERBB4, RASGRF1, NF1, RPS6KA2, MAPK8IP2, and PPM1A) derived from the PPI network of 135 genes were upregulated and involved in the regulation of cancer stem cell (CSC) development and relevant signaling pathways (Notch, Hedgehog, Wnt, and MAPK). The single-cell data analysis results indicated that 14 key genes were mainly expressed in oligodendrocyte progenitor cells, which could produce a CSC niche in the peritumoral region. The enrichment levels of 336 genes were identified as biomarkers for evaluating TMZ resistance in the solid tumor region. Eleven genes (ARID5A, CDC42EP3, CDKN1A, FLT3, JUNB, MAP2K3, MYBPC2, RGS14, RNASEK, TBC1D30, and TXNDC11) derived from the PPI network of 336 genes were upregulated and may be associated with a high risk of TMZ resistance; these genes were identified in both the TCGA and local cohorts. Furthermore, the expression patterns of ARID5A, CDKN1A, and MAP2K3 were identical to the gene signatures of TMZ-resistant cell lines. The identified enrichment levels of the two gene sets expressed in tumor and peritumoral regions are potentially helpful for evaluating TMZ resistance in GBM. Moreover, these key genes could be used as biomarkers, potentially providing new molecular strategies for GBM treatment. Full article
(This article belongs to the Special Issue The Molecular Targeting of Glioblastoma: Drug Discovery and Therapies)
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23 pages, 6897 KiB  
Article
Berberine Photo-Activation Potentiates Cytotoxicity in Human Astrocytoma Cells through Apoptosis Induction
by Francesca Carriero, Carolina Martinelli, Fabio Gabriele, Giulia Barbieri, Lisa Zanoletti, Gloria Milanesi, Claudio Casali, Alberto Azzalin, Federico Manai, Mayra Paolillo and Sergio Comincini
J. Pers. Med. 2021, 11(10), 942; https://doi.org/10.3390/jpm11100942 - 22 Sep 2021
Cited by 10 | Viewed by 2593
Abstract
Photodynamic therapy (PDT) has recently attracted interest as an innovative and adjuvant treatment for different cancers including malignant gliomas. Among these, Glioblastoma (GBM) is the most prevalent neoplasm in the central nervous system. Despite conventional therapeutic approaches that include surgical removal, radiation, and [...] Read more.
Photodynamic therapy (PDT) has recently attracted interest as an innovative and adjuvant treatment for different cancers including malignant gliomas. Among these, Glioblastoma (GBM) is the most prevalent neoplasm in the central nervous system. Despite conventional therapeutic approaches that include surgical removal, radiation, and chemotherapy, GBM is characterized by an extremely poor prognosis and a high rate of recurrence. PDT is a physical process that induces tumor cell death through the genesis and accumulation of reactive oxygen species (ROS) produced by light energy interaction with a photosensitizing agent. In this contribution, we explored the potentiality of the plant alkaloid berberine (BBR) as a photosensitizing and cytotoxic agent coupled with a PDT scheme using a blue light source in human established astrocytoma cell lines. Our data mainly indicated for the combined BBR-PDT scheme a potent activation of the apoptosis pathway, through a massive ROS production, a great extent of mitochondria depolarization, and the sub-sequent activation of caspases. Altogether, these results demonstrated that BBR is an efficient photosensitizer agent and that its association with PDT may be a potential anticancer strategy for high malignant gliomas. Full article
(This article belongs to the Special Issue The Molecular Targeting of Glioblastoma: Drug Discovery and Therapies)
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12 pages, 1418 KiB  
Article
Synergistic Effect of Perampanel and Temozolomide in Human Glioma Cell Lines
by Andrea Salmaggi, Cristina Corno, Marta Maschio, Sara Donzelli, Annachiara D’Urso, Paola Perego and Emilio Ciusani
J. Pers. Med. 2021, 11(5), 390; https://doi.org/10.3390/jpm11050390 - 10 May 2021
Cited by 26 | Viewed by 2962
Abstract
Glioblastoma is characterized by a high proliferative rate and drug resistance. The standard of care includes maximal safe surgery, followed by radiotherapy and temozolomide chemotherapy. The expression of glutamate receptors has been previously reported in human glioma cell lines. The aim of this [...] Read more.
Glioblastoma is characterized by a high proliferative rate and drug resistance. The standard of care includes maximal safe surgery, followed by radiotherapy and temozolomide chemotherapy. The expression of glutamate receptors has been previously reported in human glioma cell lines. The aim of this study was to examine the cellular effects of perampanel, a broad-spectrum antiepileptic drug acting as an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) glutamate receptor antagonist, alone or in combination with temozolomide. Four human glioma cell lines were exposed to different concentrations of perampanel and temozolomide, alone or in combination. The type of drug interaction was assessed using the Chou-Talalay method. Apoptosis, cell cycle perturbation, and glutamate receptors (GluRs) subunit expression were assessed by flow cytometry. Perampanel significantly inhibited the growth, inducing high levels of apoptosis. A strong synergistic effect of the combination of perampanel with temozolomide was detected in U87 and A172, but not in U138. Treatment with perampanel resulted in an increased GluR2/3 subunit expression in U87 and U138. Perampanel displays a pro-apoptotic effect on human glioblastoma cell lines when used alone, possibly due to increased GluR2/3 expression. The observed synergistic effect of the combination of temozolomide with perampanel suggests further investigation on the impact of this combination on oncologic outcomes in glioblastoma. Full article
(This article belongs to the Special Issue The Molecular Targeting of Glioblastoma: Drug Discovery and Therapies)
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