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Cancers
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Recent Advances in Drug Therapy for Glioblastoma
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Recent Advances in Drug Therapy for Glioblastoma

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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 25091

Special Issue Editor

Dr. Juan Manuel Sepúlveda-Sánchez

E-Mail Website
Guest Editor
Instituto de investigación I+12, Hospital 12 de Octubre, 28041 Madrid, Spain
Interests: glioblastoma; glioma; immunotherapy; targeted therapies; tumor microenvironment; epigenetics; brain tumors; neuro-oncology

Special Issue Information

Dear Colleagues,

Glioblastomas are highly aggressive tumors of the brain that are resistant to radiotherapy and temozolomide, the only treatments currently available. Therefore, effort is necessary to find novel therapeutic approaches and alternative targets in order to enhance the survival of these patients. In fact, the median overall survival after surgery and the standard treatment with radiotherapy and temozolomide is 14–16 months, and there is no standard second line treatment since lomustine and bevacizumab have modest efficacy.

Despite the lack of clear advances in the treatment of glioblastoma, molecular and cellular studies have significantly improved the knowledge of glioma biology, particularly in the fields of microenvironment regulation, tumor immunology, and in oncogenic signaling pathways control.

Clinical and translational researchers are getting the most out of these new findings in order to develop new drugs targeting not only tumor growth pathways but also the glioma microenvironment. In this respect, this Special Issue will focus on new therapeutic approaches that try to overcome previous failures in glioblastoma management. We welcome preclinical and clinical studies evaluating new targets in glioblastoma and also new drugs with a classic mechanism of action that could improve the survival rate of temozolomide and lomustine.

Dr. Juan Manuel Sepúlveda-Sánchez
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 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

  • glioblastomas
  • novel therapeutics
  • new drugs

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Published Papers (7 papers)

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Research

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20 pages, 6899 KiB  
Article
Characterization of Glioblastoma Cells Response to Regorafenib
by Maria Patrizia Mongiardi, Mariachiara Buccarelli, Alessia Formato, Elisa Orecchini, Maria Salbini, Valentina Ricci, Tiziana Orsini, Sabrina Putti, Silvia Chiesa, Lucia Ricci-Vitiani, Quintino Giorgio D’Alessandris, Roberto Pallini, Andrea Levi and Maria Laura Falchetti
Cancers 2022, 14(24), 6193; https://doi.org/10.3390/cancers14246193 - 15 Dec 2022
Cited by 4 | Viewed by 2216
Abstract
Glioblastoma (GBM), the most malignant primary brain tumor in adults. Although not frequent, it has a relevant social impact because the peak incidence coincides with the age of professional maturity. A number of novel treatments have been proposed, yet clinical trials have been [...] Read more.
Glioblastoma (GBM), the most malignant primary brain tumor in adults. Although not frequent, it has a relevant social impact because the peak incidence coincides with the age of professional maturity. A number of novel treatments have been proposed, yet clinical trials have been disappointing. Recently, a phase II clinical trial (REGOMA) demonstrated that the multikinase inhibitor regorafenib significantly increased the median overall survival (OS) of GBM patients when compared to lomustine-treated patients. On this basis, the National Comprehensive Cancer Network (NCCN) 2020 Guidelines included regorafenib as a preferred regimen in relapsed GBM treatment. Despite the use in GBM patients’ therapy, little is known about the molecular mechanisms governing regorafenib effectiveness on the GBM tumor. Here we report an in vitro characterization of GBM tumor cells’ response to regorafenib, performed both on cell lines and on patient-derived glioma stem cells (GSCs). Overall, regorafenib significantly reduced cell growth of 2D tumor cell cultures and of 3D tumor spheroids. Strikingly, this effect was accompanied by transcriptional regulation of epithelial to mesenchymal transition (EMT) genes and by an increased ability of surviving tumor cells to invade the surrounding matrix. Taken together, our data suggest that regorafenib limits cell growth, however, it might induce an invasive phenotype. Full article
(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)
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22 pages, 3245 KiB  
Article
The Combination of Δ9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins
by Anne Rupprecht, Ulrike Theisen, Franziska Wendt, Marcus Frank and Burkhard Hinz
Cancers 2022, 14(13), 3129; https://doi.org/10.3390/cancers14133129 - 27 Jun 2022
Cited by 16 | Viewed by 3218
Abstract
Phytocannabinoids represent a promising approach in glioblastoma therapy. Previous work has shown that a combined treatment of glioblastoma cells with submaximal effective concentrations of psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD) greatly increases cell death. In the present work, the glioblastoma [...] Read more.
Phytocannabinoids represent a promising approach in glioblastoma therapy. Previous work has shown that a combined treatment of glioblastoma cells with submaximal effective concentrations of psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD) greatly increases cell death. In the present work, the glioblastoma cell lines U251MG and U138MG were used to investigate whether the combination of THC and CBD in a 1:1 ratio is associated with a disruption of cellular energy metabolism, and whether this is caused by affecting mitochondrial respiration. Here, the combined administration of THC and CBD (2.5 µM each) led to an inhibition of oxygen consumption rate and energy metabolism. These effects were accompanied by morphological changes to the mitochondria, a release of mitochondrial cytochrome c into the cytosol and a marked reduction in subunits of electron transport chain complexes I (NDUFA9, NDUFB8) and IV (COX2, COX4). Experiments with receptor antagonists and inhibitors showed that the degradation of NDUFA9 occurred independently of the activation of the cannabinoid receptors CB1, CB2 and TRPV1 and of usual degradation processes mediated via autophagy or the proteasomal system. In summary, the results describe a previously unknown mitochondria-targeting mechanism behind the toxic effect of THC and CBD on glioblastoma cells that should be considered in future cancer therapy, especially in combination strategies with other chemotherapeutics. Full article
(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)
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14 pages, 2206 KiB  
Article
Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
by María Martínez-García, Guillermo Velasco, Estela Pineda, Miguel Gil-Gil, Francesc Alameda, Jaume Capellades, Mari Cruz Martín-Soberón, Israel López-Valero, Elena Tovar Ambel, Palmira Foro, Álvaro Taus, Montserrat Arumi, Aurelio Hernández-Laín and Juan Manuel Sepúlveda-Sánchez
Cancers 2022, 14(10), 2393; https://doi.org/10.3390/cancers14102393 - 12 May 2022
Cited by 11 | Viewed by 2786
Abstract
Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) [...] Read more.
Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis. Results: The study enrolled 38 patients. The median age was 52 years (33–76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade ≥3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7–13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1–31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy. Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study. Full article
(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)
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21 pages, 7075 KiB  
Article
Discovery of a New CaMKII-Targeted Synthetic Lethal Therapy against Glioblastoma Stem-like Cells
by Jang Mi Han, Yu Jin Kim and Hye Jin Jung
Cancers 2022, 14(5), 1315; https://doi.org/10.3390/cancers14051315 - 4 Mar 2022
Cited by 14 | Viewed by 5037
Abstract
Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for improving treatment for glioblastoma multiforme (GBM). We previously identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an emerging molecular target for eliminating [...] Read more.
Glioblastoma stem-like cells (GSCs) drive tumor initiation, cancer invasion, immune evasion, and therapeutic resistance and are thus a key therapeutic target for improving treatment for glioblastoma multiforme (GBM). We previously identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an emerging molecular target for eliminating GSCs. In this study, we aim to explore a new CaMKII-targeted synthetic lethal therapy for GSCs. Through high-throughput drug combination screening using CaMKII inhibitors and a bioactive compound library in GSCs, neurokinin 1 receptor (NK1R) inhibitors such as SR 140333 and aprepitant are found to be potential anticancer agents that exhibit chemical synthetic lethal interactions with CaMKII inhibitors, including hydrazinobenzoylcurcumin (HBC), berbamine, and KN93. Combined treatment with NK1R and CaMKII inhibitors markedly suppresses the viability and neurosphere formation of U87MG- and U373MG-derived GSCs. In addition, the combination of HBC and NK1R inhibitors significantly inhibits U87MG GSC tumor growth in a chick embryo chorioallantoic membrane (CAM) model. Furthermore, the synthetic lethal interaction is validated using RNA interference of CaMKIIγ and NK1R. Notably, the synthetic lethal effects in GSCs are associated with the activation of caspase-mediated apoptosis by inducing p53 expression and reactive oxygen species generation, as well as the suppression of stemness marker expression by reducing nuclear factor-kappa B (NF-κB) activity. This follows the downregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and a decrease in intracellular calcium concentration. Moreover, NK1R affects CaMKIIγ activation. These findings demonstrate that NK1R is a potential synthetic lethal partner of CaMKII that is involved in eradicating GSCs, and they suggest a new CaMKII-targeted combination therapy for treating GBM. Full article
(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)
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14 pages, 1590 KiB  
Article
Synthesis of Biotinylated PAMAM G3 Dendrimers Substituted with R-Glycidol and Celecoxib/Simvastatin as Repurposed Drugs and Evaluation of Their Increased Additive Cytotoxicity for Cancer Cell Lines
by Konrad Wróbel, Stanisław Wołowiec, Joanna Markowicz, Elżbieta Wałajtys-Rode and Łukasz Uram
Cancers 2022, 14(3), 714; https://doi.org/10.3390/cancers14030714 - 29 Jan 2022
Cited by 8 | Viewed by 2896
Abstract
Recent achievement in anticancer therapy considers the application of repurposed drugs in optimal combinations with the use of specific carriers for their targeted delivery. As a result, new optimized medications with reduced side effects can be obtained. In this study, two known anticancer [...] Read more.
Recent achievement in anticancer therapy considers the application of repurposed drugs in optimal combinations with the use of specific carriers for their targeted delivery. As a result, new optimized medications with reduced side effects can be obtained. In this study, two known anticancer drugs, celecoxib and/or simvastatin, were conjugated covalently with PAMAM G3 dendrimer and tested in vitro against human squamous carcinoma (SCC-15-15) and glioblastoma (U-118 MG) cells, as well as normal human fibroblasts (BJ). The obtained conjugates were also substituted with biotin and R-glycidol to increase their affinity for cancer cells and were characterized with NMR spectroscopy and dynamic light scattering technique. Conjugates furnished with two celecoxib and four simvastatin residues revealed the very high effectiveness and dramatically decreased the SCC-15 and U-118 MG cell viability at very low concentrations with IC50 equal to about 3 µM. Its action was 20–50-fold stronger than that of either drug alone or as a mixture. Combined conjugate revealed also additive action since it was 2–8-fold more effective than conjugates with either single drug. The combined conjugate revealed rather low specificity since it was also highly cytotoxic for BJ cells. Despite this, it may be concluded that biotinylated and R-glycidylated PAMAM G3 dendrimers substituted with both celecoxib and simvastatin can be considered as a new perspective anticancer agent, effective in therapy of malignant, incurable glioblastomas. Full article
(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)
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Review

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30 pages, 1799 KiB  
Review
Next Steps for Immunotherapy in Glioblastoma
by Toni Q. Cao, Derek A. Wainwright, Catalina Lee-Chang, Jason Miska, Adam M. Sonabend, Amy B. Heimberger and Rimas V. Lukas
Cancers 2022, 14(16), 4023; https://doi.org/10.3390/cancers14164023 - 20 Aug 2022
Cited by 10 | Viewed by 4906
Abstract
Outcomes for glioblastoma (GBM) patients undergoing standard of care treatment remain poor. Here we discuss the portfolio of previously investigated immunotherapies for glioblastoma, including vaccine therapy and checkpoint inhibitors, as well as novel emerging therapeutic approaches. In addition, we explore the factors that [...] Read more.
Outcomes for glioblastoma (GBM) patients undergoing standard of care treatment remain poor. Here we discuss the portfolio of previously investigated immunotherapies for glioblastoma, including vaccine therapy and checkpoint inhibitors, as well as novel emerging therapeutic approaches. In addition, we explore the factors that potentially influence response to immunotherapy, which should be considered in future research aimed at improving immunotherapy efficacy. Full article
(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)
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Other

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16 pages, 1203 KiB  
Systematic Review
Novel Pharmacological Treatment Options in Pediatric Glioblastoma—A Systematic Review
by Johanna Wyss, Nicole Alexandra Frank, Jehuda Soleman and Katrin Scheinemann
Cancers 2022, 14(11), 2814; https://doi.org/10.3390/cancers14112814 - 6 Jun 2022
Cited by 7 | Viewed by 3225
Abstract
Background: Pediatric glioblastoma (GBM) is an aggressive central nervous system tumor in children that has dismal prognosis. Standard of care is surgery with subsequent irradiation and temozolomide. We aimed to outline currently available data on novel pharmacological treatments for pediatric GBM. Methods: We [...] Read more.
Background: Pediatric glioblastoma (GBM) is an aggressive central nervous system tumor in children that has dismal prognosis. Standard of care is surgery with subsequent irradiation and temozolomide. We aimed to outline currently available data on novel pharmacological treatments for pediatric GBM. Methods: We conducted a systematic literature search in PubMed and Embase, including reports published in English from 2010 to 2021. We included randomized trials, cohort studies and case series. Phase I trials were not analyzed. We followed PRISMA guidelines, assessed the quality of the eligible reports using the Newcastle-Ottawa scale (NOS) and the RoB-2 tool and registered the protocol on PROSPERO. Results: We included 6 out of 1122 screened reports. All six selected reports were prospective, multicenter phase II trials (five single-arm and one randomized controlled trial). None of the investigated novel treatment modalities showed any benefit regarding overall or progression free survival. Conclusions: To date, the role of pharmacological approaches regarding pediatric GBM remains unclear, since no novel treatment approach could provide a significant impact on overall or progression free survival. Further research should aim to combine different treatment strategies in large international multicenter trials with central comprehensive diagnostics regarding subgrouping. These novel treatment approaches should include targeted and immunotherapeutic treatments, potentially leading to a more successful outcome. Full article
(This article belongs to the Special Issue Recent Advances in Drug Therapy for Glioblastoma)
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