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Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity

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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 (1 December 2021) | Viewed by 54992

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Special Issue Editor

Dr. Guillermo Gomez

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Guest Editor

Centre for Cancer Biology, SA Pathology and the University of South of Australia, Adelaide, SA 5000, Australia
Interests: brain tumors; precision oncology; patient-derived organoids; transcriptomics; proteomics; deep learning; microscopy; brain disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer with a 5-year relative survival (4.6% only at 5 years) that has remained stable over the last 3 decades. Intratumour heterogeneity is a key feature that makes GBM one of the most deadly types of tumours, which results from the capacity of GBM-cancer stem cells to inter-convert between different cancer cell populations in response to changes in the tumour microenvironment and/or different drug treatments. This not only explains the poor performance in single drug therapy in GBM, but also reveals a key role for GBM plasticity, the interaction of GBM and the microenvironment and brain cancer progression, and thus constitutes a novel paradigms that needs to be addressed in order to find better treatments for patients with GBM.

This special issue will be dedicated to publish original work and reviews in the areas of neuro-oncology, pharmacology, bioinformatics, cell and cancer biology, drug-screenings, bioengineering, genetics, and others, on aspects that will contribute to better understanding at the molecular level of the functional role of heterogeneity and plasticity in glioblastoma biology and treatment.

Sincerely,

Dr. Guillermo Gomez
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
heterogeneity
microenvironment
stemness
cancer stem cells
immune system
cancer cell resistance
perivascular niche
necrosis
therapy

Published Papers (13 papers)

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Research

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20 pages, 35240 KiB

Open AccessArticle

GRPEL2 Knockdown Exerts Redox Regulation in Glioblastoma

by Chi-Tun Tang, Yao-Feng Li, Chung-Hsing Chou, Li-Chun Huang, Shih-Ming Huang, Dueng-Yuan Hueng, Chia-Kuang Tsai and Yuan-Hao Chen

Int. J. Mol. Sci. 2021, 22(23), 12705; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312705 - 24 Nov 2021

Cited by 3 | Viewed by 2414

Abstract

Malignant brain tumors are responsible for catastrophic morbidity and mortality globally. Among them, glioblastoma multiforme (GBM) bears the worst prognosis. The GrpE-like 2 homolog (GRPEL2) plays a crucial role in regulating mitochondrial protein import and redox homeostasis. However, the role of GRPEL2 in human glioblastoma has yet to be clarified. In this study, we investigated the function of GRPEL2 in glioma. Based on bioinformatics analyses from the Cancer Gene Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we inferred that GRPEL2 expression positively correlates with WHO tumor grade (p < 0.001), IDH mutation status (p < 0.001), oligodendroglial differentiation (p < 0.001), and overall survival (p < 0.001) in glioma datasets. Functional validation in LN229 and GBM8401 GBM cells showed that GRPEL2 knockdown efficiently inhibited cellular proliferation. Moreover, GRPEL2 suppression induced cell cycle arrest at the sub-G1 phase. Furthermore, GRPEL2 silencing decreased intracellular reactive oxygen species (ROS) without impending mitochondria membrane potential. The cellular oxidative respiration measured with a Seahorse XFp analyzer exhibited a reduction of the oxygen consumption rate (OCR) in GBM cells by siGRPEL2, which subsequently enhanced autophagy and senescence in glioblastoma cells. Taken together, GRPEL2 is a novel redox regulator of mitochondria bioenergetics and a potential target for treating GBM in the future. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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15 pages, 5206 KiB

Open AccessArticle

A Heterotypic Tridimensional Model to Study the Interaction of Macrophages and Glioblastoma In Vitro

by María José Gattas, Ivana Gisele Estecho, María Amparo Lago Huvelle, Andrea Emilse Errasti, Eugenio Antonio Carrera Silva and Marina Simian

Int. J. Mol. Sci. 2021, 22(10), 5105; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105105 - 12 May 2021

Cited by 4 | Viewed by 4330

Abstract

Background: Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor, and macrophages account for 30–40% of its composition. Most of these macrophages derive from bone marrow monocytes playing a crucial role in tumor progression. Unraveling the mechanisms of macrophages-GBM crosstalk in an appropriate model will contribute to the development of specific and more successful therapies. We investigated the interaction of U87MG human GBM cells with primary human CD14⁺ monocytes or the THP-1 cell line with the aim of establishing a physiologically relevant heterotypic culture model. Methods: primary monocytes and THP-1 cells were cultured in the presence of U87MG conditioned media or co-cultured together with previously formed GBM spheroids. Monocyte differentiation was determined by flow cytometry. Results: primary monocytes differentiate to M2 macrophages when incubated with U87MG conditioned media in 2-dimensional culture, as determined by the increased percentage of CD14⁺CD206⁺ and CD64⁺CD206⁺ populations in CD11b⁺ cells. Moreover, the mitochondrial protein p32/gC1qR is expressed in monocytes exposed to U87MG conditioned media. When primary CD14⁺ monocytes or THP-1 cells are added to previously formed GBM spheroids, both invade and establish within them. However, only primary monocytes differentiate and acquire a clear M2 phenotype characterized by the upregulation of CD206, CD163, and MERTK surface markers on the CD11b⁺CD14⁺ population and induce alterations in the sphericity of the cell cultures. Conclusion: our results present a new physiologically relevant model to study GBM/macrophage interactions in a human setting and suggest that both soluble GBM factors, as well as cell-contact dependent signals, are strong inducers of anti-inflammatory macrophages within the tumor niche. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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27 pages, 5506 KiB

Open AccessArticle

A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma

by Sakthi Lenin, Elise Ponthier, Kaitlin G. Scheer, Erica C. F. Yeo, Melinda N. Tea, Lisa M. Ebert, Mariana Oksdath Mansilla, Santosh Poonnoose, Ulrich Baumgartner, Bryan W. Day, Rebecca J. Ormsby, Stuart M. Pitson and Guillermo A. Gomez

Int. J. Mol. Sci. 2021, 22(9), 4322; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094322 - 21 Apr 2021

Cited by 25 | Viewed by 8564

Abstract

Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6–9 months is common. To overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microenvironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cultures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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14 pages, 2359 KiB

Open AccessArticle

DYRK1A Negatively Regulates CDK5-SOX2 Pathway and Self-Renewal of Glioblastoma Stem Cells

by Brianna Chen, Dylan McCuaig-Walton, Sean Tan, Andrew P. Montgomery, Bryan W. Day, Michael Kassiou, Lenka Munoz and Ariadna Recasens

Int. J. Mol. Sci. 2021, 22(8), 4011; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084011 - 13 Apr 2021

Cited by 14 | Viewed by 3959

Abstract

Glioblastoma display vast cellular heterogeneity, with glioblastoma stem cells (GSCs) at the apex. The critical role of GSCs in tumour growth and resistance to therapy highlights the need to delineate mechanisms that control stemness and differentiation potential of GSC. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) regulates neural progenitor cell differentiation, but its role in cancer stem cell differentiation is largely unknown. Herein, we demonstrate that DYRK1A kinase is crucial for the differentiation commitment of glioblastoma stem cells. DYRK1A inhibition insulates the self-renewing population of GSCs from potent differentiation-inducing signals. Mechanistically, we show that DYRK1A promotes differentiation and limits stemness acquisition via deactivation of CDK5, an unconventional kinase recently described as an oncogene. DYRK1A-dependent inactivation of CDK5 results in decreased expression of the stemness gene SOX2 and promotes the commitment of GSC to differentiate. Our investigations of the novel DYRK1A-CDK5-SOX2 pathway provide further insights into the mechanisms underlying glioblastoma stem cell maintenance. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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14 pages, 3816 KiB

Open AccessArticle

Enhancing Anti-Tumoral Potential of CD-NHF by Modulating PI3K/Akt Axis in U87 Ex Vivo Glioma Model

by Gabriel Luta, Mihail Butura, Adrian Tiron and Crina E. Tiron

Int. J. Mol. Sci. 2021, 22(8), 3873; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083873 - 08 Apr 2021

Cited by 2 | Viewed by 2042

Abstract

Background: In the latest years, there has been an increased interest in nanomaterials that may provide promising novel approaches to disease diagnostics and therapeutics. Our previous results demonstrated that Carbon-dots prepared from N-hydroxyphthalimide (CD-NHF) exhibited anti-tumoral activity on several cancer cell lines such as MDA-MB-231, A375, A549, and RPMI8226, while U87 glioma tumor cells were unaffected. Gliomas represent one of the most common types of human primary brain tumors and are responsible for the majority of deaths. In the present in vitro study, we expand our previous investigation on CD-NHF in the U87 cell line by adding different drug combinations. Methods: Cell viability, migration, invasion, and immunofluorescent staining of key molecular pathways have been assessed after various treatments with CD-NHF and/or K252A and AKTVIII inhibitors in the U87 cell line. Results: Association of an inhibitor strongly potentiates the anti-tumoral properties of CD-NHF identified by significant impairment of migration, invasion, and expression levels of phosphorylated Akt, p70S6Kinase, or by decreasing expression levels of Bcl-2, IL-6, STAT3, and Slug. Conclusions: Using simultaneously reduced doses of both CD-NHF and an inhibitor in order to reduce side effects, the viability and invasiveness of U87 glioma cells were significantly impaired. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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21 pages, 7761 KiB

Open AccessArticle

An Integrated Bioinformatics Study of a Novel Niclosamide Derivative, NSC765689, a Potential GSK3β/β-Catenin/STAT3/CD44 Suppressor with Anti-Glioblastoma Properties

by Ntlotlang Mokgautsi, Ya-Ting Wen, Bashir Lawal, Harshita Khedkar, Maryam Rachmawati Sumitra, Alexander T. H. Wu and Hsu-Shan Huang

Int. J. Mol. Sci. 2021, 22(5), 2464; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052464 - 28 Feb 2021

Cited by 18 | Viewed by 3218

Abstract

Despite management efforts with standard surgery, radiation, and chemotherapy, glioblastoma multiform (GBM) remains resistant to treatment, which leads to tumor recurrence due to glioma stem cells (GSCs) and therapy resistance. In this study, we used random computer-based prediction and target identification to assess activities of our newly synthesized niclosamide-derived compound, NSC765689, to target GBM oncogenic signaling. Using target prediction analyses, we identified glycogen synthase kinase 3β (GSK3β), β-Catenin, signal transducer and activator of transcription 3 (STAT3), and cluster of differentiation 44 (CD44) as potential druggable candidates of NSC765689. The above-mentioned signaling pathways were also predicted to be overexpressed in GBM tumor samples compared to adjacent normal samples. In addition, using bioinformatics tools, we also identified microRNA (miR)-135b as one of the most suppressed microRNAs in GBM samples, which was reported to be upregulated through inhibition of GSK3β, and subsequently suppresses GBM tumorigenic properties and stemness. We further performed in silico molecular docking of NSC765689 with GBM oncogenes; GSK3β, β-Catenin, and STAT3, and the stem cell marker, CD44, to predict protein-ligand interactions. The results indicated that NSC765689 exhibited stronger binding affinities compared to its predecessor, LCC09, which was recently published by our laboratory, and was proven to inhibit GBM stemness and resistance. Moreover, we used available US National Cancer Institute (NCI) 60 human tumor cell lines to screen in vitro anticancer effects, including the anti-proliferative and cytotoxic activities of NSC765689 against GBM cells, and 50% cell growth inhibition (GI₅₀) values ranged 0.23~5.13 μM. In summary, using computer-based predictions and target identification revealed that NSC765689 may be a potential pharmacological lead compound which can regulate GBM oncogene (GSK3β/β-Catenin/STAT3/CD44) signaling and upregulate the miR-135b tumor suppressor. Therefore, further in vitro and in vivo investigations will be performed to validate the efficacy of NSC765689 as a novel potential GBM therapeutic. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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14 pages, 2233 KiB

Open AccessArticle

Identifying the miRNA Signature Association with Aging-Related Senescence in Glioblastoma

by Mutharasu Gnanavel, Akshaya Murugesan, Saravanan Konda Mani, Olli Yli-Harja and Meenakshisundaram Kandhavelu

Int. J. Mol. Sci. 2021, 22(2), 517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020517 - 06 Jan 2021

Cited by 6 | Viewed by 2822

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor and its malignant phenotypic characteristics are classified as grade IV tumors. Molecular interactions, such as protein–protein, protein–ncRNA, and protein–peptide interactions are crucial to transfer the signaling communications in cellular signaling pathways. Evidences suggest that signaling pathways of stem cells are also activated, which helps the propagation of GBM. Hence, it is important to identify a common signaling pathway that could be visible from multiple GBM gene expression data. microRNA signaling is considered important in GBM signaling, which needs further validation. We performed a high-throughput analysis using micro array expression profiles from 574 samples to explore the role of non-coding RNAs in the disease progression and unique signaling communication in GBM. A series of computational methods involving miRNA expression, gene ontology (GO) based gene enrichment, pathway mapping, and annotation from metabolic pathways databases, and network analysis were used for the analysis. Our study revealed the physiological roles of many known and novel miRNAs in cancer signaling, especially concerning signaling in cancer progression and proliferation. Overall, the results revealed a strong connection with stress induced senescence, significant miRNA targets for cell cycle arrest, and many common signaling pathways to GBM in the network. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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Review

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16 pages, 2393 KiB

Open AccessReview

Novel Concepts of Glioblastoma Therapy Concerning Its Heterogeneity

by Gábor Hutóczki, József Virga, Zsuzsanna Birkó and Almos Klekner

Int. J. Mol. Sci. 2021, 22(18), 10005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810005 - 16 Sep 2021

Cited by 15 | Viewed by 2583

Abstract

Although treatment outcomes of glioblastoma, the most malignant central nervous system (CNS) tumor, has improved in the past decades, it is still incurable, and survival has only slightly improved. Advances in molecular biology and genetics have completely transformed our understanding of glioblastoma. Multiple classifications and different diagnostic methods were made according to novel molecular markers. Discovering tumor heterogeneity only partially explains the ineffectiveness of current anti-proliferative therapies. Dynamic heterogeneity secures resistance to combined oncotherapy. As tumor growth proceeds, new therapy-resistant sub clones emerge. Liquid biopsy is a new and promising diagnostic tool that can step up with the dynamic genetic change. Getting a ’real-time’ picture of a specific tumor, anti-invasion and multi-target treatment can be designed. During invasion to the peri-tumoral brain tissue, glioma cells interact with the extracellular matrix components. The expressional levels of these matrix molecules give a characteristic pattern, the invasion spectrum, which possess vast diagnostical, predictive and prognostic information. It is a huge leap forward combating tumor heterogeneity and searching for novel therapies. Using the invasion spectrum of a tumor sample is a novel tool to distinguish between histological subtypes, specifying the tumor grades or different prognostic groups. Moreover, new therapeutic methods and their combinations are under trial. These are crucial steps towards personalized oncotherapy. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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29 pages, 1187 KiB

Open AccessReview

Adjusting the Molecular Clock: The Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy

by Paula M. Wagner, César G. Prucca, Beatriz L. Caputto and Mario E. Guido

Int. J. Mol. Sci. 2021, 22(15), 8289; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158289 - 01 Aug 2021

Cited by 9 | Viewed by 3879

Abstract

Gliomas are solid tumors of the central nervous system (CNS) that originated from different glial cells. The World Health Organization (WHO) classifies these tumors into four groups (I–IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as grade IV. GBMs are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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17 pages, 1196 KiB

Open AccessReview

An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

by Tamara Lah Turnšek, Xuanmao Jiao, Metka Novak, Sriharsha Jammula, Gina Cicero, Anthony W. Ashton, David Joyce and Richard G. Pestell

Int. J. Mol. Sci. 2021, 22(9), 4464; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094464 - 24 Apr 2021

Cited by 7 | Viewed by 8617

Abstract

The mechanisms governing therapeutic resistance of the most aggressive and lethal primary brain tumor in adults, glioblastoma, have increasingly focused on tumor stem cells. These cells, protected by the periarteriolar hypoxic GSC niche, contribute to the poor efficacy of standard of care treatment of glioblastoma. Integrated proteogenomic and metabolomic analyses of glioblastoma tissues and single cells have revealed insights into the complex heterogeneity of glioblastoma and stromal cells, comprising its tumor microenvironment (TME). An additional factor, which isdriving poor therapy response is the distinct genetic drivers in each patient’s tumor, providing the rationale for a more individualized or personalized approach to treatment. We recently reported that the G protein-coupled receptor CCR5, which contributes to stem cell expansion in other cancers, is overexpressed in glioblastoma cells. Overexpression of the CCR5 ligand CCL5 (RANTES) in glioblastoma completes a potential autocrine activation loop to promote tumor proliferation and invasion. CCL5 was not expressed in glioblastoma stem cells, suggesting a need for paracrine activation of CCR5 signaling by the stromal cells. TME-associated immune cells, such as resident microglia, infiltrating macrophages, T cells, and mesenchymal stem cells, possibly release CCR5 ligands, providing heterologous signaling between stromal and glioblastoma stem cells. Herein, we review current therapies for glioblastoma, the role of CCR5 in other cancers, and the potential role for CCR5 inhibitors in the treatment of glioblastoma. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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11 pages, 1521 KiB

Open AccessReview

Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) Vaccine Immunotherapy: A Review of Current Evidence and Applications in Glioblastoma

by Pashayar P. Lookian, David Zhao, Rogelio Medina, Herui Wang, Jan Zenka, Mark R. Gilbert, Karel Pacak and Zhengping Zhuang

Int. J. Mol. Sci. 2021, 22(7), 3455; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073455 - 26 Mar 2021

Cited by 7 | Viewed by 2772

Abstract

The foundation of precision immunotherapy in oncology is rooted in computational biology and patient-derived sample sequencing to enrich for and target immunogenic epitopes. Discovery of these tumor-specific epitopes through tumor sequencing has revolutionized patient outcomes in many types of cancers that were previously untreatable. However, these therapeutic successes are far from universal, especially with cancers that carry high intratumoral heterogeneity such as glioblastoma (GBM). Herein, we present the technical aspects of Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) vaccine immunotherapy, an investigational therapeutic that potentially circumvents the need for in silico tumor-neoantigen enrichment. We then review the most promising GBM vaccination strategies to contextualize the MBTA vaccine. By reviewing current evidence using translational tumor models supporting MBTA vaccination, we evaluate the underlying principles that validate its clinical applicability. Finally, we showcase the translational potential of MBTA vaccination as a potential immunotherapy in GBM, along with established surgical and immunologic cancer treatment paradigms. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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19 pages, 956 KiB

Open AccessReview

Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma

by Louise Orcheston-Findlay, Samuel Bax, Robert Utama, Martin Engel, Dinisha Govender and Geraldine O’Neill

Int. J. Mol. Sci. 2021, 22(6), 2962; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062962 - 15 Mar 2021

Cited by 14 | Viewed by 4598

Abstract

The life expectancy of patients with high-grade glioma (HGG) has not improved in decades. One of the crucial tools to enable future improvement is advanced models that faithfully recapitulate the tumour microenvironment; they can be used for high-throughput screening that in future may enable accurate personalised drug screens. Currently, advanced models are crucial for identifying and understanding potential new targets, assessing new chemotherapeutic compounds or other treatment modalities. Recently, various methodologies have come into use that have allowed the validation of complex models—namely, spheroids, tumouroids, hydrogel-embedded cultures (matrix-supported) and advanced bioengineered cultures assembled with bioprinting and microfluidics. This review is designed to present the state of advanced models of HGG, whilst focusing as much as is possible on the paediatric form of the disease. The reality remains, however, that paediatric HGG (pHGG) models are years behind those of adult HGG. Our goal is to bring this to light in the hope that pGBM models can be improved upon. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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16 pages, 969 KiB

Open AccessReview

Bivalent Genes Targeting of Glioma Heterogeneity and Plasticity

by Mariam Markouli, Dimitrios Strepkos, Kostas A. Papavassiliou, Athanasios G. Papavassiliou and Christina Piperi

Int. J. Mol. Sci. 2021, 22(2), 540; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020540 - 07 Jan 2021

Cited by 8 | Viewed by 3262

Abstract

Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options. Full article

(This article belongs to the Special Issue Novel Therapeutic Treatments to Target Glioblastoma Intratumoral Heterogeneity and Plasticity)

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