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Novel Therapeutic Strategies for the Treatment of Brain Tumors

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Keywords
Published Papers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 15245

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Special Issue Editors

Dr. Georg Karpel-Massler

E-Mail Website
Guest Editor

Department of Neurological Surgery, Ulm University | UULM, Ulm, Germany
Interests: tumor cell metabolism; intelligent intracerebral implants; drug repurposing
Special Issues, Collections and Topics in MDPI journals

Dr. Mike-Andrew Westhoff

E-Mail Website
Guest Editor

Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
Interests: cell adhesion and motility; evolution and cancer; drug repurposing

Special Issue Information

Dear Colleagues,

Malignant brain tumors constitute a major therapeutic challenge which is in part due to the heterogenous nature of the diseases and the very special microenvironment within the brain. As a consequence, first- and second-line therapies widely fail to provide satisfactory clinical outcomes in these patients urging the search for more efficient therapies.

This Special Issue on “Novel Therapeutic Strategies for the Treatment of Brain Tumors” aims to provide a summary of novel developments for the treatment of adult and pediatric brain tumors. Emphasis will be given to novel mechanisms of tumor pathogenesis, immunologic approaches and therapeutics that target the tumor cell metabolism.

In this Issue, original research articles as well as full reviews, including perspectives in the field on the current understanding of the pathogenesis and emerging therapies for brain tumors in children and adults are going to be presented. Manuscripts from both, basic and clinical researchers are welcome.

Dr. Georg Karpel-Massler
Dr. Mike-Andrew Westhoff
Guest Editors

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. Cells 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 2700 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

brain tumor
glioblastoma
medulloblastoma
tumor immunology
tumor cell metabolism

Published Papers (6 papers)

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Research

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16 pages, 2943 KiB

Open AccessArticle

Progesterone Receptor Membrane Component 1 (PGRMC1) Modulates Tumour Progression, the Immune Microenvironment and the Response to Therapy in Glioblastoma

by Claudia Alexandra Dumitru, Hannah Schröder, Frederik Till Alexander Schäfer, Jan Friedrich Aust, Nina Kreße, Carl Ludwig Raven Siebert, Klaus-Peter Stein, Aiden Haghikia, Ludwig Wilkens, Christian Mawrin and Ibrahim Erol Sandalcioglu

Cells 2023, 12(20), 2498; https://doi.org/10.3390/cells12202498 - 20 Oct 2023

Cited by 2 | Viewed by 1407

Abstract

Progesterone Receptor Membrane Component 1 (PGRMC1) is a tumour-promoting factor in several types of cancer but its role in brain tumours is poorly characterized thus far. Our study aimed to determine the effect of PGRMC1 on glioblastoma (GBM) pathophysiology using two independent cohorts of IDH wild-type GBM patients and stable knockdown GBM models. We found that high levels of PGRMC1 significantly predicted poor overall survival in both cohorts of GBM patients. PGRMC1 promoted the proliferation, anchorage-independent growth, and invasion of GBM cells. We identified Integrin beta-1 (ITGB1) and TCF 1/7 as potential members of the PGRMC1 pathway in vitro. The levels of ITGB1 and PGRMC1 also correlated in neoplastic tissues from GBM patients. High expression of PGRMC1 rendered GBM cells less susceptible to the standard GBM chemotherapeutic agent temozolomide but more susceptible to the ferroptosis inducer erastin. Finally, PGRMC1 enhanced Interleukin-8 production in GBM cells and promoted the recruitment of neutrophils. The expression of PGRMC1 significantly correlated with the numbers of tumour-infiltrating neutrophils also in tissues from GBM patients. In conclusion, PGRMC1 enhances tumour-related inflammation and promotes the progression of GBM. However, PGRMC1 might be a promising target for novel therapeutic strategies using ferroptosis inducers in this type of cancer. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for the Treatment of Brain Tumors)

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19 pages, 3681 KiB

Open AccessArticle

Dual Targeting of EGFR and MTOR Pathways Inhibits Glioblastoma Growth by Modulating the Tumor Microenvironment

by Maxim Sidorov, Pratiksha Dighe, Rinette W. L. Woo, Aida Rodriguez-Brotons, Michelle Chen, Ryan J. Ice, Edith Vaquero, Damon Jian, Pierre-Yves Desprez, Mehdi Nosrati, Leah Galvez, Lewis Leng, Lawrence Dickinson, Mohammed Kashani-Sabet, Sean David McAllister and Liliana Soroceanu

Cells 2023, 12(4), 547; https://doi.org/10.3390/cells12040547 - 8 Feb 2023

Cited by 8 | Viewed by 2103

Abstract

Glioblastoma’s (GBM) aggressive growth is driven by redundant activation of a myriad of signaling pathways and genomic alterations in tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), which is altered in over 50% of cases. Single agents targeting EGFR have not proven effective against GBM. In this study, we aimed to identify an effective anti-tumor regimen using pharmacogenomic testing of patient-derived GBM samples, in culture and in vivo. High-throughput pharmacological screens of ten EGFR-driven GBM samples identified the combination of erlotinib (EGFRi) and MLN0128 (a mammalian target of rapamycin inhibitor, or MTORi) as the most effective at inhibiting tumor cell viability. The anti-tumor activity of erlonitib+MLN0128 was synergistic and produced inhibition of the p-EGFR, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-kinase (PI3K) pathways in culture. Using an orthotopic murine model of GBM, we show that erlotinib+MLN0128 inhibited tumor growth in vivo and significantly prolonged the survival of tumor-bearing mice. Expression profiling of tumor tissues from treated mice revealed a unique gene signature induced by erlotinib+MLN0128, consisting of downregulation of immunosuppressive chemokines in the tumor microenvironment, including C-C motif chemokine ligand 2 (CCL2) and periostin. Lower periostin levels resulted in the inhibition of Iba1+ (tumor-promoting) macrophage infiltration of GBM xenografts. Taken together, our results demonstrate that pharmacological co-targeting of EGFR and MTOR using clinically available drugs represents an effective treatment paradigm for EGFR-driven GBMs, acting both by inhibiting tumor cell growth and modulating the immune tumor microenvironment. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for the Treatment of Brain Tumors)

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17 pages, 6341 KiB

Open AccessArticle

CHRDL1 Regulates Stemness in Glioma Stem-like Cells

by Inka Berglar, Stephanie Hehlgans, Andrej Wehle, Caterina Roth, Christel Herold-Mende, Franz Rödel, Donat Kögel and Benedikt Linder

Cells 2022, 11(23), 3917; https://doi.org/10.3390/cells11233917 - 3 Dec 2022

Cited by 1 | Viewed by 1934

Abstract

Glioblastoma (GBM) still presents as one of the most aggressive tumours in the brain, which despite enormous research efforts, remains incurable today. As many theories evolve around the persistent recurrence of this malignancy, the assumption of a small population of cells with a stem-like phenotype remains a key driver of its infiltrative nature. In this article, we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of bone morphogenic protein 4 (BMP4), which induces GSC differentiation and, hence, reduces tumorigenicity. We, therefore, employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using the stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell-based assays (MTT, limiting dilution, and sphere formation assays), Western blots, irradiation procedures, and quantitative real-time PCR that the depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1 expression might also serve as a marker protein to determine BMP4 susceptibility. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for the Treatment of Brain Tumors)

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Review

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18 pages, 1084 KiB

Open AccessReview

Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions

by Abdulhameed Al-Ghabkari, Bruce Huang and Morag Park

Cells 2024, 13(3), 218; https://doi.org/10.3390/cells13030218 - 25 Jan 2024

Cited by 2 | Viewed by 2181

Abstract

Brain tumors represent a heterogeneous group of neoplasms characterized by a high degree of aggressiveness and a poor prognosis. Despite recent therapeutic advances, the treatment of brain tumors, including glioblastoma (GBM), an aggressive primary brain tumor associated with poor prognosis and resistance to therapy, remains a significant challenge. Receptor tyrosine kinases (RTKs) are critical during development and in adulthood. Dysregulation of RTKs through activating mutations and gene amplification contributes to many human cancers and provides attractive therapeutic targets for treatment. Under physiological conditions, the Met RTK, the hepatocyte growth factor/scatter factor (HGF/SF) receptor, promotes fundamental signaling cascades that modulate epithelial-to-mesenchymal transition (EMT) involved in tissue repair and embryogenesis. In cancer, increased Met activity promotes tumor growth and metastasis by providing signals for proliferation, survival, and migration/invasion. Recent clinical genomic studies have unveiled multiple mechanisms by which MET is genetically altered in GBM, including focal amplification, chromosomal rearrangements generating gene fusions, and a splicing variant mutation (exon 14 skipping, METex14del). Notably, MET overexpression contributes to chemotherapy resistance in GBM by promoting the survival of cancer stem-like cells. This is linked to distinctive Met-induced pathways, such as the upregulation of DNA repair mechanisms, which can protect tumor cells from the cytotoxic effects of chemotherapy. The development of MET-targeted therapies represents a major step forward in the treatment of brain tumours. Preclinical studies have shown that MET-targeted therapies (monoclonal antibodies or small molecule inhibitors) can suppress growth and invasion, enhancing the efficacy of conventional therapies. Early-phase clinical trials have demonstrated promising results with MET-targeted therapies in improving overall survival for patients with recurrent GBM. However, challenges remain, including the need for patient stratification, the optimization of treatment regimens, and the identification of mechanisms of resistance. This review aims to highlight the current understanding of mechanisms underlying MET dysregulation in GBM. In addition, it will focus on the ongoing preclinical and clinical assessment of therapies targeting MET dysregulation in GBM. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for the Treatment of Brain Tumors)

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31 pages, 2679 KiB

Open AccessReview

Targeting Transcription Factors ATF5, CEBPB and CEBPD with Cell-Penetrating Peptides to Treat Brain and Other Cancers

by Lloyd A. Greene, Qing Zhou, Markus D. Siegelin and James M. Angelastro

Cells 2023, 12(4), 581; https://doi.org/10.3390/cells12040581 - 11 Feb 2023

Cited by 5 | Viewed by 3560

Abstract

Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for the Treatment of Brain Tumors)

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17 pages, 1410 KiB

Open AccessReview

Novel Nano-Drug Delivery System for Brain Tumor Treatment

by Ziyi Qiu, Zhenhua Yu, Ting Xu, Liuyou Wang, Nanxin Meng, Huawei Jin and Bingzhe Xu

Cells 2022, 11(23), 3761; https://doi.org/10.3390/cells11233761 - 24 Nov 2022

Cited by 14 | Viewed by 3401

Abstract

As the most dangerous tumors, brain tumors are usually treated with surgical removal, radiation therapy, and chemotherapy. However, due to the aggressive growth of gliomas and their resistance to conventional chemoradiotherapy, it is difficult to cure brain tumors by conventional means. In addition, the higher dose requirement of chemotherapeutic drugs caused by the blood–brain barrier (BBB) and the untargeted nature of the drug inevitably leads to low efficacy and systemic toxicity of chemotherapy. In recent years, nanodrug carriers have attracted extensive attention because of their superior drug transport capacity and easy-to-control properties. This review systematically summarizes the major strategies of novel nano-drug delivery systems for the treatment of brain tumors in recent years that cross the BBB and enhance brain targeting, and compares the advantages and disadvantages of several strategies. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for the Treatment of Brain Tumors)

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