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Advances in the Development of New Drugs and Treatment Targets for Brain Cancers

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuro-oncology".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 16060

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Dr. Luis Ibarra

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Institute of Environmental Biotechnology and Health (INBIAS), National Council for Scientific and Technical Research (CONICET) and National University of Río Cuarto (UNRC), Rio Cuarto, Argentina
Interests: nanomedicine; cell therapy; tumor microenvironment; photodynamic therapy; cell targeting
Special Issues, Collections and Topics in MDPI journals

Dr. Laura Natalia Milla Sanabria

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Institute of Environmental Biotechnology and Health (INBIAS), National Council for Scientific and Technical Research (CONICET) and National University of Río Cuarto (UNRC), Rio Cuarto, Argentina
Interests: glioblastoma; photodynamic therapy; cancer stem cells; resistance
Special Issues, Collections and Topics in MDPI journals

Dr. Nuria Arias-Ramos

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Biomedical Magnetic Resonance Lab, Department of Endocrine and Nervous System Pathophysiology, Instituto de Investigaciones Biomedicas Alberto Sols (IIBM), CSIC-UAM, 28029-Madrid, Spain
Interests: magnetic resonance imaging (MRI); magnetic resonance spectroscopy (MRS); positron emission tomography (PET); brain tumors; nanoparticles; contrast agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brain cancers represent a significant challenge for current oncology and drug development. Despite being rare in the general population, malignant brain tumors can occur in both adults and children, accounting for up to 33% of cancer-related deaths in children, as an indicator of the severity of these tumors. Standard treatment regimens consist of maximal surgical resection followed by radiotherapy and chemotherapy. However, the main issue with this type of tumor is that they are ‘protected’ by the most impermeable biological barrier—the blood–brain barrier. In addition, the 2021 edition of the WHO Classification of Tumors of the Central Nervous System (CNS) emphasizes the advanced role of molecular diagnostics in the identification of molecular biomarkers, in addition to histologic features in the classification of CNS tumors, in order to improve the newly developed treatments. In recent decades, potent chemotherapeutic agents, oligonucleotides and antibodies for targeted therapy, multifunctional nanomedicines, immunotherapies and cell-based therapies have been developed and proposed to overcome most of the issues that arise due to the location of brain tumors and their biological barriers. This Special Issue invites original research articles and review articles covering new therapeutic strategies and target drugs, exploring the importance of brain tumors at cellular and molecular levels.

Dr. Luis Exequiel Ibarra
Dr. Laura Natalia Milla Sanabria
Dr. Nuria Arias-Ramos
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. Brain Sciences 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 2200 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 tumors
targeted therapy
multifunctional nanoparticles
blood–brain barrier
cell-based therapy
molecular and cellular biology

Published Papers (10 papers)

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Research

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17 pages, 3326 KiB

Open AccessArticle

Integrative Magnetic Resonance Imaging and Metabolomic Characterization of a Glioblastoma Rat Model

by Nuria Arias-Ramos, Cecilia Vieira, Rocío Pérez-Carro and Pilar López-Larrubia

Brain Sci. 2024, 14(5), 409; https://doi.org/10.3390/brainsci14050409 - 23 Apr 2024

Viewed by 335

Abstract

Glioblastoma (GBM) stands as the most prevalent and lethal malignant brain tumor, characterized by its highly infiltrative nature. This study aimed to identify additional MRI and metabolomic biomarkers of GBM and its impact on healthy tissue using an advanced-stage C6 glioma rat model. Wistar rats underwent a stereotactic injection of C6 cells (GBM group, n = 10) or cell medium (sham group, n = 4). A multiparametric MRI, including anatomical T₂W and T₁W images, relaxometry maps (T₂, T₂*, and T₁), the magnetization transfer ratio (MTR), and diffusion tensor imaging (DTI), was performed. Additionally, ex vivo magnetic resonance spectroscopy (MRS) HRMAS spectra were acquired. The MRI analysis revealed significant differences in the T₂ maps, T₁ maps, MTR, and mean diffusivity parameters between the GBM tumor and the rest of the studied regions, which were the contralateral areas of the GBM rats and both regions of the sham rats (the ipsilateral and contralateral). The ex vivo spectra revealed markers of neuronal loss, apoptosis, and higher glucose uptake by the tumor. Notably, the myo-inositol and phosphocholine levels were elevated in both the tumor and the contralateral regions of the GBM rats compared to the sham rats, suggesting the effects of the tumor on the healthy tissue. The MRI parameters related to inflammation, cellularity, and tissue integrity, along with MRS-detected metabolites, serve as potential biomarkers for the tumor evolution, treatment response, and impact on healthy tissue. These techniques can be potent tools for evaluating new drugs and treatment targets. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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14 pages, 4140 KiB

Open AccessArticle

Flavonoid Rutin Presented Anti-Glioblastoma Activity Related to the Modulation of Onco miRNA-125b Expression and STAT3 Signaling and Impact on Microglia Inflammatory Profile

by Irlã Santos Lima, Érica Novaes Soares, Carolina Kymie Vasques Nonaka, Bruno Solano de Freitas Souza, Balbino Lino dos Santos and Silvia Lima Costa

Brain Sci. 2024, 14(1), 90; https://doi.org/10.3390/brainsci14010090 - 17 Jan 2024

Viewed by 1092

Abstract

Glioblastoma (GBM) is the most aggressive and treatment-resistant brain tumor. In the GBM microenvironment, interaction with microglia is associated with the dysregulation of cytokines, chemokines, and miRNAs, contributing to angiogenesis, proliferation, anti-apoptosis, and chemoresistance. The flavonoid rutin can inhibit glioma cell growth associated with microglial activation and production of pro-inflammatory mediators by mechanisms that are still poorly understood. The present study investigated the effect of rutin on viability, regulation of miRNA-125b, and the STAT3 expression in GBM cells, as well as the effects on the modulation of the inflammatory profile and STAT3 expression in microglia during indirect interaction with GBM cells. Human GL15-GBM cells and human C20 microglia were treated or not with rutin for 24 h. Rutin (30–50 μM) significantly reduced the viability of GL15 cells; however, it did not affect the viability of microglia. Rutin (30 μM) significantly reduced the expression of miRNA-125b in the cells and secretome and STAT3 expression. Microglia submitted to the conditioned medium from GBM cells treated with rutin showed reactive morphology associated with reduced expression of IL-6, TNF, and STAT3. These results reiterate the anti-glioma effects of the flavonoid, which may also modulate microglia towards a more responsive anti-tumor phenotype, constituting a promising molecule for adjuvant therapy to GBM. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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14 pages, 7092 KiB

Open AccessArticle

Polymersomes for Sustained Delivery of a Chalcone Derivative Targeting Glioblastoma Cells

by Ana Alves, Ana M. Silva, Joana Moreira, Claúdia Nunes, Salette Reis, Madalena Pinto, Honorina Cidade, Francisca Rodrigues, Domingos Ferreira, Paulo C. Costa and Marta Correia-da-Silva

Brain Sci. 2024, 14(1), 82; https://doi.org/10.3390/brainsci14010082 - 14 Jan 2024

Viewed by 1419

Abstract

Glioblastoma (GBM) is a primary malignant tumor of the central nervous system responsible for the most deaths among patients with primary brain tumors. Current therapies for GBM are not effective, with the average survival of GBM patients after diagnosis being limited to a few months. Chemotherapy is difficult in this case due to the heterogeneity of GBM and the high efficacy of the blood–brain barrier, which makes drug absorption into the brain extremely difficult. In a previous study, 3′,4′,3,4,5-trimethoxychalcone (MB) showed antiproliferative and anti-invasion activities toward GBM cells. Polymersomes (PMs) are an attractive, new type of nanoparticle for drug administration, due to their high stability, enhanced circulation time, biodegradability, and sustained drug release. In the present study, different MB formulations, PEG2000-PCL and PEG5000-PCL, were synthesized, characterized, and compared in terms of 14-day stability and in vitro cytotoxicity (hCMEC/D3 and U-373 MG). Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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12 pages, 3139 KiB

Open AccessArticle

Actin Alpha 2, Smooth Muscle (ACTA2) Is Involved in the Migratory Potential of Malignant Gliomas, and Its Increased Expression at Recurrence Is a Significant Adverse Prognostic Factor

by Takumi Hoshimaru, Naosuke Nonoguchi, Takuya Kosaka, Motomasa Furuse, Shinji Kawabata, Ryokichi Yagi, Yoshitaka Kurisu, Hideki Kashiwagi, Masahiro Kameda, Toshihiro Takami, Yuko Kataoka-Sasaki, Masanori Sasaki, Osamu Honmou, Ryo Hiramatsu and Masahiko Wanibuchi

Brain Sci. 2023, 13(10), 1477; https://doi.org/10.3390/brainsci13101477 - 19 Oct 2023

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Abstract

Malignant glioma is a highly invasive tumor, and elucidating the glioma invasion mechanism is essential for developing novel therapies. We aimed to highlight actin alpha 2, smooth muscle (ACTA2) as potential biomarkers of brain invasion and distant recurrence in malignant gliomas. Using the human malignant glioma cell line, U251MG, we generated ACTA2 knockdown (KD) cells treated with small interfering RNA, and the cell motility and proliferation of the ACTA2 KD group were analyzed. Furthermore, tumor samples from 12 glioma patients who underwent reoperation at the time of tumor recurrence were utilized to measure ACTA2 expression in the tumors before and after recurrence. Thereafter, we examined how ACTA2 expression correlates with the time to tumor recurrence and the mode of recurrence. The results showed that the ACTA2 KD group demonstrated a decline in the mean motion distance and proliferative capacity compared to the control group. In the clinical glioma samples, ACTA2 expression was remarkably increased in recurrent samples compared to the primary samples from the same patients, and the higher the change in ACTCA2 expression from the start to relapse, the shorter the progression-free survival. In conclusion, ACTA2 may be involved in distant recurrence in clinical gliomas. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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13 pages, 1855 KiB

Open AccessArticle

The Role of Ketone Bodies in Treatment Individualization of Glioblastoma Patients

by Corina Tamas, Flaviu Tamas, Attila Kovecsi, Georgiana Serban, Cristian Boeriu and Adrian Balasa

Brain Sci. 2023, 13(9), 1307; https://doi.org/10.3390/brainsci13091307 - 11 Sep 2023

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Abstract

Glioblastoma is the most common and aggressive primary brain tumor in adults. According to the 2021 WHO CNS, glioblastoma is assigned to the IDH wild-type classification, fulfilling the specific characteristic histopathology. We have conducted a prospective observational study to identify the glucose levels, ketone bodies, and the glucose-ketone index in three groups of subjects: two tumoral groups of patients with histopathological confirmation of glioblastoma (9 male patients, 7 female patients, mean age 55.6 years old) or grade 4 astrocytoma (4 male patients, 2 female patients, mean age 48.1 years old) and a control group (13 male patients, 9 female patients, mean age 53.9 years old) consisting of subjects with no personal pathological history. There were statistically significant differences between the mean values of glycemia (p value = 0.0003), ketones (p value = 0.0061), and glucose-ketone index (p value = 0.008) between the groups of patients. Mortality at 3 months in glioblastoma patients was 0% if the ketone levels were below 0.2 mM and 100% if ketones were over 0.5 mM. Patients with grade 4 astrocytoma and the control subjects all presented with ketone values of less than 0.2 mM and 0.0% mortality. In conclusion, highlighting new biomarkers which are more feasible to determine such as ketones or glucose-ketone index represents an essential step toward personalized medicine and survival prolongation in patients suffering from glioblastoma and grade 4 astrocytoma. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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14 pages, 2661 KiB

Open AccessArticle

Melatonin in Combination with Albendazole or Albendazole Sulfoxide Produces a Synergistic Cytotoxicity against Malignant Glioma Cells through Autophagy and Apoptosis

by Miguel Hernández-Cerón, Víctor Chavarria, Camilo Ríos, Benjamin Pineda, Francisca Palomares-Alonso, Irma Susana Rojas-Tomé and Helgi Jung-Cook

Brain Sci. 2023, 13(6), 869; https://doi.org/10.3390/brainsci13060869 - 27 May 2023

Viewed by 2098

Abstract

Glioblastoma is the most aggressive and lethal brain tumor in adults, presenting diffuse brain infiltration, necrosis, and drug resistance. Although new drugs have been approved for recurrent patients, the median survival rate is two years; therefore, new alternatives to treat these patients are required. Previous studies have reported the anticancer activity of albendazole, its active metabolite albendazole sulfoxide, and melatonin; therefore, the present study was performed to evaluate if the combination of melatonin with albendazole or with albendazole sulfoxide induces an additive or synergistic cytotoxic effect on C6 and RG2 rat glioma cells, as well as on U87 human glioblastoma cells. Drug interaction was determined by the Chou–Talalay method. We evaluated the mechanism of cell death by flow cytometry, immunofluorescence, and crystal violet staining. The cytotoxicity of the combinations was mainly synergistic. The combined treatments induced significantly more apoptotic and autophagic cell death on the glioma cell lines. Additionally, albendazole and albendazole sulfoxide inhibited proliferation independently of melatonin. Our data justify continuing with the evaluation of this proposal since the combinations could be a potential strategy to aid in the treatment of glioblastoma. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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14 pages, 2863 KiB

Open AccessArticle

Locomotion Outcome Improvement in Mice with Glioblastoma Multiforme after Treatment with Anastrozole

by Irene Guadalupe Aguilar-García, Ismael Jiménez-Estrada, Rolando Castañeda-Arellano, Jonatan Alpirez, Gerardo Mendizabal-Ruiz, Judith Marcela Dueñas-Jiménez, Coral Estefania Gutiérrez-Almeida, Laura Paulina Osuna-Carrasco, Viviana Ramírez-Abundis and Sergio Horacio Dueñas-Jiménez

Brain Sci. 2023, 13(3), 496; https://doi.org/10.3390/brainsci13030496 - 15 Mar 2023

Cited by 1 | Viewed by 1530

Abstract

Glioblastoma Multiforme (GBM) is a tumor that infiltrates several brain structures. GBM is associated with abnormal motor activities resulting in impaired mobility, producing a loss of functional motor independence. We used a GBM xenograft implanted in the striatum to analyze the changes in Y (vertical) and X (horizontal) axis displacement of the metatarsus, ankle, and knee. We analyzed the steps dissimilarity factor between control and GBM mice with and without anastrozole. The body weight of the untreated animals decreased compared to treated mice. Anastrozole reduced the malignant cells and decreased GPR30 and ERα receptor expression. In addition, we observed a partial recovery in metatarsus and knee joint displacement (dissimilarity factor). The vertical axis displacement of the GBM+anastrozole group showed a difference in the right metatarsus, right knee, and left ankle compared to the GBM group. In the horizontal axis displacement of the right metatarsus, ankle, and knee, the GBM+anastrozole group exhibited a difference at the last third of the step cycle compared to the GBM group. Thus, anastrozole partially modified joint displacement. The dissimilarity factor and the vertical and horizontal displacements study will be of interest in GBM patients with locomotion alterations. Hindlimb displacement and gait locomotion analysis could be a valuable methodological tool in experimental and clinical studies to help diagnose locomotive deficits related to GBM. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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Review

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22 pages, 4142 KiB

Open AccessReview

An Update on Emergent Nano-Therapeutic Strategies against Pediatric Brain Tumors

by Ammu V. V. V. Ravi Kiran, G. Kusuma Kumari, Praveen T. Krishnamurthy, Asha P. Johnson, Madhuchandra Kenchegowda, Riyaz Ali M. Osmani, Amr Selim Abu Lila, Afrasim Moin, H. V. Gangadharappa and Syed Mohd Danish Rizvi

Brain Sci. 2024, 14(2), 185; https://doi.org/10.3390/brainsci14020185 - 18 Feb 2024

Viewed by 1194

Abstract

Pediatric brain tumors are the major cause of pediatric cancer mortality. They comprise a diverse group of tumors with different developmental origins, genetic profiles, therapeutic options, and outcomes. Despite many technological advancements, the treatment of pediatric brain cancers has remained a challenge. Treatment options for pediatric brain cancers have been ineffective due to non-specificity, inability to cross the blood–brain barrier, and causing off-target side effects. In recent years, nanotechnological advancements in the medical field have proven to be effective in curing challenging cancers like brain tumors. Moreover, nanoparticles have emerged successfully, particularly in carrying larger payloads, as well as their stability, safety, and efficacy monitoring. In the present review, we will emphasize pediatric brain cancers, barriers to treating these cancers, and novel treatment options. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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19 pages, 1059 KiB

Open AccessReview

Low-Grade Gliomas: Histological Subtypes, Molecular Mechanisms, and Treatment Strategies

by Corneliu Toader, Lucian Eva, Daniel Costea, Antonio Daniel Corlatescu, Razvan-Adrian Covache-Busuioc, Bogdan-Gabriel Bratu, Luca Andrei Glavan, Horia Petre Costin, Andrei Adrian Popa and Alexandru Vlad Ciurea

Brain Sci. 2023, 13(12), 1700; https://doi.org/10.3390/brainsci13121700 - 09 Dec 2023

Cited by 4 | Viewed by 1480

Abstract

Low-Grade Gliomas (LGGs) represent a diverse group of brain tumors originating from glial cells, characterized by their unique histopathological and molecular features. This article offers a comprehensive exploration of LGGs, shedding light on their subtypes, histological and molecular aspects. By delving into the World Health Organization’s grading system, 5th edition, various specificities were added due to an in-depth understanding of emerging laboratory techniques, especially genomic analysis. Moreover, treatment modalities are extensively discussed. The degree of surgical resection should always be considered according to postoperative quality of life and cognitive status. Adjuvant therapies focused on chemotherapy and radiotherapy depend on tumor grading and invasiveness. In the current literature, emerging targeted molecular therapies are well discussed due to their succinctly therapeutic effect; in our article, those therapies are summarized based on posttreatment results and possible adverse effects. This review serves as a valuable resource for clinicians, researchers, and medical professionals aiming to deepen their knowledge on LGGs and enhance patient care. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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24 pages, 2414 KiB

Open AccessEditor’s ChoiceReview

Exploring Monocytes-Macrophages in Immune Microenvironment of Glioblastoma for the Design of Novel Therapeutic Strategies

by Matías Daniel Caverzán, Lucía Beaugé, Paula Martina Oliveda, Bruno Cesca González, Eugenia Micaela Bühler and Luis Exequiel Ibarra

Brain Sci. 2023, 13(4), 542; https://doi.org/10.3390/brainsci13040542 - 24 Mar 2023

Cited by 5 | Viewed by 2792

Abstract

Gliomas are primary malignant brain tumors. These tumors seem to be more and more frequent, not only because of a true increase in their incidence, but also due to the increase in life expectancy of the general population. Among gliomas, malignant gliomas and more specifically glioblastomas (GBM) are a challenge in their diagnosis and treatment. There are few effective therapies for these tumors, and patients with GBM fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the last decade, it is now appreciated that these tumors are composed of numerous distinct tumoral and non-tumoral cell populations, which could each influence the overall tumor biology and response to therapies. Monocytes have been proved to actively participate in tumor growth, giving rise to the support of tumor-associated macrophages (TAMs). In GBM, TAMs represent up to one half of the tumor mass cells, including both infiltrating macrophages and resident brain microglia. Infiltrating macrophages/monocytes constituted ~ 85% of the total TAM population, they have immune functions, and they can release a wide array of growth factors and cytokines in response to those factors produced by tumor and non-tumor cells from the tumor microenvironment (TME). A brief review of the literature shows that this cell population has been increasingly studied in GBM TME to understand its role in tumor progression and therapeutic resistance. Through the knowledge of its biology and protumoral function, the development of therapeutic strategies that employ their recruitment as well as the modulation of their immunological phenotype, and even the eradication of the cell population, can be harnessed for therapeutic benefit. This revision aims to summarize GBM TME and localization in tumor niches with special focus on TAM population, its origin and functions in tumor progression and resistance to conventional and experimental GBM treatments. Moreover, recent advances on the development of TAM cell targeting and new cellular therapeutic strategies based on monocyte/macrophages recruitment to eradicate GBM are discussed as complementary therapeutics. Full article

(This article belongs to the Special Issue Advances in the Development of New Drugs and Treatment Targets for Brain Cancers)

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