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Special Issue "Tumors of the Nervous System: New Insights into Signaling, Genetics and Therapeutic Targeting"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (28 February 2021).

Special Issue Editors

Dr. Sabrina Di Bartolomeo
E-Mail Website
Guest Editor
Department of Biosciences and Territory, University of Molise, 86090 Pesche (IS), Italy
Interests: autophagy; cellular signalling; mTOR; EMT; glioma
Special Issues and Collections in MDPI journals
Dr. Marco Segatto
E-Mail Website
Guest Editor
Department of Biosciences and Territory, University of Molise, Pesche (Is), Italy
Interests: cholesterol; cell metabolism; neurotrophins; neurodegeneration; neurogenesis; epigenetics; skeletal muscle; inflammation; autophagy; cell signaling
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Brain tumors and other nervous system tumors are an extremely heterogeneous group of benign and malignant tumors characterized by different aggressiveness and variable clinical outcomes. Among them, the most common primary brain tumors in adults are gliomas, meningiomas and pituitary adenomas. Otherwise, medulloblastoma is the most common brain tumor in children. Despite their diversity, nervous system tumors share the tendency of being refractory to radical surgical resection, and radio-chemotherapy is often ineffective because of resistance mechanisms. For these reasons, clinical management of these kinds of tumors is frequently challenging and prognosis is still poor. In this scenario, precision medicine approaches are emerging as promising therapeutic avenues against nervous system tumors, and highlight the need to acquire an in-depth knowledge about the genetic mutations, signaling pathways, metabolic alterations and environmental effects involved in tumor biology and resistance to therapies.

This Special Issue focuses on the current understanding of signaling pathways, as well as genetic and epigenetic features involved in the pathogenesis of brain tumors and other nervous system tumors, with emphasis on the development of novel therapeutic approaches aimed at improving the current standard care. Original articles and up-to-date reviews are encouraged, in order to provide a comprehensive knowledge of the state of the art and future directions.

Dr. Sabrina Di Bartolomeo
Dr. Marco Segatto
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 papers will be 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

  • brain tumors
  • gliomas
  • medulloblastomas
  • neuroblastoma
  • cell signaling
  • molecular mechanisms
  • genetic mutations
  • cancer therapy
  • drug resistance
  • drug repositioning

Published Papers (6 papers)

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Research

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Article
Exosomes from Plasma of Neuroblastoma Patients Contain Doublestranded DNA Reflecting the Mutational Status of Parental Tumor Cells
Int. J. Mol. Sci. 2021, 22(7), 3667; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073667 - 01 Apr 2021
Cited by 1 | Viewed by 398
Abstract
Neuroblastoma (NB) is an aggressive infancy tumor, leading cause of death among preschool age diseases. Here we focused on characterization of exosomal DNA (exo-DNA) isolated from plasma cell-derived exosomes of neuroblastoma patients, and its potential use for detection of somatic mutations present in [...] Read more.
Neuroblastoma (NB) is an aggressive infancy tumor, leading cause of death among preschool age diseases. Here we focused on characterization of exosomal DNA (exo-DNA) isolated from plasma cell-derived exosomes of neuroblastoma patients, and its potential use for detection of somatic mutations present in the parental tumor cells. Exosomes are small extracellular membrane vesicles secreted by most cells, playing an important role in intercellular communications. Using an enzymatic method, we provided evidence for the presence of double-stranded DNA in the NB exosomes. Moreover, by whole exome sequencing, we demonstrated that NB exo-DNA represents the entire exome and that it carries tumor-specific genetic mutations, including those occurring on known oncogenes and tumor suppressor genes in neuroblastoma (ALK, CHD5, SHANK2, PHOX2B, TERT, FGFR1, and BRAF). NB exo-DNA can be useful to identify variants responsible for acquired resistance, such as mutations of ALK, TP53, and RAS/MAPK genes that appear in relapsed patients. The possibility to isolate and to enrich NB derived exosomes from plasma using surface markers, and the quick and easy extraction of exo-DNA, gives this methodology a translational potential in the clinic. Exo-DNA can be an attractive non-invasive biomarker for NB molecular diagnostic, especially when tissue biopsy cannot be easily available. Full article
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Article
The BET Inhibitor OTX015 Exhibits In Vitro and In Vivo Antitumor Activity in Pediatric Ependymoma Stem Cell Models
Int. J. Mol. Sci. 2021, 22(4), 1877; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041877 - 13 Feb 2021
Viewed by 572
Abstract
Childhood ependymomas are heterogenous chemoresistant neoplasms arising from aberrant stem-like cells. Epigenome deregulation plays a pivotal role in ependymoma pathogenesis, suggesting that epigenetic modifiers hold therapeutic promise against this disease. Bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in [...] Read more.
Childhood ependymomas are heterogenous chemoresistant neoplasms arising from aberrant stem-like cells. Epigenome deregulation plays a pivotal role in ependymoma pathogenesis, suggesting that epigenetic modifiers hold therapeutic promise against this disease. Bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in histones and coactivators for oncogenic and stemness-related transcriptional networks, including MYC/MYCN (Proto-Oncogene, BHLH Transcritpion Factor)-regulated genes. We explored BET inhibition as an anticancer strategy in a panel of pediatric patient-derived ependymoma stem cell models by OTX015-mediated suppression of BET/acetylated histone binding. We found that ependymoma tissues and lines express BET proteins and their targets MYC and MYCN. In vitro, OTX015 reduced cell proliferation by inducing G0/G1-phase accumulation and apoptosis at clinically tolerable doses. Mechanistically, inhibitory p21 and p27 increased in a p53-independent manner, whereas the proliferative driver, phospho-signal transducer and activator of transcription 3 (STAT3), decreased. Upregulation of apoptosis-related proteins and survivin downregulation were correlated with cell line drug sensitivity. Minor alterations of MYC/MYCN expression were reported. In vivo, OTX015 significantly improved survival in 2/3 orthotopic ependymoma models. BET proteins represent promising targets for pharmaceutical intervention with OTX015 against ependymoma. The identification of predictive determinants of sensitivity may help identify ependymoma molecular subsets more likely to benefit from BET inhibitor therapies. Full article
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Review

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Review
Epigenetic-Based Therapy—A Prospective Chance for Medulloblastoma Patients’ Recovery
Int. J. Mol. Sci. 2021, 22(9), 4925; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094925 - 06 May 2021
Viewed by 350
Abstract
Medulloblastoma (MB) is one of the most frequent and malignant brain tumors in children. The prognosis depends on the advancement of the disease and the patient’s age. Current therapies, which include surgery, chemotherapy, and irradiation, despite being quite effective, cause significant side effects [...] Read more.
Medulloblastoma (MB) is one of the most frequent and malignant brain tumors in children. The prognosis depends on the advancement of the disease and the patient’s age. Current therapies, which include surgery, chemotherapy, and irradiation, despite being quite effective, cause significant side effects that influence the central nervous system’s function and cause neurocognitive deficits. Therefore, they substantially lower the quality of life, which is especially severe in a developing organism. Thus, there is a need for new therapies that are less toxic and even more effective. Recently, knowledge about the epigenetic mechanisms that are responsible for medulloblastoma development has increased. Epigenetics is a phenomenon that influences gene expression but can be easily modified by external factors. The best known epigenetic mechanisms are histone modifications, DNA methylation, or noncoding RNAs actions. Epigenetic mechanisms comprehensively explain the complex phenomena of carcinogenesis. At the same time, they seem to be a potential key to treating medulloblastoma with fewer complications than past therapies. This review presents the currently known epigenetic mechanisms that are involved in medulloblastoma pathogenesis and the potential therapies that use epigenetic traits to cure medulloblastoma while maintaining a good quality of life and ensuring a higher median overall survival rate. Full article
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Review
Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update
Int. J. Mol. Sci. 2021, 22(9), 4899; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094899 - 05 May 2021
Viewed by 430
Abstract
Gliomas are the most common and challenging malignancies of the central nervous system (CNS), due to their infiltrative nature, tendency to recurrence, and poor response to treatments. Indeed, despite the advances in neurosurgical techniques and in radiation therapy, the modest effects of therapy [...] Read more.
Gliomas are the most common and challenging malignancies of the central nervous system (CNS), due to their infiltrative nature, tendency to recurrence, and poor response to treatments. Indeed, despite the advances in neurosurgical techniques and in radiation therapy, the modest effects of therapy are still challenging. Moreover, tumor recurrence is associated with the onset of therapy resistance; it is therefore critical to identify effective and well-tolerated pharmacological approaches capable of inducing durable responses in the appropriate patient groups. Molecular alterations of the RTK/PI3K/Akt/mTOR signaling pathway are typical hallmarks of glioma, and several clinical trials targeting one or more players of this axis have been launched, showing disappointing results so far, due to the scarce BBB permeability of certain compounds or to the occurrence of resistance/tolerance mechanisms. However, as RTK/PI3K/mTOR is one of the pivotal pathways regulating cell growth and survival in cancer biology, targeting still remains a strong rationale for developing strategies against gliomas. Future rigorous clinical studies, aimed at addressing the tumor heterogeneity, the interaction with the microenvironment, as well as diverse posology adjustments, are needed—which might unravel the therapeutic efficacy and response prediction of an RTK/PI3K/mTOR-based approach. Full article
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Review
Challenging Hurdles of Current Targeting in Glioblastoma: A Focus on Immunotherapeutic Strategies
Int. J. Mol. Sci. 2021, 22(7), 3493; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073493 - 28 Mar 2021
Viewed by 487
Abstract
Glioblastoma is the most frequent primary neoplasm of the central nervous system and still suffers from very poor therapeutic impact. No clear improvements over current standard of care have been made in the last decade. For other cancers, but also for brain metastasis, [...] Read more.
Glioblastoma is the most frequent primary neoplasm of the central nervous system and still suffers from very poor therapeutic impact. No clear improvements over current standard of care have been made in the last decade. For other cancers, but also for brain metastasis, which harbors a very distinct biology from glioblastoma, immunotherapy has already proven its efficacy. Efforts have been pursued to allow glioblastoma patients to benefit from these new approaches, but the road is still long for broad application. Here, we aim to review key glioblastoma immune related characteristics, current immunotherapeutic strategies being explored, their potential caveats, and future directions. Full article
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Review
Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities
Int. J. Mol. Sci. 2020, 21(24), 9654; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249654 - 17 Dec 2020
Cited by 4 | Viewed by 668
Abstract
In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These [...] Read more.
In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies. Full article
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