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Exploring Novel Molecular, Metabolic and Cellular Mechanisms for Developing New Therapeutic Targets against Childhood Cancers

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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 (30 April 2024) | Viewed by 5526

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Special Issue Editors

Dr. Silvia Codenotti

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Guest Editor

Department of Molecular and Translational Medicine (DMMT), University of Brescia, Brescia, Italy
Interests: rhabdomyosarcoma
Special Issues, Collections and Topics in MDPI journals

Dr. Alessandro Fanzani

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Guest Editor

Department of Molecular and Translational Medicine (DMMT), University of Brescia, Viale Europa 11, 25123 Brescia, Italy
Interests: rhabdomyosarcoma; caveolins; cavins; oxidative stress; muscle
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

This Special Issue is dedicated to childhood cancers, mainly including blood tumors (leukemias, lymphomas), embryonal tumors (retinoblastoma, neuroblastoma, Wilms tumor), central nervous system tumors (medulloblastoma, glioma, astrocytoma, oligodendroglioma, and ependymoma), bone and soft tissue sarcoma (osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma), which are the leading cause of pediatric death in developed countries. Unlike what is observed in adults, in which the onset of cancer is commonly due to the acquisition of gene mutations in one or more somatic cells, pediatric tumors are more often genetically inherited. Indeed, there are several examples of cancer syndromes causing pediatric tumors, including Fanconi anemia and Xeroderma pigmentosum, retinoblastoma, Li-Fraumeni syndrome, DICER1 syndrome and neurofibromatosis, one RAS mosaic condition, and Down syndrome. Therefore, in this Special Issue, we want to collect studies on pediatric tumors focusing on the molecular/cellular landscape, metabolic vulnerabilities and new therapies for accelerating the development of combined anti-tumor strategies.

Dr. Silvia Codenotti
Dr. Alessandro Fanzani
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. 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

childhood cancers
rhabdomyosarcoma
leukemias
lymphomas
central nervous system tumors
sarcomas of bone and soft tissue
neuroblastoma
retinoblastoma
rhabdoid tumors
rare cancers
genomic alterations
molecular drivers
tissue microenvironment
development of drugs
therapies

Published Papers (5 papers)

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Research

24 pages, 7450 KiB

Open AccessArticle

EGCG Disrupts the LIN28B/Let-7 Interaction and Reduces Neuroblastoma Aggressiveness

by Simona Cocchi, Valentina Greco, Viktoryia Sidarovich, Jacopo Vigna, Francesca Broso, Diana Corallo, Jacopo Zasso, Angela Re, Emanuele Filiberto Rosatti, Sara Longhi, Andrea Defant, Federico Ladu, Vanna Sanna, Valentina Adami, Vito G. D’Agostino, Mattia Sturlese, Mario Sechi, Sanja Aveic, Ines Mancini, Denise Sighel and Alessandro Quattrone Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(9), 4795; https://doi.org/10.3390/ijms25094795 - 27 Apr 2024

Viewed by 369

Abstract

Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (−)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation. Full article

(This article belongs to the Special Issue Exploring Novel Molecular, Metabolic and Cellular Mechanisms for Developing New Therapeutic Targets against Childhood Cancers)

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Graphical abstract

10 pages, 1410 KiB

Open AccessArticle

PIM Kinase Inhibition Attenuates the Malignant Progression of Metastatic Hepatoblastoma

by Janet R. Julson, Colin H. Quinn, Swatika Butey, Michael H. Erwin, Raoud Marayati, Nazia Nazam, Jerry E. Stewart and Elizabeth A. Beierle

Int. J. Mol. Sci. 2024, 25(1), 427; https://doi.org/10.3390/ijms25010427 - 28 Dec 2023

Viewed by 744

Abstract

Hepatoblastoma is the most common primary pediatric liver tumor. Children with pulmonary metastases at diagnosis experience survival rates as low as 25%. We have shown PIM kinases play a role in hepatoblastoma tumorigenesis. In this study, we assessed the role of PIM kinases in metastatic hepatoblastoma. We employed the metastatic hepatoblastoma cell line, HLM_2. PIM kinase inhibition was attained using PIM3 siRNA and the pan-PIM inhibitor, AZD1208. Effects of PIM inhibition on proliferation were evaluated via growth curve. Flow cytometry determined changes in cell cycle. AlamarBlue assay assessed effects of PIM kinase inhibition and cisplatin treatment on viability. The lethal dose 50% (LD₅₀) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. PIM kinase inhibition resulted in decreased HLM_2 proliferation, likely through cell cycle arrest mediated by p21. Combination therapy with AZD1208 and cisplatin resulted in synergy, potentially through downregulation of the ataxia-telangiectasia mutated (ATM) kinase DNA damage response pathway. When assessing the combined effects of pharmacologic PIM kinase inhibition with cisplatin on HLM_2 cells, we found the agents to be synergistic, potentially through inhibition of the ATM pathway. These findings support further exploration of PIM kinase inhibition as a therapeutic strategy for metastatic hepatoblastoma. Full article

(This article belongs to the Special Issue Exploring Novel Molecular, Metabolic and Cellular Mechanisms for Developing New Therapeutic Targets against Childhood Cancers)

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20 pages, 1732 KiB

Open AccessArticle

Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors

by Aleksa Jovanović, Nataša Tošić, Irena Marjanović, Jovana Komazec, Branka Zukić, Marina Nikitović, Rosanda Ilić, Danica Grujičić, Dragana Janić and Sonja Pavlović

Int. J. Mol. Sci. 2023, 24(24), 17387; https://doi.org/10.3390/ijms242417387 - 12 Dec 2023

Viewed by 1218

Abstract

Central nervous system (CNS) tumors comprise around 20% of childhood malignancies. Germline variants in cancer predisposition genes (CPGs) are found in approximately 10% of pediatric patients with CNS tumors. This study aimed to characterize variants in CPGs in pediatric patients with CNS tumors and correlate these findings with clinically relevant data. Genomic DNA was isolated from the peripheral blood of 51 pediatric patients and further analyzed by the next-generation sequencing approach. Bioinformatic analysis was done using an “in-house” gene list panel, which included 144 genes related to pediatric brain tumors, and the gene list panel Neoplasm (HP:0002664). Our study found that 27% of pediatric patients with CNS tumors have a germline variant in some of the known CPGs, like ALK, APC, CHEK2, ELP1, MLH1, MSH2, NF1, NF2 and TP53. This study represents the first comprehensive evaluation of germline variants in pediatric patients with CNS tumors in the Western Balkans region. Our results indicate the necessity of genomic research to reveal the genetic basis of pediatric CNS tumors, as well as to define targets for the application and development of innovative therapeutics that form the basis of the upcoming era of personalized medicine. Full article

(This article belongs to the Special Issue Exploring Novel Molecular, Metabolic and Cellular Mechanisms for Developing New Therapeutic Targets against Childhood Cancers)

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8 pages, 560 KiB

Open AccessCommunication

Hematologic Neoplasms Associated with Down Syndrome: Cellular and Molecular Heterogeneity of the Diseases

by Edoardo Peroni, Michele Gottardi, Lucia D’Antona, Maria Luigia Randi, Antonio Rosato and Giacomo Coltro

Int. J. Mol. Sci. 2023, 24(20), 15325; https://doi.org/10.3390/ijms242015325 - 18 Oct 2023

Viewed by 1303

Abstract

The molecular basis of Down syndrome (DS) predisposition to leukemia is not fully understood but involves various factors such as chromosomal abnormalities, oncogenic mutations, epigenetic alterations, and changes in selection dynamics. Myeloid leukemia associated with DS (ML-DS) is preceded by a preleukemic phase called transient abnormal myelopoiesis driven by GATA1 gene mutations and progresses to ML-DS via additional mutations in cohesin genes, CTCF, RAS, or JAK/STAT pathway genes. DS-related ALL (ALL-DS) differs from non-DS ALL in terms of cytogenetic subgroups and genetic driver events, and the aberrant expression of CRLF2, JAK2 mutations, and RAS pathway-activating mutations are frequent in ALL-DS. Recent advancements in single-cell multi-omics technologies have provided unprecedented insights into the cellular and molecular heterogeneity of DS-associated hematologic neoplasms. Single-cell RNA sequencing and digital spatial profiling enable the identification of rare cell subpopulations, characterization of clonal evolution dynamics, and exploration of the tumor microenvironment’s role. These approaches may help identify new druggable targets and tailor therapeutic interventions based on distinct molecular profiles, ultimately improving patient outcomes with the potential to guide personalized medicine approaches and the development of targeted therapies. Full article

(This article belongs to the Special Issue Exploring Novel Molecular, Metabolic and Cellular Mechanisms for Developing New Therapeutic Targets against Childhood Cancers)

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16 pages, 3738 KiB

Open AccessArticle

CRISPR-Cas9 Library Screening Identifies Novel Molecular Vulnerabilities in KMT2A-Rearranged Acute Lymphoblastic Leukemia

by Pauline Schneider, Priscilla Wander, Susan T. C. J. M. Arentsen-Peters, Kirsten S. Vrenken, Dedeke Rockx-Brouwer, Fabienne R. S. Adriaanse, Veerle Hoeve, Irene Paassen, Jarno Drost, Rob Pieters and Ronald W. Stam

Int. J. Mol. Sci. 2023, 24(17), 13207; https://doi.org/10.3390/ijms241713207 - 25 Aug 2023

Cited by 1 | Viewed by 1326

Abstract

In acute lymphoblastic leukemia (ALL), chromosomal translocations involving the KMT2A gene represent highly unfavorable prognostic factors and most commonly occur in patients less than 1 year of age. Rearrangements of the KMT2A gene drive epigenetic changes that lead to aberrant gene expression profiles that strongly favor leukemia development. Apart from this genetic lesion, the mutational landscape of KMT2A-rearranged ALL is remarkably silent, providing limited insights for the development of targeted therapy. Consequently, identifying potential therapeutic targets often relies on differential gene expression, yet the inhibition of these genes has rarely translated into successful therapeutic strategies. Therefore, we performed CRISPR-Cas9 knock-out screens to search for genetic dependencies in KMT2A-rearranged ALL. We utilized small-guide RNA libraries directed against the entire human epigenome and kinome in various KMT2A-rearranged ALL, as well as wild-type KMT2A ALL cell line models. This screening approach led to the discovery of the epigenetic regulators ARID4B and MBD3, as well as the receptor kinase BMPR2 as novel molecular vulnerabilities and attractive therapeutic targets in KMT2A-rearranged ALL. Full article

(This article belongs to the Special Issue Exploring Novel Molecular, Metabolic and Cellular Mechanisms for Developing New Therapeutic Targets against Childhood Cancers)

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