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Cancers
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Targeted Therapies for Pediatric Solid Tumors (2nd Edition)
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Targeted Therapies for Pediatric Solid Tumors (2nd Edition)

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 20896

Special Issue Editor

Dr. Michele Bernasconi

E-Mail Website
Guest Editor
1. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, Freiburgstrasse 15, 3010 Bern, Switzerland
2. Department for BioMedical Research (DBMR), University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland
Interests: pediatric tumor targeting; nanomedicine; pediatric soft tissue sarcomas; rhabdomyosarcoma; medulloblastoma; immunotherapies; CAR T cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue, “Targeted Therapies for Pediatric Solid Tumors” (https://www.mdpi.com/journal/cancers/special_issues/Targeted_Therapies_Pediatric_Solid).

Pediatric solid tumors are an heterogenous group of tumors, the most common being brain tumors, neuroblastoma, rhabdomyosarcoma, Wilms tumor, Ewing sarcoma, and osteosarcoma. Despite the continuous progress in the treatment of pediatric solid tumors, prognosis is still dismal for most relapsed and metastatic diseases. Moreover, toxicity associated with aggressive chemotherapies, needed to control advanced diseases, imposes a significant burden on pediatric cancer survivors.

The intensive investigation of the molecular bases of pediatric solid tumors in the past years has led to the identification of a wide number of targets for specific treatments that have the potential to increase the efficacy of tumor control and eradication and decrease long-term side effects.

This Special Issue “Targeted Therapies for Pediatric Solid Tumors 2.0” has the goal to summarize recent progresses and outline future developments in targeted molecular therapies, targeted drug delivery, and targeted adaptive immunotherapies for pediatric solid tumors.

Dr. Michele Bernasconi
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 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. Cancers 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 2900 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

  • pediatric solid tumors
  • targeted therapies
  • immunotherapies
  • CAR T cells
  • nanomedicine
  • rhabdomyosarcoma
  • Ewing sarcoma
  • neuroblastoma
  • medulloblastoma
  • osteosarcoma
  • diffuse intrinsic pontine glioma (DIPG)
  • high-grade glioma
  • Wilms tumor

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Published Papers (5 papers)

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Research

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21 pages, 2734 KiB  
Article
The Chimeric Antigen Receptor T Cell Target Claudin 6 Is a Marker for Early Organ-Specific Epithelial Progenitors and Is Expressed in Some Pediatric Solid Tumor Entities
by Larissa Seidmann, Arthur Wingerter, Marie Oliver Metzig, Angelina Bornas, Khalifa El Malki, Arsenij Ustjanzew, Franziska Ortmüller, Yevgeniy Kamyshanskiy, Thomas Kindler, Mark Laible, Xenia Mohr, Nicole Henninger, Alexandra Russo, Olaf Beck, Francesca Alt, Pia Wehling, Wilfried Roth, Claudia Paret and Jörg Faber
Cancers 2025, 17(6), 920; https://doi.org/10.3390/cancers17060920 - 7 Mar 2025
Viewed by 1044
Abstract
Background/Objectives: The oncofetal membrane protein Claudin 6 (CLDN6) is an attractive target for T cell-based therapies. There is a lack of detailed analyses on the age-dependent expression of CLDN6 in normal tissues is lacking, which limits the expansion of CLDN6 CAR-T cell [...] Read more.
Background/Objectives: The oncofetal membrane protein Claudin 6 (CLDN6) is an attractive target for T cell-based therapies. There is a lack of detailed analyses on the age-dependent expression of CLDN6 in normal tissues is lacking, which limits the expansion of CLDN6 CAR-T cell clinical trials to pediatric populations. Methods: We analyzed CLDN6 expression in extracranial solid tumors and normal tissues of children using RNA-sequencing data from over 500 pediatric solid tumor samples, qRT-PCR and immunohistochemistry (IHC) in more than 100 fresh-frozen tumor samples and, approximately, 250 formalin-fixed paraffin-embedded (FFPE) samples. We examined normal tissue expression via qRT-PCR in 32 different infant tissues and via IHC in roughly 290 tissues from donors across four age groups, as well as in fetal autopsy samples. Results: In fetal tissues, we detected CLDN6 expression primarily in the epithelial cells of several organs, including the skin, lungs, kidneys, intestinal tract, and pancreas, but not in undifferentiated blastemal cells. Postnatally, we found CLDN6-positive epithelial progenitors only during the first few weeks of life. In older-age groups, isolated clusters of CLDN6-positive progenitors were present, but in scarce quantities. In tumor tissues, we found strong and homogeneous CLDN6 expression in desmoplastic small round cell tumors and germ cell tumors. Wilms tumors demonstrated heterogeneous CLDN6 expression, notably absent in the blastemal component. Conclusions: These findings highlight an organ-specific presence of CLDN6-positive epithelial precursors that largely disappear in terminally differentiated epithelia within weeks after birth. Therefore, our data support CLDN6 as a viable therapeutic target in pediatric patients and justify their inclusion in basket studies for anti-CLDN6-based therapies. Full article
(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors (2nd Edition))
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18 pages, 3350 KiB  
Article
Super-Enhancer Dysregulation in Rhabdoid Tumor Cells Is Regulated by the SWI/SNF ATPase BRG1
by Cheyenne A. Jones, Jing Wang, James R. Evans, Hannah R. Sisk, Carl B. Womack, Qi Liu, William P. Tansey and April M. Weissmiller
Cancers 2024, 16(5), 916; https://doi.org/10.3390/cancers16050916 - 24 Feb 2024
Viewed by 2280
Abstract
Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention [...] Read more.
Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1—which becomes essential in the absence of SMARCB1—but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression in SMARCB1-deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines. We find that although BRG1-regulated open chromatin sites are distinct at the locus level, the biological characteristics of the loci are very similar, converging on a set of thematically related genes and pointing to the involvement of the AP-1 transcription factor. The open chromatin sites regulated by BRG1 colocalize with histone-marked enhancers and intriguingly include almost all super-enhancers, revealing that BRG1 plays a critical role in maintaining super-enhancer function in this setting. These studies can explain the essentiality of BRG1 to rhabdoid tumor cell identity and survival and implicate the involvement of AP-1 as a critical downstream effector of rhabdoid tumor cell transcriptional programs. Full article
(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors (2nd Edition))
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15 pages, 5682 KiB  
Article
Carbonic Anhydrase Inhibitors Induce Ferroptosis through Inhibition of AKT/FTH1 Signaling in Ewing Sarcoma Tumor Cells
by Darya Fayzullina, Semyon Yakushov, Kamilla Kantserova, Elizaveta Belyaeva, Denis Aniskin, Sergey Tsibulnikov, Nafisa Fayzullina, Stanislav Kalinin, Olga Romantsova, Peter S. Timashev, Brett A. Schroeder and Ilya V. Ulasov
Cancers 2023, 15(21), 5225; https://doi.org/10.3390/cancers15215225 - 31 Oct 2023
Cited by 4 | Viewed by 2231
Abstract
Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have [...] Read more.
Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES. Full article
(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors (2nd Edition))
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15 pages, 1711 KiB  
Article
Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX)
by Pierre Leblond, Emmanuelle Tresch-Bruneel, Alicia Probst, Nadège Néant, Caroline Solas, Arthur Sterin, Thomas Boulanger, Isabelle Aerts, Cécile Faure-Conter, Anne-Isabelle Bertozzi, Pascal Chastagner, Natacha Entz-Werlé, Emilie De Carli, Marie-Cécile Le Deley, Gauthier Bouche and Nicolas André
Cancers 2023, 15(7), 2020; https://doi.org/10.3390/cancers15072020 - 28 Mar 2023
Cited by 4 | Viewed by 2372
Abstract
Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin [...] Read more.
Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries. Full article
(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors (2nd Edition))
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Review

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72 pages, 12929 KiB  
Review
Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies
by Ali Zarrabi, David Perrin, Mahboubeh Kavoosi, Micah Sommer, Serap Sezen, Parvaneh Mehrbod, Bhavya Bhushan, Filip Machaj, Jakub Rosik, Philip Kawalec, Saba Afifi, Seyed Mohammadreza Bolandi, Peiman Koleini, Mohsen Taheri, Tayyebeh Madrakian, Marek J. Łos, Benjamin Lindsey, Nilufer Cakir, Atefeh Zarepour, Kiavash Hushmandi, Ali Fallah, Bahattin Koc, Arezoo Khosravi, Mazaher Ahmadi, Susan Logue, Gorka Orive, Stevan Pecic, Joseph W. Gordon and Saeid Ghavamiadd Show full author list remove Hide full author list
Cancers 2023, 15(21), 5269; https://doi.org/10.3390/cancers15215269 - 2 Nov 2023
Cited by 34 | Viewed by 11773
Abstract
Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. [...] Read more.
Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration. Full article
(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors (2nd Edition))
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