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Cancers
Special Issues
Targeted Therapy of Pediatric Cancer
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Targeted Therapy of Pediatric Cancer

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

Deadline for manuscript submissions: closed (20 February 2024) | Viewed by 4798

Special Issue Editors

Prof. Dr. Günther H.S. Richter

E-Mail Website
Guest Editor
Department of Paediatrics, Division of Oncology and Haematology, Charité – Universitätsmedizin Berlin, 13353 Berlin, Germany
Interests: pediatric sarcoma; genetics; epigenetics; targeted therapy
Prof. Dr. Beat W. Schäfer

E-Mail Website
Guest Editor
Department of Oncology, University Children’s Hospital Zurich, 8032 Zurich, Switzerland
Interests: sarcoma; oncogenic fusion transcription factors; precision medicine

Special Issue Information

Dear Colleagues,

Today, more than 80% of children diagnosed with cancer can be cured. However, cancer remains one of the leading causes of death in children and adolescents. Established therapies such as chemotherapy, radiation and surgery have often reached their limits of toxicity, and further therapy intensification seems impossible. In more than half of all cancer survivors, these therapies are associated with mutilation, mental retardation and/or genetic damage. At the same time, the therapeutic success for refractory or relapsed tumors is unsatisfactory, with progression-free overall survival rates between 10% and 20% at two years, despite intensive multimodal treatment approaches.

Global (epi)genetic NGS sequencing approaches have demonstrated that pediatric tumors are fundamentally different from adult malignancies in terms of their cellular origin, epidemiology, lower mutational burden, driver mutations and underlying mutational processes. They have also established extensive molecular diagnostic pipelines to identify biomarkers and, to date, have identified potentially druggable mutations in 25-50% of pediatric tumors. These results led to novel targeted and immunotherapeutic treatment approaches and, in some patients with refractory cancers, to the exploration of these agents as components of first-line treatment.

However, it must also be noted that for many tumor entities, effective therapy approaches have not yet been identified. However, their development is very dynamic and new pre-clinical models such as PDX models and 3D cultures of primary tumor material, as well as phase II clinical trials of targeted therapeutics, are driving this development, giving rise to the hope that these treatments have the potential to improve cure rates and reduce its effects.

The purpose of this Special Issue is to review the current developments in the field of molecular therapies, to highlight advances in the use of targeted drugs and immunotherapies, and to point out problems that still need to be solved for the treatment of pediatric tumors.

Prof. Dr. Günther H.S. Richter
Prof. Dr. Beat W. Schäfer
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. 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

  • leukemia
  • lymphoma
  • pediatric solid malignancies
  • targeted therapy
  • biomarker discovery
  • actionable mutations
  • drug vulnerabilities
  • combination therapy
  • immunotherapeutic approaches
  • preclinical studies

Published Papers (5 papers)

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Research

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17 pages, 1464 KiB  
Article
Opaganib Downregulates N-Myc Expression and Suppresses In Vitro and In Vivo Growth of Neuroblastoma Cells
by Lynn W. Maines, Staci N. Keller, Ryan A. Smith, Randy S. Schrecengost and Charles D. Smith
Cancers 2024, 16(9), 1779; https://doi.org/10.3390/cancers16091779 (registering DOI) - 05 May 2024
Viewed by 130
Abstract
Neuroblastoma (NB), the most common cancer in infants and the most common solid tumor outside the brain in children, grows aggressively and responds poorly to current therapies. We have identified a new drug (opaganib, also known as ABC294640) that modulates sphingolipid metabolism by [...] Read more.
Neuroblastoma (NB), the most common cancer in infants and the most common solid tumor outside the brain in children, grows aggressively and responds poorly to current therapies. We have identified a new drug (opaganib, also known as ABC294640) that modulates sphingolipid metabolism by inhibiting the synthesis of sphingosine 1-phosphate (S1P) by sphingosine kinase-2 and elevating dihydroceramides by inhibition of dihydroceramide desaturase. The present studies sought to determine the potential therapeutic activity of opaganib in cell culture and xenograft models of NB. Cytotoxicity assays demonstrated that NB cells, including cells with amplified MYCN, are effectively killed by opaganib concentrations well below those that accumulate in tumors in vivo. Opaganib was shown to cause dose-dependent decreases in S1P and hexosylceramide levels in Neuro-2a cells, while concurrently elevating levels of dihydroceramides. As with other tumor cells, opaganib reduced c-Myc and Mcl-1 protein levels in Neuro-2a cells, and also reduced the expression of the N-Myc protein. The in vivo growth of xenografts of human SK-N-(BE)2 cells with amplified MYCN was suppressed by oral administration of opaganib at doses that are well tolerated in mice. Combining opaganib with temozolomide plus irinotecan, considered the backbone for therapy of relapsed or refractory NB, resulted in increased antitumor activity in vivo compared with temozolomide plus irinotecan or opaganib alone. Mice did not lose additional weight when opaganib was combined with temozolomide plus irinotecan, indicating that the combination is well tolerated. Opaganib has additive antitumor activity toward Neuro-2a tumors when combined with the checkpoint inhibitor anti-CTLA-4 antibody; however, the combination of opaganib with anti-PD-1 or anti-PD-L1 antibodies did not provide increased antitumor activity over that seen with opaganib alone. Overall, the data demonstrate that opaganib modulates sphingolipid metabolism and intracellular signaling in NB cells and inhibits NB tumor growth alone and in combination with other anticancer drugs. Amplified MYCN does not confer resistance to opaganib, and, in fact, the drug attenuates the expression of both c-Myc and N-Myc. The safety of opaganib has been established in clinical trials with adults with advanced cancer or severe COVID-19, and so opaganib has excellent potential for treating patients with NB, particularly in combination with temozolomide and irinotecan or anti-CTLA-4 antibody. Full article
(This article belongs to the Special Issue Targeted Therapy of Pediatric Cancer)
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27 pages, 1688 KiB  
Article
L-Glyceraldehyde Inhibits Neuroblastoma Cell Growth via a Multi-Modal Mechanism on Metabolism and Signaling
by Martin Forbes, Richard Kempa, Guido Mastrobuoni, Liam Rayman, Matthias Pietzke, Safak Bayram, Birte Arlt, Annika Spruessel, Hedwig E. Deubzer and Stefan Kempa
Cancers 2024, 16(9), 1664; https://doi.org/10.3390/cancers16091664 - 25 Apr 2024
Viewed by 315
Abstract
Glyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which [...] Read more.
Glyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits neuroblastoma cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and 13C-labeling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in neuroblastoma cells. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. Analysis of nucleotide pools in L-GA-treated cells depicted a previously unreported observation, in which nucleotide biosynthesis is significantly inhibited. The inhibitory action of L-GA was partially relieved with the co-application of the antioxidant N-acetyl-cysteine. We present novel evidence for a simple sugar that inhibits cancer cell proliferation via dysregulating its fragile homeostatic environment. Full article
(This article belongs to the Special Issue Targeted Therapy of Pediatric Cancer)
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14 pages, 2047 KiB  
Article
Anti-PD-1 Therapy in Advanced Pediatric Malignancies in Nationwide Study: Good Outcome in Skin Melanoma and Hodgkin Lymphoma
by Agata Marjańska, Katarzyna Pawińska-Wąsikowska, Aleksandra Wieczorek, Monika Drogosiewicz, Bożenna Dembowska-Bagińska, Katarzyna Bobeff, Wojciech Młynarski, Katarzyna Adamczewska-Wawrzynowicz, Jacek Wachowiak, Małgorzata A. Krawczyk, Ninela Irga-Jaworska, Jadwiga Węcławek-Tompol, Krzysztof Kałwak, Małgorzata Sawicka-Żukowska, Maryna Krawczuk-Rybak, Anna Raciborska, Agnieszka Mizia-Malarz, Agata Sobocińska-Mirska, Paweł Łaguna, Walentyna Balwierz and Jan Styczyńskiadd Show full author list remove Hide full author list
Cancers 2024, 16(5), 968; https://doi.org/10.3390/cancers16050968 - 28 Feb 2024
Cited by 1 | Viewed by 911
Abstract
Background/aim: The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a [...] Read more.
Background/aim: The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a median age of 13.6 years, with various types of advanced malignancies treated in pediatric oncology centers in Poland between 2015 and 2023. Results: The indications for treatment with anti-PD1 were as follows: Hodgkin lymphoma (11); malignant skin melanoma (9); neuroblastoma (8); and other malignancies (14). At the end of follow-up, complete remission (CR) was observed in 37.7% (15/42) of children and disease stabilization in 9.5% (4/42), with a mean survival 3.6 (95% CI = 2.6–4.6) years. The best survival (OS = 1.0) was observed in the group of patients with Hodgkin lymphoma. For malignant melanoma of the skin, neuroblastoma, and other rare malignancies, the estimated 3-year OS values were, respectively, 0.78, 0.33, and 0.25 (p = 0.002). The best progression-free survival value (0.78) was observed in the group with malignant melanoma. Significantly better effects of immunotherapy were confirmed in patients ≥ 14 years of age and good overall performance ECOG status. Severe adverse events were observed in 30.9% (13/42) patients. Full article
(This article belongs to the Special Issue Targeted Therapy of Pediatric Cancer)
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21 pages, 6889 KiB  
Article
Inducing Mitotic Catastrophe as a Therapeutic Approach to Improve Outcomes in Ewing Sarcoma
by Soumya M. Turaga, Vikalp Vishwakarma, Stacey L. Hembruff, Benjamin K. Gibbs, Priya Sabu, Rajni V. Puri, Harsh B. Pathak, Glenson Samuel and Andrew K. Godwin
Cancers 2023, 15(20), 4911; https://doi.org/10.3390/cancers15204911 - 10 Oct 2023
Viewed by 1326
Abstract
Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including [...] Read more.
Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora kinase A (AURKA) and kinesin family member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical-grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911) given that phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥ 10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1–3%) and increased percentage accumulation of cells in the G2/M phase with the combination treatment (45–52%) upon cell cycle analysis, indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs. vehicle control (p ≤ 0.01), SB-743921 (p ≤ 0.01) and VIC-1911 (p ≤ 0.05). Kaplan–Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p ≤ 0.0001). Full article
(This article belongs to the Special Issue Targeted Therapy of Pediatric Cancer)
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Review

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27 pages, 2783 KiB  
Review
Functional Classification of Fusion Proteins in Sarcoma
by Marco Wachtel, Didier Surdez, Thomas G. P. Grünewald and Beat W. Schäfer
Cancers 2024, 16(7), 1355; https://doi.org/10.3390/cancers16071355 - 29 Mar 2024
Viewed by 1398
Abstract
Sarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin. More than 80 entities are associated with different mesenchymal lineages. Sarcomas with fibroblastic, muscle, bone, vascular, adipocytic, and other characteristics are distinguished. Nearly half of all entities contain specific chromosomal translocations that [...] Read more.
Sarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin. More than 80 entities are associated with different mesenchymal lineages. Sarcomas with fibroblastic, muscle, bone, vascular, adipocytic, and other characteristics are distinguished. Nearly half of all entities contain specific chromosomal translocations that give rise to fusion proteins. These are mostly pathognomonic, and their detection by various molecular techniques supports histopathologic classification. Moreover, the fusion proteins act as oncogenic drivers, and their blockade represents a promising therapeutic approach. This review summarizes the current knowledge on fusion proteins in sarcoma. We categorize the different fusion proteins into functional classes, including kinases, epigenetic regulators, and transcription factors, and describe their mechanisms of action. Interestingly, while fusion proteins acting as transcription factors are found in all mesenchymal lineages, the others have a more restricted pattern. Most kinase-driven sarcomas belong to the fibroblastic/myofibroblastic lineage. Fusion proteins with an epigenetic function are mainly associated with sarcomas of unclear differentiation, suggesting that epigenetic dysregulation leads to a major change in cell identity. Comparison of mechanisms of action reveals recurrent functional modes, including antagonism of Polycomb activity by fusion proteins with epigenetic activity and recruitment of histone acetyltransferases by fusion transcription factors of the myogenic lineage. Finally, based on their biology, we describe potential approaches to block the activity of fusion proteins for therapeutic intervention. Overall, our work highlights differences as well as similarities in the biology of fusion proteins from different sarcomas and provides the basis for a functional classification. Full article
(This article belongs to the Special Issue Targeted Therapy of Pediatric Cancer)
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