Pediatric Cancer: From Molecular Targets to Effective Therapies

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

Deadline for manuscript submissions: closed (26 May 2024) | Viewed by 8170

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Guest Editor
Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Interests: pediatric cancer; molecular target; nanomedicine; precision therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There is a long-standing and multifaceted need to develop more efficacious and less toxic therapies for patients with pediatric cancer, which is the leading cause of disease-related death in children and adolescents. Importantly, along with aiming to increase the 5-year survival rates, efforts must made to guarantee many decades of healthy life for these children. Extensive genomic sequencing of tumors undertaken in the last 10–15 years has revealed new molecular targets and is expected to establish more precision-based therapeutic approaches. These targets should allow more research on uncovering the mechanism of drug action and drug resistance and, therefore, enhanced rational drug combinations leading to clinical trials. Combining molecularly targeted therapeutics with drug delivery systems (nanoparticles, antibody-drug conjugates (ADC), bispecific T-cell engaging antibodies, etc.) has been successful in recent years, and further development of this approach is warranted to achieve lower systemic toxicity for better therapies.

Dr. Raushan Kurmasheva
Guest Editor

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Keywords

  • pediatric cancer
  • molecular target
  • nanomedicine
  • precision therapy
  • molecular targets

Published Papers (6 papers)

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Research

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26 pages, 4121 KiB  
Article
Synergistic Antitumor Activity of Talazoparib and Temozolomide in Malignant Rhabdoid Tumors
by Elena Mironova, Sebastian Molinas, Vanessa Del Pozo, Abhik M. Bandyopadhyay, Zhao Lai, Dias Kurmashev, Eric L. Schneider, Daniel V. Santi, Yidong Chen and Raushan T. Kurmasheva
Cancers 2024, 16(11), 2041; https://doi.org/10.3390/cancers16112041 - 28 May 2024
Viewed by 394
Abstract
Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 [...] Read more.
Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4)—a pivotal component of the SWI/SNF chromatin remodeling complex—is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss of SMARCB1 was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response. Full article
(This article belongs to the Special Issue Pediatric Cancer: From Molecular Targets to Effective Therapies)
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12 pages, 1457 KiB  
Article
Extracranial Germ Cell Tumors in Children: Ten Years of Experience in Three Children’s Medical Centers in Shanghai
by Shayi Jiang, Kuiran Dong, Kai Li, Jiangbin Liu, Xin Du, Can Huang, Yangyang Jiao, Yali Han, Jingwei Yang, Xuelian Liao, Yanhua Li, Ting Zhang, Shanshan Li, Zhibao Lv and Yijin Gao
Cancers 2023, 15(22), 5412; https://doi.org/10.3390/cancers15225412 - 14 Nov 2023
Cited by 1 | Viewed by 811
Abstract
Objective: The aim was to describe the clinical features of extracranial germ cell tumors (GCTs) in pediatrics and study the clinical risk factors related to survival for malignant germ cell tumors (MGCTs) in order to optimize therapeutic options. Methods: The clinical data of [...] Read more.
Objective: The aim was to describe the clinical features of extracranial germ cell tumors (GCTs) in pediatrics and study the clinical risk factors related to survival for malignant germ cell tumors (MGCTs) in order to optimize therapeutic options. Methods: The clinical data of children with extracranial GCTs in three children’s medical centers in Shanghai were retrospectively analyzed. Results: In total, 1007 cases of extracranial GCTs diagnosed between 2010 and 2019 were included in this study, including teratomas (TERs) 706 (70.11%) and MGCTs 301 (29.89%). There were twice as many TER cases as MGCT cases. Approximately 50% of children with GCTs were <3 years old (43.39% for TERs, 67.13% for MGCTs). GCTs in children of different ages show differences in tumor anatomical locations and pathological subtypes. The 5-year event-free survival (EFS) and overall survival (OS) of all patients with MGCTs were 82.33% (95% CI, 77.32%, 86.62%) and 94.13% (95% CI, 90.02%, 96.69%), respectively. The multivariate Cox regression analysis identified a primary site in the mediastinum and alpha fetoprotein (AFP) levels ≥10,000 ng/mL as independent adverse prognostic factors (p < 0.0.0001, χ2 = 23.6638, p = 0.0225, χ2 = 5.2072.). There were no significant differences in OS among children receiving various chemotherapy regimens, such as the BEP, PEB, JEB and other regimens (VBP/VIP and AVCP/IEV) (p < 0.05). Conclusions: The clinical features of GCTs in Chinese pediatrics are similar to those reported in children in Europe and America. The age distribution of pathological types and primary sites in GCTs reflect the developmental origin of type I and type II GCTs transformed from mismigration primordial germ cells (PGCs). Optimizing the current platinum-based chemotherapy regimens and exploring the treatment strategies for MGCTs of the mediastinum are future research directions. Full article
(This article belongs to the Special Issue Pediatric Cancer: From Molecular Targets to Effective Therapies)
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19 pages, 4382 KiB  
Article
Integrative Transcriptomic Profiling of the Wilms Tumor
by Simona Lucija Avčin, Klementina Črepinšek, Barbara Jenko Bizjan, Robert Šket, Jernej Kovač, Blaž Vrhovšek, Jerca Blazina, Olga Blatnik, Robert Kordič, Lidija Kitanovski, Janez Jazbec, Maruša Debeljak and Tine Tesovnik
Cancers 2023, 15(15), 3846; https://doi.org/10.3390/cancers15153846 - 28 Jul 2023
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Abstract
Our study aimed to identify relevant transcriptomic biomarkers for the Wilms tumor, the most common pediatric kidney cancer, independent of the histological type and stage. Using next-generation sequencing, we analyzed the miRNA profiles of 74 kidney samples, which were divided into two independent [...] Read more.
Our study aimed to identify relevant transcriptomic biomarkers for the Wilms tumor, the most common pediatric kidney cancer, independent of the histological type and stage. Using next-generation sequencing, we analyzed the miRNA profiles of 74 kidney samples, which were divided into two independent groups: fresh frozen tissue and formalin-fixed paraffin-embedded tissue samples. Subsequent mRNA expression profiling and pathway analysis were performed to establish the interplay and potential involvement of miRNAs and mRNA in the Wilms tumor. Comparative analysis, irrespective of post-dissection tissue processing, revealed 41 differentially expressed miRNAs, with 27 miRNAs having decreased expression and 14 miRNAs having increased expression in the Wilms tumor tissue compared to healthy kidney tissue. Among global mRNA transcriptomic profile differences, cross-sectional analysis suggested a limited list of genes potentially regulated by differentially expressed miRNAs in the Wilms tumor. This study identified the comprehensive miRNA and mRNA profile of the Wilms tumor using next-generation sequencing and bioinformatics approach, providing better insights into the pathogenesis of the Wilms tumor. The identified Wilms tumor miRNAs have potential as biomarkers for the diagnosis and treatment of the Wilms tumor, regardless of histological subtype and disease stage. Full article
(This article belongs to the Special Issue Pediatric Cancer: From Molecular Targets to Effective Therapies)
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Review

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28 pages, 2706 KiB  
Review
The PAX Genes: Roles in Development, Cancer, and Other Diseases
by Taryn Shaw, Frederic G. Barr and Aykut Üren
Cancers 2024, 16(5), 1022; https://doi.org/10.3390/cancers16051022 - 29 Feb 2024
Viewed by 1305
Abstract
Since their 1986 discovery in Drosophila, Paired box (PAX) genes have been shown to play major roles in the early development of the eye, muscle, skeleton, kidney, and other organs. Consistent with their roles as master regulators of tissue formation, the PAX [...] Read more.
Since their 1986 discovery in Drosophila, Paired box (PAX) genes have been shown to play major roles in the early development of the eye, muscle, skeleton, kidney, and other organs. Consistent with their roles as master regulators of tissue formation, the PAX family members are evolutionarily conserved, regulate large transcriptional networks, and in turn can be regulated by a variety of mechanisms. Losses or mutations in these genes can result in developmental disorders or cancers. The precise mechanisms by which PAX genes control disease pathogenesis are well understood in some cases, but much remains to be explored. A deeper understanding of the biology of these genes, therefore, has the potential to aid in the improvement of disease diagnosis and the development of new treatments. Full article
(This article belongs to the Special Issue Pediatric Cancer: From Molecular Targets to Effective Therapies)
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22 pages, 4046 KiB  
Review
PRMT5 as a Potential Therapeutic Target in MYC-Amplified Medulloblastoma
by Devendra Kumar, Stuti Jain, Don W. Coulter, Shantaram S. Joshi and Nagendra K. Chaturvedi
Cancers 2023, 15(24), 5855; https://doi.org/10.3390/cancers15245855 - 15 Dec 2023
Cited by 1 | Viewed by 1840
Abstract
MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Recently, protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with tumorigenic MYC functions in cancers, particularly in brain cancers such [...] Read more.
MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Recently, protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with tumorigenic MYC functions in cancers, particularly in brain cancers such as glioblastoma and medulloblastoma. PRMT5 regulates oncogenes, including MYC, that are often deregulated in medulloblastomas. However, the role of PRMT5-mediated post-translational modification in the stabilization of these oncoproteins remains poorly understood. The potential impact of PRMT5 inhibition on MYC makes it an attractive target in various cancers. PRMT5 inhibitors are a promising class of anti-cancer drugs demonstrating preclinical and preliminary clinical efficacies. Here, we review the publicly available preclinical and clinical studies on PRMT5 targeting using small molecule inhibitors and discuss the prospects of using them in medulloblastoma therapy. Full article
(This article belongs to the Special Issue Pediatric Cancer: From Molecular Targets to Effective Therapies)
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18 pages, 711 KiB  
Review
Strategy for Pediatric Patients with Relapsed or Refractory Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma: A Review
by Kazuhiro Noguchi and Yasuhiro Ikawa
Cancers 2023, 15(24), 5733; https://doi.org/10.3390/cancers15245733 - 7 Dec 2023
Cited by 1 | Viewed by 1652
Abstract
Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a [...] Read more.
Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody–drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL. Full article
(This article belongs to the Special Issue Pediatric Cancer: From Molecular Targets to Effective Therapies)
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