Novel Molecular Targets and Therapies for Pediatric Extracranial Solid Tumors

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About this Research Topic

Submission deadlines

  1. Manuscript Submission Deadline 30 December 2024

  2. This Research Topic is still accepting articles.

Background

Although the outcome of childhood solid cancers has improved over the last few decades, the main line of therapy still relies on conventional treatments, including DNA-damaging agents, and radiotherapy, neither of which address the underlying disease mechanisms, and in turn have significant short- and long-term toxicities, which can limit optimal dosing. Furthermore, some pediatric cancers, such as relapsed neuroblastoma and rhabdomyosarcoma, remain difficult to treat using conventional approaches and carry significant morbidity and mortality. Therefore, it is imperative to explore proteins and signaling pathways that act as drivers of disease, thereby identifying potential drug targets and pharmaceutical agents that could provide novel and selective treatment options.

The advent of genomic sequencing has enabled the discovery of potential driver mutations in many childhood and adult cancers, including new mutations and clonal changes that arise in relapsed disease, thus paving the way for personalized and targeted treatment. There has been an exponential growth in scientific publications about molecular disease mechanisms and new targets for childhood cancers, leading to preclinical testing of promising compounds. Unfortunately, this revolutionary change has yet to reach the clinic, and pediatric oncologists still struggle with the paucity of new agents and treatment options.

The introduction of new drugs into clinical practice in pediatric oncology faces many challenges, including the difficulty of recruitment into clinical trials due to small patient numbers, and the unknown safety profiles of drugs in children. Nevertheless, repurposing of compounds already approved for treatment in adults can significantly speed up the drug development process. Several drugs have reached clinical trials for childhood cancers, such as the ALK inhibitor lorlatinib, already approved for use in lung cancer in adults, being introduced in front-line treatment of neuroblastoma. Similarly, the tyrosine kinase inhibitor regorafenib has entered clinical trials for rhabdomyosarcoma and the MDM2 inhibitor idasanutlin is being trialled for neuroblastoma. Immunotherapies have come to the forefront of emerging treatment options. Dinutuximab, targeting GD2, has become a front-line treatment in neuroblastoma, while other modalities of immunotherapy, including CAR-T cells, are also in the development pipeline.

Some oncogenes, like MYCN, have a strong association with poor prognosis and a well-established causal link to pathogenesis, yet there has been limited success in directly targeting this transcription factor for therapeutic intervention. Although inhibition of transcription factors remains challenging, characterizing the oncogenic network around this oncoprotein enabled the discovery of a few promising “druggable” candidates, including SIRT2, Aurora kinase A, and PRMT5, which can affect the stability of the MYCN protein, or downstream effectors, like ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme involved in polyamine synthesis. The ODC1 inhibitor DMFO is now in clinical trials for neuroblastoma.

Despite these recent advances, personalized treatment options are scarce in childhood and adolescent cancers. This research topic focuses on the emergence of molecular targets and small molecule inhibitors that may lead to the development of novel targeted therapies for pediatric extracranial solid tumors, such as embryonal solid tumors, including neuroblastoma and Wilms’ tumor, as well as bone and soft tissue sarcomas. We welcome original scientific publications and reviews characterizing novel molecular targets, mechanisms of tumorigenesis, and small molecule inhibitors for these and other solid tumors in children and adolescents.

Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.

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Keywords: Neuroblastoma, Wilms’ tumour, Targeted therapy, Bone sarcomas, Soft tissue sarcomas, Small molecule inhibitors, Tumorigenesis

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