Pediatric tumors are a field of oncology that has always had special attention that needs no explanation. Tumors such as neuroblastoma and medulloblastoma are among the most frequent tumors of the nervous system in children and basic research is making great strides in understanding the molecular defects affecting these types of cancer. For example, it has been understood that among the thousands of transcription factors that regulate the gene expression of these tumors, there are some that become preferential and that confer an advantage to malignant cells. FOXR2 (Forkhead Box R2) is a transcription factor belonging to a large family of highly conserved FOX proteins, known for their role in regulating gene expression and in a wide range of cellular functions. Normally expressed only in the testis, FOXR2 has been identified as an epigenetically activated oncogene in many tumors.
More recent studies indicate that FOXR2 could be implicated in a wider range of tumors of the central nervous system. These studies have highlighted the involvement of FOXR2 in pineoblastoma (PIB), medulloblastoma (MEB) and high-grade glioma (HIG) subtypes. Interested in understanding more about the regulation of this protein in pediatric nerve tumors, a team of researchers at St. Jude Children’s Hospital performed a detailed molecular and histopathological investigation. The scientists first examined the downstream effects of FOXR2 activation in CNS tumors at the level of DNA methylation by comparing the DNA methylome profiles of FOXR2-overexpressing tumors in their pediatric cohort (n=30 with sufficient data quality) with those of brain tumors without FOXR2 activation (n=25).
In particular, the analysis results suggested the activation of the c-Myc proto-oncogene and ETS family transcription factors (ELK1, ETS1, ELF2, ELF5, GABPA, GABPB2, NRF2. DIDO1 and EPC1) in FOXR2-overexpressing brain tumors. The downstream genes of FOXR2 have a wide range of functions, including RNA metabolism (RBM10, ELAVL2), transcriptional regulation (BCoR, FAM156A), epigenetic modification (KMT5B, MED13L), proteasome system (RNF144A, USP51, MARCHF6, TBL1XR1), neural development (NLGN4X, ZC4H2) and cell signaling (TAB2, ITFG1, CHM). The researchers’ findings support the hypothesis that FOXR2-overexpressing brain tumors exhibit diverse histopathological, molecular, and clinical features, indicating that FOXR2 alterations are not pathognomonic only for FOXR2-positive neuroblastoma.
In contrast, a broad spectrum of brain gliomas, including diffuse median glioma (DMG), embryonal tumors of the central nervous system (neuroblastoma, medulloblastoma, pinealoblastoma, and pilocytic astrocytoma), and parenchymal pinealoma of intermediate differentiation (PPTID), can harbor FOXR2 activation. The study also reveals a unique enrichment of radiation-induced malignant gliomas with FOXR2 activation, a finding not previously reported. The finding that both the MYC signaling pathway and ETS transcription factors are commonly activated in FOXR2-overexpressing brain tumors may offer a unique therapeutic opportunity. Concomitant alterations in diffuse median gliomas and high-grade gliomas with overexpression of FOXR2 (including BRAF, PDGFRA, EGFR, FGFR1, NRAS, PIK3CA, PTEN and ACVR1), offer additional therapeutic opportunities.
Pharmacological inhibitors of several of these genetranscs (or rather of their protein translations) already exist and can, therefore, find further repositioning in the treatment of pediatric brain tumors, as well as in tumors external to the nervous system. It should be remembered that these molecules are part of the family of “inibs” (e.g. erlotinib, gefitinib, crizotinib and others) which represent the new generation “targeted therapy” with fewer side effects than conventional chemotherapy. This point is particularly in favor of children in the lower pediatric age group (3-10 years) who have not yet reached complete brain development.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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