NFkB inhibition as a therapeutic alternative for ZFTA/RELA positive ependymoma

• Grant number: 21/11870-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2022
• End date: December 31, 2023
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: María Sol Brassesco Annichini
• Grantee: David Bastos Santos
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Ependymoma (EPN) is a primary tumor of the Central Nervous System that presents a reddish-gray and well-defined coloration, being categorized as a solid tumor. Even though its origin is still under discussion, it is believed that it originates from glial ependymal cells, while it has also been suggested that an origin is from glial stem cells. EPN has a wide possibility of distribution within the brain, and it occurs anywhere along the spinal cord and cerebral ventricular system. These tumors are very rare in adults, while in children the annual incidence of comprises about 2 cases per million in Western countries, making it the third most recurrent brain tumor in pediatric populations. Despite its low incidence, progress in the treatment of this disease has decreased over the years, for a number of factors, including the variability in the extension and localization of the tumor. Treatment is based on surgical resection, followed by adjuvant radiotherapy. However, the survival of children affected by EPN is still disappointing, with 5-year overall survival (OS) estimated as 50% to 85%, while the 5-year event-free survival (EFS) is even lower (between 23% to 70%). Such problems with regard to worse prognosis, treatment, and high local recurrence of the tumor expose the need to study new therapies for EPN, especially a variant characterized by the ZFTA-RELA gene fusion, as this is correlated with worse prognosis. This gene fusion results in a chimeric protein between RELA (the main effector of the NF-kB canonical signaling) and ZFTA (which is an uncharacterized gene). Interestingly, the dysregulation of the transcription factor NF-kB (nuclear factor Kappa B) is associated with multiple aspects of the oncogenesis process, configuring itself as a promising target for new therapies. Currently, several NF-kB inhibitors have already been developed, among them those obtained by the research group of Professor Umezawa (Department of Target-Directed Medicine, University of Aichi - Japan), including DHMEQ and SEMBL. From this perspective, this project proposes to analyze the effects of these synthetic inhibitors, on the NF-kB pathway, in the Ependymoma BXD-1425 cell line, through in vitro assays, thus aiming for a better life perspective for patients affected by the disease.(AU)