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Understanding treatment resistance and evaluating new therapies for pediatric ependymoma

Grant number: 18/25924-4
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): May 01, 2019
Effective date (End): April 30, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Luiz Gonzaga Tone
Grantee:Keteryne Rodrigues da Silva
Supervisor abroad: Raelene Endersby
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Telethon Kids Institute, Australia  
Associated to the scholarship:16/19799-7 - Research therapeutic targets from gene expression networks of members of the TGF-b pathway associated with tumor progression of ependymomas of worse prognosis, BP.DR

Abstract

Ependymoma (EPN) is the third most frequent brain tumor in children. This tumor is a heterogeneous disease, which can be classified into nine molecular subgroups. The ST-EPN-YAP1 and ST-EPN-RELA subgroups affect children, with RELA-positive subgroup specifically associated with poor prognosis and resistance to therapy. DNA methylation, an epigenetic alteration, has been shown to be an important mechanism for transcriptional inactivation of tumor suppressor genes and has been studied among molecular subgroups of EPN. Despite these studies, little is still known about the molecular mechanisms that determine differential behaviors and drug sensitivities in EPN cells. Some studies have shown that a DNA methylation inhibitor, decitabine, is a promising drug for the treatment of EPN. In the present project we aimed to test the efficacy of the combination of decitabine with gemcitabine in ST-EPN-RELA and ST-EPN-YAP mouse models. Furthermore, in order to better understand the molecular mechanism behind the aggressive tumor behavior and the treatment resistance of EPN, this project aims to perform molecular analyses of highly aggressive EPN through DNA/RNAseq and EPIC (DNA methylation) array techniques. We expect that this study will contribute to novel therapies for pediatric EPNs and to a better understanding of EPN biology.