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Nuclear actin and Rho GTPases as targets for sensitization of radio and chemoresistant glioblastoma in Zebrafish and mice animal models

Grant number: 22/12337-9
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): April 01, 2023
Effective date (End): March 31, 2025
Field of knowledge:Biological Sciences - Genetics - Mutagenesis
Principal Investigator:Fábio Luis Forti
Grantee:Yuli Thamires Magalhães
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Glioblastoma (GBM) is the most incident and malignant glial tumor, and its high resistance to usual therapies contributes to its poor prognosis. Molecular analyzes have identified a high frequency of mutations in Rho GTPase pathway and actin cytoskeleton organization genes that seem to contribute to the maintenance of glioma stem cell (GSC) properties and to the infiltration of adjacent brain tissue. Within this context, four relevant questions were raised about the unexplored biology of the Rho GTPase pathway and actin cytoskeleton organization in GBMs: i) its role in therapeutic resistance and, therefore, as a potential target in the treatment of relapsed tumors; ii) the effectiveness of F-actin depolymerizing drugs in GBM sensitizing to conventional therapy; iii) the role of nuclear actin in this context; and iv) its relationship with the maintenance of the population of GSCs. Therefore, the general goal of this project is to prove the efficacy of the Rho pathway inhibition and the destabilization of the actin cytoskeleton for the treatment of GBM resistant to radio and chemotherapy. As study models, cultures of immortalized GBM cells and GSCs in vitro or xenotransplanted in Zebrafish and immunodeficient mice will be used. The sensitization of GBM cells will be evaluated after Rho inhibition together with genotoxic stress in both animal models, analyzing tumor development and survival and health of the animals, where they will finally be analyzed histologically for different stemness markers, from death, proliferation and signaling of DNA damage and repair after different treatments with radio and chemotherapy. With these methodologies, we will seek to prove the efficiency of inhibitors of the Rho/actin pathway as potential therapeutic clinical agents, sensitizing and improving the prognosis of GBM tumors resistant to usual therapies.

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