Bioinformatics investigation of Rho GTPase pathway regulators in the multiple therapeutic resistance phenotype in glioblastoma multiforme tumors

• Grant number: 25/06603-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2025
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Fábio Luis Forti
• Grantee: Lucas Farhat Silveira Soubihe
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 24/13597-0 - Chemo and radioresistance of glioblastomas: the role of DUSP12 phosphatase and Rho GTPase, AP.R

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and frequently diagnosed type of brain tumor among glioma subtypes. Treatments begin with radiotherapy and chemotherapy and, when possible, surgical resection of the tumor, either prior to or as an adjuvant to these treatments. In addition to gamma ionizing radiation (IR), the main drug used in chemotherapy against these tumors is temozolomide (TMZ), which induces alkylation of DNA bases that are extremely toxic to cells. However, tumor recurrence is common in GBM patients, and when it occurs, tumor cells become resistant to previously used treatments. Various alternative therapies and strategies to minimize acquired resistance in these cells primarily involve the modulation of DNA recognition, signaling, and repair mechanisms. Previous studies from our group have shown that GBM cells resistant to chemo- and radiotherapy are sensitive to the inhibition of the Rho GTPase pathway and actin cytoskeleton dynamics, which can reverse the multidrug resistance phenotype of these cells. This project aims to investigate whether and how regulators of the Rho GTPase pathway, such as GAPs, GEFs, and GDIs, affect the survival and proliferation of both normal GBM cells and multidrug-resistant GBM cells with distinct mechanisms of action, as well as their response to gamma ionizing radiation. From this, we seek to analyze the correlation between resistance acquired through different therapeutic agents and the modulation of the Rho GTPase pathway in patient-derived glioblastoma samples, which has been identified as a potential therapeutic target for tumor sensitization. A deeper understanding of these regulatory proteins and their combination with new therapies that sensitize and/or inhibit tumor progression is a clinically relevant challenge in GBM treatment.