Induction of the resistance to chemotherapy phenotype after prolonged treatment of glioblastoma organoids with Temozolomide

• Grant number: 23/14178-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2024
• End date: December 31, 2024
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Oswaldo Keith Okamoto
• Grantee: Gustavo Sartorelli de Carvalho Rego
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID

Abstract

Glioblastoma (GBM) is the most common type of central nervous system tumors, and its patients have an extremely low survival rate. One of the factors responsible for this is the inefficacy of available therapies, among which the drug Temozolomide (TMZ) stands out. This chemotherapy drug saw its use solidified after being adopted as a standard treatment protocol. Its cytotoxicity arises from its ability to induce methylations in the nitrogenous base Guanine. These alterations activate cellular mechanisms for DNA repair, but they are unable to correct them and eventually lead to DNA chain breaks. However, more than half of the tumors manage to develop resistance to TMZ through various mechanisms. In parallel to that, a model that has gained relevance in the study of GBMs is Glioblastoma Organoids (GBO), which can replicate the heterogeneity and complexity of the tumor microenvironment with greater fidelity. This makes them a very interesting model for studying the development of resistance. With this in mind, the present project aims to make GBOs resistant to TMZ through prolonged treatment with the chemotherapy drug and then compare their viability and death with that of untreated GBOs when subjected to a TMZ dose-response curve.