Evaluation of loss of expression of MTAP as a strategy of response to therapy in brain tumors

• Grant number: 22/14702-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2023
• End date: April 30, 2024
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Lucas Tadeu Bidinotto
• Grantee: Gabriel Tadeu Heitor Canas
• Host Institution: Faculdade de Ciências da Saúde de Barretos Dr Paulo Prata (FACISB). Barretos , SP, Brazil

Abstract

Our research group found loss in regions of the short arm of chromosome 9 in a high percentage of patients diagnosed with glioma, where the MTAP gene is present. This gene encodes an enzyme essential for the recycling processes of adenine and methionine formed during the degradation of nucleotides. Studies have shown that the administration of MTA, a substrate of MTAP, has attenuated the toxicity of some drugs in cells that express this protein. The aim of the present project is to evaluate the effects of administration of MTA+2 fluoroadenine (2-FU) in nude mice that received xenograft of silenced cells for MTAP, and to compare this treatment with the standard treatment for GBM (temozolamide+radiotherapy). The MTAP gene will be silenced in U251MG cells by CRISPR/Cas9. Then, the IC50 of the combination MTA+2-FU and temozolamide will be determined to determine the dose that will be administered to mice. Finally, 48 mice will be distributed in 6 experimental groups (8 animals each). G1 to G3 will receive xenograft from MTAP+ cells (control), while G4 to G6 will receive MTAP- cells. Groups G1 and G4 will receive the vehicles of the studied drugs; G2 and G5 will receive i.p. temozolamide+radiotherapy; G3 and G6 will receive MTA+2-FU. The animals will be monitored by imaging equipment and euthanized after 8 days of experiment. Histological slides of brain tissue (tumor analysis) and other organs will be performed for toxicity analysis. The experimental groups will be compared in terms of tumor volume, histological analysis of tumors and toxicity.