Analysis of tryptophanyl tRNA synthetase (WARS) as a potential prognostic marker and therapeutic target in Bladder Cancer

• Grant number: 22/15575-8
• Support Opportunities: Regular Research Grants
• Duration: February 01, 2024 - January 31, 2026
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Humberto Dellê
• Grantee: Humberto Dellê
• Host Institution: Universidade Nove de Julho (UNINOVE). Campus Vergueiro. São Paulo , SP, Brazil
• Associated researchers: Henrique Roman Ramos

Abstract

Bladder cancer (BC) is one of the most common neoplasms in the world, and its non-muscle invasive form (NMIBC) is treated with resection followed by instillation with BCG. Many types of cancer produce the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which, by modulating the immune system, protects the tumor, favoring its progression. In addition to having been identified in NMICBC, IDO1 can be induced by BCG through interferon-gamma (IFN-gamma), making it special in this type of neoplasia. When IDO1 is expressed, it degrades tryptophan from the microenvironment, producing kynurenine catabolites. This situation blocks the local immune response, but does not affect the IDO1-producing cell itself. The mechanisms for this resistance remain unknown, but there is evidence that stores are generated by the enzyme tryptophanyl tRNA synthetase (WARS), which loads tRNA with the amino acid, ensuring protein synthesis and the cell proliferation. In this way, the inhibition of WARS1 can end the resistance of neoplastic cells producing IDO1, leading them to death. The objective of the project is to verify whether the WARS1 and IDO1 molecules are related to the pathophysiology of BC, and whether the inhibition of WARS1 can open therapeutic perspectives. The present study will have two phases. In the first, the expression of IDO1 and WARS molecules in human specimens of BC will be analyzed in order to verify the relationship between these molecules and clinicopathological data. In the second phase, the relationship between molecules and BCG in the BC will be investigated, working with chemical and molecular inhibition of the enzymes, in established cell lines of BC and normal urothelium. Two strategies for inhibition of WARS will be evaluated, tryptamine and siRNA, carried or not by exosomes. The results of this project may open important perspectives for the prognosis and treatment of BC. (AU)