IDO1 inhibitor and anti IL-23 as a therapy for in vitro renal cell Carcinoma

• Grant number: 21/13304-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2021
• End date: November 30, 2022
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Leandro Machado Colli
• Grantee: Letícia Helena Kaça do Carmo
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 20/10960-5 - Renal cancer genetic susceptibility, AP.JP

Abstract

Kidney cancer is responsible for more than 400,000 new diagnoses and 175,000 deaths annually. The most common form of this cancer is the Renal Cell Carcinoma - RCC-, which comprises a heterogeneous group of tumors originated by the epithelial cells of the renal tubules, the main subtype being the Clear Cell Carcinoma - ccRCC. The treatment of the RCC has undergone major changes over the past two decades. In addition to advances in immunotherapy, inhibitors of important pathways for the tumor microenvironment have been developed. In this context, the enzyme IDO1 stands out, which mediates acquired immunosuppression leading to local and systemic immunological tolerance in relation to the tumor, helping it to escape immunological surveillance. This is due to the depletion of tryptophan in the tumor microenvironment, which results in T cell anergy and inhibition of natural killer cell activity. IDO1 is correlated with poor prognosis, increased tumor progression, and reduced survival in RCC. Several IDO1 inhibitors have been developed, the most prominent being indoximod. This drug acts in the resuscitation of the mTORC1 protein complex with greater potency than L-tryptophan replacement itself. Despite the encouraging results, no studies have been performed to assess the therapeutic response of indoximod in RCC. In this project, we propose to study the effect of indoximod on tumor growth and progression when used in combination with anti-IL-23. Such cytokine, already studied in our laboratory, according to recent articles, would be related to the activation of regulatory T cells despiting of cytotoxic T cells in the tumor microenvironment, similarly promoting the escape of the immune system and the progression of cancer.(AU)