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Evaluation of prognostic factors of adrenal cortex tumors and predictors of response to treatment with mitotane in carcinomas

Grant number: 17/26345-5
Support type:Regular Research Grants
Duration: September 01, 2018 - August 31, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Maria Candida Barisson Villares Fragoso
Grantee:Maria Candida Barisson Villares Fragoso
Home Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Madson Queiroz Almeida ; Maria Cláudia Nogueira Zerbini

Abstract

Adrenal cortex carcinoma (CCS) is a rare and extremely aggressive malignant neoplasm. The southern and southeastern regions of Brazil are characterized by a significantly higher incidence of this condition in the pediatric population, which is 10 to 15 times higher than the global incidence due to the high prevalence of a specific germinative allelic variant in the TP53 gene (R337H). In the last two decades this condition has been the target of numerous studies; these have resulted in substantial advances in the knowledge of the molecular and genomic mechanisms involved in the pathogenesis of CCS. In this context, the involvement of ATRX and ZNRF3 genes in CCS tumorigenesis has been demonstrated. On the other hand, in relation to the treatment of CCS, no effective target therapy has been introduced so far, with therapeutic alternatives being limited. Mitotane, the only approved drug for the treatment of CCS, remains the cornerstone in the treatment of these patients and a better selection of patients through the prediction of the efficacy of this medication is necessary. In recent years, in vivo and in vitro studies have suggested that RRM1 gene expression and SOAT1 expression may influence the mitotane response. The most efficient prediction of the evolution of patients with this condition will enable them to be classified into distinct subgroups in relation to the aggressiveness of the disease, as well as to enable the selection of patients for the use of mitotane based on molecular factors predictive of the efficacy of this drug. The objectives of this project are, in an adult and pediatric cohort of CCS and pediatric adrenal tumors: 1) To evaluate ATRX deletions and the gene expression of ZNRF3; 2) To evaluate the influence of variations in the immunoexpression pattern of the SOAT1 and RRM1 proteins on the response to treatment with mitotane, in the adjuvant setting and in the context of the treatment of advanced disease in this same cohort, and 3) To correlate the above findings with disease-free survival and overall survival. With this project we hope to determine the prognostic importance of the genetic alterations in the ATRX and ZNRF3 in this cohort and to develop new tools to aid in the therapeutic decisions regarding mitotane in patients with CCS. (AU)