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Study of aurora kinases as potential biomarkers and its correlation with PKA dysfunction in adrenocortical tumors

Grant number: 15/23713-8
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): October 24, 2016
Effective date (End): October 23, 2017
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Luiz Gonzaga Tone
Grantee:Andrea Gutierrez Maria
Supervisor abroad: Constantine A. Stratakis
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : National Institutes of Health, Bethesda (NIH), United States  
Associated to the scholarship:14/16839-2 - Study of pathways involved in Aurora kinases signaling and mechanisms of action of the inhibitor AMG 900 in adrenocortical tumor, BP.PD

Abstract

Adrenocortical carcinomas are relatively rare tumors. However, a mutation in the TP53 gene, commonly found in Southern Brazil, increases the predisposition to the disease. There are no effective therapies for advanced stage adrenocortical carcinomas, which leads to a low survival index for patients with stage IV tumors. Therefore, discovery of new therapeutic targets and new methods for early diagnosis of the disease is of great importance for adrenocortical carcinoma treatment. Several studies suggest that the dysregulation of Aurora kinases might be strongly associated with tumorigenesis. A study performed by our laboratory showed that the treatment of adrenocortical carcinoma cell lineage with the pan Aurora kinase inhibitor, AMG 900, decreases cell proliferation and hormone synthesis. PKA is an important enzyme that controls cortisol hormone secretion and activates Aurora kinase A phosphorylating its T288 residue. Studies have shown that PKA dysregulation is associated with adrenocortical tumorigenesis. Thus, the aim of this study is to investigate the correlation of PKA dysregulation with the activity of Aurora kinases and to investigate the latter as potential markers for diagnosis and prognosis of adrenocortical tumors. We intend to analyze the differential expression levels of Aurora kinases in different grades of adrenocortical tumors by immunohistochemistry and to correlate patients who have PKA dysfunction with Aurora kinase activity. Also, we intend to inhibit and stimulate PKA/cAMP in H295R and CAR47 adrenocortical tumor cells to further investigate the activity of Aurora kinases. Considering that Aurora kinases are highly expressed in tumor cells, studying these kinases and their activity in adrenocortical tumor might be an effective tool for new strategies for diagnosis of adrenocortical and other tumor models in clinics. Moreover, the achieved data might allow us to establish a general strategy to effectively predict survival in patients with adrenocortical tumors as well as to correlate PKA dysfunction, which has been already shown to be a potent regulator of adrenocortical tumorigenesis, with Aurora kinase activity. This work will be done with the collaboration of Dr. Constantine Stratakis and his staff at the Section on Endocrinology and Genetics, NICHD, NIH. Dr. Stratakis' laboratory has been extensively studying the PKA system in adrenocortical diseases and has a great record of publication in this area. (AU)

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