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Investigation of the Molecular basis of adrenocortical tumors and search for new therapeutic targets.

Abstract

Background: To date, there is no effective adjuvant treatment for patients with advanced or recurrent adrenocortical carcinomas (ACC). A good knowledge of the molecular abnormalities involved in this process is crucial to determine molecular prognostic markers and to discover new and individualized therapeutically targets. Aim: To investigate the role of the Wnt/beta-catenin, SHH, Vitamin D/VDR, mTOR and the YAP1/Hippo pathways on adrenal steroidogenesis and on tumorigenesis in pediatric and adult ACC and ACC cell lines. In addition, to evaluate the antitumor effects of drugs targeting these pathways on a xenograft mouse model (in vivo). Material and Methods: We will evaluate the expression pattern of genes involved in the Vitamin D/VDR, mTOR, YAPI/via Hippo and the WNT pathways in fetal and postnatal normal adrenals and in pediatric and adult ACTs and their association with clinical characteristics and outcome. In immortalized cell line (H295A) and in ACC secondary cultures, we will perform gene silencing by RNAi or pharmacological modulation in components of these pathways to evaluate these effects on cell viability, cell proliferation, gene expression, apoptosis, cell cycle, cell invasion and epithelial-mesenchymal transition and on adrenal steroidogenesis. In addition, using the H295A cell line we will develop a xenograft mouse model of ACC we will test in vivo the antitumor effects of drugs targeting some of these molecular pathways.Perspectives: To gain insights into adrenal tumorigenesis process and to find novel therapeutic targets. Key-words: adrenocortical tumorigenesis, steroidogenesis, Wnt/beta-catenin, SHH, Vitamin D, mTOR, YAP. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
STECCHIN, MONICA F.; BRAID, ZILDA; MORE, CANDY B.; ARAGON, DAVI C.; CASTRO, MARGARET; MOREIRA, AYRTON C.; ANTONINI, SONIR R. Gonadotropin-dependent pubertal disorders are common in patients with virilizing adrenocortical tumors in childhood. ENDOCRINE CONNECTIONS, v. 8, n. 5, p. 579-589, MAY 2019. Web of Science Citations: 2.

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