Endocrine Abstracts

Overexpression and aberrant activation of the insulin-like growth factor system plays a key role in tumor cell proliferation and tumorigenesis in many human tumors. Different therapies targeting IGF1-receptor (IGF1-R) have been developed and currently, some of these agents are evaluated in preclinical and early clinical trials with promising results. Moreover, recent studies have demonstrated that combined treatments with doxorubicin, enhance the efficiency of anti-IGF1-R ther...

IntroductionAdrenocortical Carcinoma (ACC) is a rare aggressive cancer which carries a poor prognosis. Adjuvant mitotane improves survival but is limited by poor response rates and resistance following tumour recurrence. Mitotane’s efficacy has been attributed to intracellular accumulation of toxic free cholesterol (FC) predominantly through inhibition of cholesterol storage through SOAT1. Yet SOAT1 specific inhibitors demonstrate inferior efficacy ...

Adrenocortical carcinoma (ACC) is a rare aggressive cancer with poor survival. Adjuvant mitotane is the only approved drug for treatment of ACC. It improves survival but its use is limited by poor tolerability and drug resistance. For metastatic ACC, combination chemotherapy, using mitotane and etoposide, doxorubicin, and cisplatin improves survival, but efficacy is limited. Better understating the cytotoxic mechanisms of mitotane offers potential to develop improved therapeut...

Adrenocortical carcinoma (ACC) is a rare malignancy with dismal prognosis. Deregulated microRNA (miRNA) expression has been implicated in ACC aggressiveness. Nevertheless, the mechanisms underlying such deregulations remain unknown. Aberrant Wnt/β-Catenin signaling has been reported in about 40% of ACC and is associated with poor outcome. In the present work, we aimed to investigate the link between constitutive activation of Wnt/β-Catenin pathway and miRNA expressio...

Background: Adrenocortical carcinoma (ACC) is a rare aggressive cancer with limited treatment options for advanced stages. By targeted RNA expression screening, we identified polo-like kinase 1 (PLK1) as one of most overexpressed genes, thus representing a potential drug target for ACC. PLK1 inhibitors are under evaluation in clinical trials for other solid cancers and seem to be more effective in TP53 mutated tumours. The aim of the study was to evaluate PLK1 protein levels i...

Background: Mitotane is the only approved treatment for advanced adrenocortical carcinoma and was shown to inhibit Sterol-O-Acyl transferase 1 (SOAT1) which leads to the depletion of cholesterol esters and increase of free cholesterol in the ACC cell line H295R. Downstream activation of the endoplasmic reticulum stress (ER-stress) pathway results in decreased adrenocortical cell viability.Aim: To better characterize the effects of SOAT1 inhibition in ACC...

Although primary aldosteronism (PA) is considered to be the most prevalent cause of secondary hypertension the underlying genetic mechanisms have been elucidated only for the rare familial forms of the disease. In an attempt to define novel genetic loci involved in the pathophysiology of PA a phenotype-driven mutagenesis screening after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. The aldosterone values ...

According to recent studies, primary aldosteronism is considered to be responsible for almost 10% of all cases of arterial hypertension. The genetic background of this common disease, however, has been elucidated only for the rare familial types whereas in the large majority of sporadic cases it still remains unclear. In an attempt to define novel genetic mechanisms of hyperaldosteronism we utilized a random mutagenesis screen after treatment with the alkylating agent N...

Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. We identified polo-like kinase 1 (PLK1) as one of the most overexpressed genes and potential drug target in ACC. PLK1 inhibitors (PLK1i) are under evaluation in clinical trials for other malignancies, being more effective in TP53-mutated tumours. Here we test PLK1i efficacy in four ACC cell lines with different genetic background. Efficacy of three PLK1i (i.e. Volaserti...

Adrenocortical carcinoma (ACC) is a rare malignancy associated with a poor prognosis (1). Current treatments are limited with surgical resection the only option for a complete cure (2). The development of translational therapies is limited by pre-clinical disease models. Three-dimensional (3D) cell culture models can accurately reflect the tumour micro-environment but are lacking in ACC (3). In the current study, we developed and characterised novel 3D models of MUC-1, HAC15 a...