EYES2023 ESE Young Endocrinologists and Scientists (EYES) 2023 Oral communication 3: Adrenal Tumors and Neuroendocrine Tumors (7 abstracts)
Preclinical and clinical evidence of progesterone/megestrol acetate activity in metastatic adrenocortical carcinoma
Mariangela Tamburello 1 , Andrea Abate 1 , Antonella Turla 2 , Marta Laganà 2 , Elisa Rossini 1 , Constanze Hantel 3,4 , Guido Alberto Massimo Tiberio 5 , Deborah Cosentini 2 , Salvatore Grisanti 2 , Alfredo Berruti 2 & Sandra Sigala 1
1Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; 2Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili di Brescia, Brescia, Italy; 3Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zürich, Switzerland; 4Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany; 5Surgical Clinic, Department of Clinical and Experimental Sciences, University of Brescia at ASST Spedali Civili di Brescia, Brescia, Italy.
Background: Adrenocortical carcinoma (ACC) is a rare cancer for which available systemic treatments, mitotane ± etoposide, doxorubicin and cisplatin (EDP-M), have limited efficacy.
Objectives: Here, we strengthen the effect of progesterone (Pg) on metastatic ACC cell lines, studying whether it could influence growth, invasiveness, and metastasis formation. Additionally, we investigate if the Pg analogue megestrol-acetate administered with EDP-M could improve its tolerability and efficacy in advanced ACC patients.
Methods: NCI-H295R, MUC-1, and TVBF-7 ACC cell lines were used. Apoptosis and cell cycle were analyzed by flow cytometry. Cell migration and invasiveness were studied using transwell assays, and metalloprotease 2 (MMP2) activity by zymography. Cell xenografts in Danio rerio embryos were performed measuring both the tumor areas and the number of embryos with metastasis. Metastatic ACC patients (pts) with low-performance status (PS) were treated with EDP-M+ oral megestrol-acetate (EDP-MM) (n=24). Toxicity and efficacy of EDP-MM were compared with EDP-M administered to a control group of 48 patients.
Results: Pg exerted a cytotoxic effect, that was maintained after drug withdrawal, inducing apoptosis and changes in cell cycle distribution in NCI-H295R and MUC-1 cells. Pg significantly reduced the xenograft area of each ACC cell line, and metastasis formation in embryos injected with MUC-1 and TVBF-7, confirming the in vitro results. This phenomenon is mediated at least in part by the reduction of MMP2 levels. Treatment with megestrol-acetate was overall well tolerated: 54.2% of EDP-MM pts developed progestin-related toxicities; 16.7% discontinued megestrol-acetate for toxicity. Clinical benefit rate was 75.0% vs 60.4% in EDP-MM and EDP-M pts, respectively. Progression-free survival and overall survival curves were similar in both groups.
Conclusions: Our results support the use of progestins in ACC. The efficacy of megestrol-acetate in reducing ACC progression in patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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