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Endocrine Abstracts (2019) 63 GP99 | DOI: 10.1530/endoabs.63.GP99

ECE2019 Guided Posters Adrenal and Neuroendocrine - Basic (14 abstracts)

Implementation of two preclinical ACC models for a comparative drug screen and initial mechanistic investigations

Ashish Sharma 1 , Igor Shapiro 1 , Pal Perge 2 , Peter Igaz 2 & Constanze Hantel 1,

1Department of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zürich, Zürich, Switzerland; 22nd Department of Medicine, Semmelweis University, Budapest, Hungary; 3Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.

Current systemic treatments are not satisfying for the treatment of adrenocortical carcinoma (ACC). However, translation of preclinically promising approaches were often disappointing indicating that existing tumor models might have inadequately predicted clinical applicability. Thus, our workgroup initiated a comparative drug screen of relevant chemotherapies and therapies targeting IGFR, EGFR, VEGFR/PDGFR and Wnt signalling pathway in the classical NCI-H295R and recently developed MUC-1 tumor model. BrdU-assay based investigation of cell-proliferation demonstrated significant anti-proliferative activity for almost all tested single agents and combinatory approaches (n=20) with more pronounced effects for classical chemotherapies. Subsequent analysis by MTT-assays revealed e.g. for Etoposide (E) and Cisplatin (P) the inhibition of cell viability of NCI-H295R cells in a highly significant (E 180 uM: 2.5%; P 160 uM: 17%) and dose-dependent manner, while even at extraordinary high drug concentrations cell viability remained high for MUC-1 (E 180 uM: 67%; P 160 uM: 70%, both P<0.001 vs NCI-H295R). Moreover, for single treatments with Doxorubicin (D), 9-cis-Retinoic acid (RA), Erlotinib (Erl), XAV-939 (X) and Isoquercitrin (I) we detected comparably low or even a complete lack of toxicity in either MUC-1 alone (for D and Erl) or both tumor models (for I). Of-note, Mitotane (M), Paclitaxel (PTX), Linsitinib (L), Sunitinib (S) and Sorafenib (SF) displayed overall improved toxicities. Interestingly, among combinatory approaches tested so far (such as EDP-M, S+M, S+ PTX, S+P, PTX + SF, P+ RA, PTX +G, G+P and P+ PTX), additive reduction of cellular viability and diminished clonogenicity was observed with treatment of G+P in both tumor models (P<0.001). Additionally, P+ PTX displayed most promising anti-tumoral efficacy and reduced clonogenicity in both tumor models among all tested drug combinations (P<0.001). Mechanistically, G alone induced a dose-dependent increase in expression of, both RRM1 and RRM2, genes that are involved in the development of clinically relevant G-resistance. Interestingly, in combination with either P or PTX these effects were significantly reversed down to basal levels or even below (NCI-H295R RRM1, G: 791% P<0.001; G+P: 188%; RRM2, G: 336% P<0.001; G+P: 60% and in MUC-1 RRM1, G: 275% P<0.01; G+P: 97%; RRM2, G: 474% P<0.01; G+P: 175%; vs. 100% controls). Of note, also siRNA-mediated RRM2 silencing alone led to a significant decrease of cell count in both tumor models (P<0.001). In summary, our findings indicate that a combination of both tumor models might help to identify potentially new drug combinations for the treatment of ACC.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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