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Endocr Relat Cancer. 2016 Oct;23(10):825-37. doi: 10.1530/ERC-16-0249. Epub 2016 Aug 22.

Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma.

Author information

1
Endocrine Research UnitMedizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany.
2
2nd Department of MedicineSemmelweis University, Faculty of Medicine, Budapest, Hungary.
3
Department of Internal Medicine IDivision of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany Comprehensive Cancer Center MainfrankenUniversity of Würzburg, Würzburg, Germany.
4
Department of PathologySt Jude Children's Research Hospital, Memphis, Tennessee, USA.
5
Institute of PathologyLudwig-Maximilians-University, Munich, Germany.
6
Endocrine Research UnitMedizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany Constanze.Hantel@med.uni-muenchen.de.

Abstract

Systemic therapy of adrenocortical carcinoma (ACC) is limited by heterogeneous tumor response and adverse effects. Recently, we demonstrated anti-tumor activity of LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane), a liposomal variant of EDP-M (etoposide, doxorubicin, cisplatin, mitotane). To improve the therapeutic efficacy and off-target profiles of the clinical gold standard EDP-M, we investigated liposomal EDP-M regimens in different preclinical settings and in a small number of ACC patients with very advanced disease. Short- and long-term experiments were performed on two ACC models (SW-13 and SJ-ACC3) in vivo We evaluated the anti-tumoral effects and off-target profiles of EDP-M, LEDP-M and a novel regimen L(l)EDP-M including liposomal etoposide. Furthermore, the role of plasma microRNA-210 as a therapeutic biomarker and first clinical data were assessed. Classical and liposomal protocols revealed anti-proliferative efficacy against SW-13 (EDP-M P < 0.01; LEDP-M: P < 0.001; L(l)EDP-M: P < 0.001 vs controls), whereas in SJ-ACC3, only EDP-M (P < 0.05 vs controls) was slightly effective. Long-term experiments in SW-13 demonstrated anti-tumor efficacy for all treatment schemes (EDP-M: P < 0.01, LEDP-M: P < 0.05, L(l)EDP-M P < 0.001 vs controls). The analysis of pre-defined criteria leading to study termination revealed significant differences for control (P < 0.0001) and EDP-M (P = 0.003) compared to L(l)EDP-M treatment. Raising its potential for therapy monitoring, we detected elevated levels of circulating microRNA-210 in SW-13 after LEDP-M treatment (P < 0.05). In contrast, no comparable effects were detectable for SJ-ACC3. However, overall histological evaluation demonstrated improved off-target profiles following liposomal regimens. The first clinical data indicate improved tolerability of liposomal EDP-M, thus confirming our results. In summary, liposomal EDP-M regimens represent promising treatment options to improve clinical treatment of ACC.

KEYWORDS:

Caelyx; Lipoplatin; Myocet; NCI-H295R; SJ-ACC3; SW-13; adrenocortical carcinoma; liposomal cisplatin; liposomal doxorubicin; liposomal etoposide; microRNA-210; microRNA-483-5p

PMID:
27550961
DOI:
10.1530/ERC-16-0249
[Indexed for MEDLINE]

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