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

• Published in: Endocrine-related cancer Vol. 23; no. 10; pp. 825 - 837
• Main Authors: Jung, Sara, Nagy, Zoltan, Fassnacht, Martin, Zambetti, Gerard, Weiss, Max, Reincke, Martin, Igaz, Peter, Beuschlein, Felix, Hantel, Constanze
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.10.2016
• Subjects: Adrenal Cortex Neoplasms - drug therapy; Adrenocortical Carcinoma - drug therapy; Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Cisplatin - administration & dosage; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Drug Carriers; Drug Delivery Systems; Drug Screening Assays, Antitumor - methods; Drug Screening Assays, Antitumor - trends; Etoposide - administration & dosage; Female; Humans; Liposomes - therapeutic use; Male; Mice; Mice, Nude; Middle Aged; Mitotane - administration & dosage; Polyethylene Glycols - administration & dosage; Translational Medical Research - methods; Translational Medical Research - trends; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; microRNA-210; SW-13; liposomal cisplatin; liposomal etoposide; Lipoplatin; NCI-H295R; liposomal doxorubicin; microRNA-483-5p; adrenocortical carcinoma; SJ-ACC3; Myocet; Caelyx
• ISSN: 1351-0088; 1479-6821
• DOI: 10.1530/ERC-16-0249

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 , liposomal EDP-M regimens represent promising treatment options to improve clinical treatment of ACC.