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adrenocortical carcinoma (ACC) is limited by heterogeneous tumor response and adverse effects. Recently, we demonstrated anti-tumor activity for LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane), a liposomal variant of EDP-M (etoposide, doxorubicin, cisplatin, mitotane). To improve 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 anti-tumoral effects and off-target profiles of EDP-M, LEDP-M as well as a novel regimen L(l)EDP-M including liposomal etoposide. Furthermore, plasma microRNA-210 as therapeutic biomarker and first clinical data were assessed. Liposomal protocols revealed highest anti-proliferative efficacy against SW-13 (EDP-M p<0.01; LEDP-M: p<0.001; L(l)EDP-M: p<0.001 versus controls), while in SJ-ACC3 only EDP-M (p<0.05 versus controls) was slightly effective. Long-term experiments demonstrated in SW-13 anti-tumor efficacy for all treatment schemes (EDP-M: p<0.01, LEDP-M: p<0.05, L(l)EDP-M p<0.001 versus controls). L(l)EDP-M improved furthermore overall survival compared to controls (p<0.0001) and EDP-M (p=0.003). 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. Confirming our results, first clinical data indicate improved tolerability of liposomal EDP-M. 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