Endocrine Abstracts

Recently, we demonstrated for adrenocortical carcinoma (ACC) promising antitumoural effects for LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane) a novel liposomal variant of the classical EDP-M protocol (etoposide, doxorubicin, cisplatin, mitotane). However, clinical translation of novel therapeutic regimens remains challenging due to high tumor heterogeneity. Thus, to obtain preclinical results with more clinically predictive power we investigated for the first time LEDP-M in three different xenograft models for ACC in vivo. Moreover, we included liposomal etoposide resulting in a novel treatment scheme called L(l)EDP-M. After one therapeutic cycle NCI-H295R, SW-13 and SJ-ACC3 tumours were excised and immunohistochemically (cells/high power fields (HPF)) analysed regarding total number of tumor cells (Ki67 positive and negative/HPF) and apoptosis (TUNEL positive cells/HPF). In previous experiments on NCI-H295R xenografts we detected a significant reduction in overall tumor cell count for LEDP-M which was in the current study not reached by L(l)EDP-M. In contrast, regarding apoptosis L(l)EDP-M (P<0.01) led to a further improvement of therapeutic efficacy as compared with LEDP-M (P<0.05 vs controls). In SW-13 xenografts, the number of tumor cells decreased in all treatment schemes with highest therapeutic efficacy of the liposomal variants (EDP-M: 20.5±1.6 P<0.01; LEDP-M: 17.2±1.3 P<0.001; L(l)EDP-M: 14.7±0.9 P<0.001) vs. controls (28.9±2.2). In addition, most distinctive necrosis was detectable for L(l)EDP-M followed by LEDP-M, EDP-M and controls. In SJ-ACC3 xenografts a decrease in tumor cell number was found only following EDP-M treatment (30.3±1.2 vs controls 35.9±1.3, P<0.05). In summary, these data indicate that liposomal regimens could represent promising treatment options for clinical translation for adult, but not for pediatric ACC. However, our results also show that tumor heterogeneity should be taken into account in preclinical studies.