title: Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma.
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.
authors.affiliation: Endocrine Research UnitMedizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Jung
authors.affiliation: 2nd Department of MedicineSemmelweis University, Faculty of Medicine, Budapest, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Nagy
authors.affiliation: Department of Internal Medicine IDivision of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany Comprehensive Cancer Center MainfrankenUniversity of Würzburg, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Department of PathologySt Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Zambetti
authors.affiliation: Institute of PathologyLudwig-Maximilians-University, Munich, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Weiss
authors.affiliation: Endocrine Research UnitMedizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.affiliation: 2nd Department of MedicineSemmelweis University, Faculty of Medicine, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Igaz
authors.affiliation: Endocrine Research UnitMedizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.affiliation: Endocrine Research UnitMedizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany Constanze.Hantel@med.uni-muenchen.de.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hantel
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy*; D018268:Adrenocortical Carcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor / Q000379:methods / Q000639:trends; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008081:Liposomes / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008939:Mitotane / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D057170:Translational Research, Biomedical / Q000379:methods / Q000639:trends; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D005047:Etoposide; D008939:Mitotane; D004317:Doxorubicin; D002945:Cisplatin
keywords: Caelyx; Lipoplatin; Myocet; NCI-H295R; SJ-ACC3; SW-13; adrenocortical carcinoma; liposomal cisplatin; liposomal doxorubicin; liposomal etoposide; microRNA-210; microRNA-483-5p