title: Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation.
abstract: In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3βHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M (etoposide, doxorubicin, cisplatin and mitotane) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively. In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC.
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hantel
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Shapiro
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Poli
authors.affiliation: Department of Surgery, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Costanza
authors.initials: C
authors.lastname: Chiapponi
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Michaela
authors.initials: M
authors.lastname: Luconi
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Jung
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism; D005047:Etoposide / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008939:Mitotane / Q000008:administration & dosage / Q000627:therapeutic use; D018396:Mucin-1 / Q000378:metabolism; D009368:Neoplasm Transplantation; D000072260:RNA Splicing Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D018396:Mucin-1; D000072260:RNA Splicing Factors; C491514:Sf1 protein, mouse; C577056:muc1 protein, mouse; D005047:Etoposide; D008939:Mitotane; D004317:Doxorubicin; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D002945:Cisplatin
keywords: adrenocortical carcinoma; cell line; clinical translation; patient-derived tumor-xenograft; preclinical animal model