Oncotarget

Research Papers:

Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation

Constanze Hantel _, Igor Shapiro, Giada Poli, Costanza Chiapponi, Martin Bidlingmaier, Martin Reincke, Michaela Luconi, Sara Jung and Felix Beuschlein

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:79292-79304. https://doi.org/10.18632/oncotarget.12685

Metrics: PDF 935 views  |   HTML 955 views  |   ?  


Abstract

Constanze Hantel1, Igor Shapiro1, Giada Poli3, Costanza Chiapponi2, Martin Bidlingmaier1, Martin Reincke1, Michaela Luconi3, Sara Jung1, Felix Beuschlein1

1Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany

2Department of Surgery, Ludwig-Maximilians-Universität, Munich, Germany

3Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

Correspondence to:

Constanze Hantel, email: Constanze.Hantel@med.uni-muenchen.de

Keywords: adrenocortical carcinoma, patient-derived tumor-xenograft, preclinical animal model, cell line, clinical translation

Abbreviations: ACC: adrenocortical carcinoma; STR: short tandem repeat; PDTX: patient derived tumor xenografts

Received: August 16, 2016    Accepted: September 22, 2016    Published: October 15, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 12685