Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity

Gabriele Manzella, Leonie D. Schreck, Willemijn B. Breunis, Jan Molenaar, Hans Merks, Frederic G. Barr, Wenyue Sun, Michaela Römmele, Luduo Zhang, Joelle Tchinda, Quy A. Ngo, Peter Bode, Olivier Delattre, Didier Surdez, Bharat Rekhi, Felix K. Niggli, Beat W. Schäfer () and Marco Wachtel
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Gabriele Manzella: University Children’s Hospital, Department of Oncology and Children’s Research Center
Leonie D. Schreck: University Children’s Hospital, Department of Oncology and Children’s Research Center
Willemijn B. Breunis: University Children’s Hospital, Department of Oncology and Children’s Research Center
Jan Molenaar: Princess Máxima Center for Pediatric Oncology
Hans Merks: Princess Máxima Center for Pediatric Oncology
Frederic G. Barr: Center for Cancer Research, National Cancer Institute
Wenyue Sun: Center for Cancer Research, National Cancer Institute
Michaela Römmele: University Children’s Hospital, Department of Oncology and Children’s Research Center
Luduo Zhang: University Children’s Hospital, Department of Oncology and Children’s Research Center
Joelle Tchinda: University Children’s Hospital, Department of Oncology and Children’s Research Center
Quy A. Ngo: University Children’s Hospital, Department of Oncology and Children’s Research Center
Peter Bode: University Hospital Zurich, Institute of Surgical Pathology
Olivier Delattre: France INSERM U830, Équipe Labellisé LNCC, PSL Université, SIREDO Oncology Centre, Institut Curie
Didier Surdez: France INSERM U830, Équipe Labellisé LNCC, PSL Université, SIREDO Oncology Centre, Institut Curie
Bharat Rekhi: Tata Memorial Hospital, Department of Pathology
Felix K. Niggli: University Children’s Hospital, Department of Oncology and Children’s Research Center
Beat W. Schäfer: University Children’s Hospital, Department of Oncology and Children’s Research Center
Marco Wachtel: University Children’s Hospital, Department of Oncology and Children’s Research Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.

Date: 2020
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DOI: 10.1038/s41467-020-18388-7

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