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

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.

• Authors: 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, Marco Wachtel
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4629 (09 15 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32934208 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Biological Specimen Banks
• Drug Screening Assays, Antitumor (methods)
• Gene Expression Profiling
• Humans
• Phenotype
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• Rhabdomyosarcoma (drug therapy, genetics, metabolism)
• Tumor Cells, Cultured (drug effects)
• Xenograft Model Antitumor Assays