Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity
Manzella, Gabriele; Schreck, Leonie D; Breunis, Willemijn B; Molenaar, Jan; Merks, Hans; Barr, Frederic G; Sun, Wenyue; Römmele, Michaela; Zhang, Luduo; Tchinda, Joelle; Ngo, Quy A; Bode, Peter; Delattre, Olivier; Surdez, Didier; Rekhi, Bharat; Niggli, Felix K; Schäfer, Beat W; Wachtel, Marco
(2020) Nature Communications, volume 11, issue 1
(Article)
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
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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.
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Keywords: 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, Rhabdomyosarcoma/drug therapy, Tumor Cells, Cultured/drug effects, Xenograft Model Antitumor Assays
ISSN: 2041-1723
Publisher: Nature Publishing Group
(Peer reviewed)
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