Patient-derived xenografts and organoids model therapy response in prostate cancer

Sofia Karkampouna, Federico La Manna, Andrej Benjak, Mirjam Kiener, Marta De Menna, Eugenio Zoni, Joël Grosjean, Irena Klima, Andrea Garofoli, Marco Bolis, Arianna Vallerga, Jean-Philippe Theurillat, Maria R. De Filippo, Vera Genitsch, David Keller, Tijmen H. Booij, Christian U. Stirnimann, Kenneth Eng, Andrea Sboner, Charlotte K. Y. Ng, Salvatore Piscuoglio, Peter C. Gray, Martin Spahn, Mark A. Rubin, George N. Thalmann and Marianna Kruithof- de Julio ()
Additional contact information
Sofia Karkampouna: University of Bern
Federico La Manna: University of Bern
Andrej Benjak: University of Bern
Mirjam Kiener: University of Bern
Marta De Menna: University of Bern
Eugenio Zoni: University of Bern
Joël Grosjean: University of Bern
Irena Klima: University of Bern
Andrea Garofoli: University of Basel
Marco Bolis: Università della Svizzera italiana
Arianna Vallerga: Università della Svizzera italiana
Jean-Philippe Theurillat: Università della Svizzera italiana
Maria R. De Filippo: University of Bern
Vera Genitsch: University of Bern
David Keller: ETH Zurich
Tijmen H. Booij: ETH Zurich
Christian U. Stirnimann: ETH Zurich
Kenneth Eng: Weill Cornell Medicine
Andrea Sboner: Weill Cornell Medicine
Charlotte K. Y. Ng: University of Bern
Salvatore Piscuoglio: University of Basel
Peter C. Gray: The Salk Institute for Biological Studies
Martin Spahn: Lindenhofspital
Mark A. Rubin: University of Bern
George N. Thalmann: University of Bern
Marianna Kruithof- de Julio: University of Bern

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21300-6

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DOI: 10.1038/s41467-021-21300-6

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