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

View ORCID ProfileSofia Karkampouna, View ORCID ProfileFederico La Manna, View ORCID ProfileMaria R. De Filippo, View ORCID ProfileMirjam Kiener, Marta De Menna, View ORCID ProfileEugenio Zoni, Joël Grosjean, Irena Klima, Andrea Garofoli, Marco Bolis, View ORCID ProfileJean-Philippe Theurillat, Vera Genitsch, David Keller, Tijmen H. Booij, Christian U. Stirnimann, View ORCID ProfileKenneth Eng, Andrea Sboner, View ORCID ProfileCharlotte K. Y. Ng, View ORCID ProfileSalvatore Piscuoglio, Gray PC, Martin Spahn, View ORCID ProfileMark A. Rubin, George N. Thalmann, View ORCID ProfileMarianna Kruithof-de Julio
doi: https://doi.org/10.1101/2020.03.17.994350
Sofia Karkampouna
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
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  • ORCID record for Sofia Karkampouna
Federico La Manna
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
2Department of Urology, Leiden University Medical Center, Leiden, the Netherlands
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Maria R. De Filippo
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
3Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
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Mirjam Kiener
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
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Marta De Menna
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
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Eugenio Zoni
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
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Joël Grosjean
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
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Irena Klima
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
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Andrea Garofoli
3Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
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Marco Bolis
4Institute of Oncology Research, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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Jean-Philippe Theurillat
4Institute of Oncology Research, Università della Svizzera italiana, 6500 Bellinzona, Switzerland
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Vera Genitsch
5Institute of Pathology, University of Bern, Murtenstrasse 31, Bern 3008, Switzerland
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David Keller
6NEXUS Personalized Health Technologies, ETH Zurich, 8093 Zurich, Switzerland
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Tijmen H. Booij
6NEXUS Personalized Health Technologies, ETH Zurich, 8093 Zurich, Switzerland
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Christian U. Stirnimann
6NEXUS Personalized Health Technologies, ETH Zurich, 8093 Zurich, Switzerland
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Kenneth Eng
7Department of Physiology and Biophysics, Institute for Precision Medicine and Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, USA
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Andrea Sboner
8Department of Pathology and Laboratory Medicine, Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, USA
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Charlotte K. Y. Ng
9Department for BioMedical Research, Oncogenomics Laboratory, University of Bern, Bern, Switzerland
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Salvatore Piscuoglio
3Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
10Visceral surgery research laboratory, Clarunis, Department of Biomedicine, University of Basel, Basel, Switzerland
11Clarunis Universitäres Bauchzentrum Basel, Basel, Switzerland
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Gray PC
12ScienceMedia Inc, 8910 University Center Ln Suite 400, San Diego, CA, 92122, USA
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Martin Spahn
13Lindenhofspital Bern, Switzerland
14Department of Urology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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Mark A. Rubin
15Department for BioMedical Research, Precision Oncology Laboratory, University of Bern, Bern, Switzerland
16Bern Center for Precision Medicine, University of Bern and Inselspital, Bern, Switzerland
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George N. Thalmann
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
17Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland
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Marianna Kruithof-de Julio
1Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland
17Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland
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  • ORCID record for Marianna Kruithof-de Julio
  • For correspondence: marianna.kruithofdejulio@dbmr.unibe.ch
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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 a novel 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 harbours 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 modelled 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.

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Posted March 18, 2020.
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Patient-derived xenografts and organoids model therapy response in prostate cancer
Sofia Karkampouna, Federico La Manna, Maria R. De Filippo, Mirjam Kiener, Marta De Menna, Eugenio Zoni, Joël Grosjean, Irena Klima, Andrea Garofoli, Marco Bolis, Jean-Philippe Theurillat, Vera Genitsch, David Keller, Tijmen H. Booij, Christian U. Stirnimann, Kenneth Eng, Andrea Sboner, Charlotte K. Y. Ng, Salvatore Piscuoglio, Gray PC, Martin Spahn, Mark A. Rubin, George N. Thalmann, Marianna Kruithof-de Julio
bioRxiv 2020.03.17.994350; doi: https://doi.org/10.1101/2020.03.17.994350
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Patient-derived xenografts and organoids model therapy response in prostate cancer
Sofia Karkampouna, Federico La Manna, Maria R. De Filippo, Mirjam Kiener, Marta De Menna, Eugenio Zoni, Joël Grosjean, Irena Klima, Andrea Garofoli, Marco Bolis, Jean-Philippe Theurillat, Vera Genitsch, David Keller, Tijmen H. Booij, Christian U. Stirnimann, Kenneth Eng, Andrea Sboner, Charlotte K. Y. Ng, Salvatore Piscuoglio, Gray PC, Martin Spahn, Mark A. Rubin, George N. Thalmann, Marianna Kruithof-de Julio
bioRxiv 2020.03.17.994350; doi: https://doi.org/10.1101/2020.03.17.994350

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