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

Sofia Karkampouna, et al.

Go to the profile of Nature Communications
Mar 18, 2020
0
0

Received Date: 15th January 20

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 Booij, Christian Stirnimann, Kenneth Eng, Andrea Sboner, Charlotte KY Ng, Salvatore Piscuoglio, Peter C Gray, Martin Spahn, Mark A Rubin, George N Thalmann, Marianna Kruithof-de Julio

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.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Go to the profile of Nature Communications

Nature Communications

Nature Research, Springer Nature