Karkampouna, Sofia; La Manna, Federico; Benjak, Andrej; Kiener, Mirjam; De Menna, Marta; Zoni, Eugenio; Grosjean, Joël; Klima, Irena; Garofoli, Andrea; Bolis, Marco; Vallerga, Arianna; Theurillat, Jean-Philippe; De Filippo, Maria R.; Genitsch, Vera; Keller, David; Booij, Tijmen H; Stirnimann, Christian U; Eng, Kenneth; Sboner, Andrea; Ng, Kiu Yan Charlotte; ... (2021). Patient-derived xenografts and organoids model therapy response in prostate cancer. Nature communications, 12(1), p. 1117. 10.1038/s41467-021-21300-6
|
Text
Tha_Patient_derived_xenografts_and_organoids_model_therapy_response_in_prostate_cancer.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (4MB) | Preview |
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.
Actions (login required)
 |
Edit item |