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

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

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology

UniBE Contributor:

Karkampouna, Sofia; La Manna, Federico; Benjak, Andrej; Kiener, Mirjam Susanna; De Menna, Marta; Zoni, Eugenio; Grosjean, Joël; Klima, Irena; De Filippo, Maria Rosaria; Genitsch Gratwohl, Vera; Ng, Kiu Yan Charlotte; Piscuoglio, Salvatore; Rubin, Mark Andrew; Thalmann, George and Kruithof-de Julio, Marianna

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

2041-1723

Language:

English

Submitter:

Jeannine Wiemann

Date Deposited:

13 Oct 2021 14:46

Last Modified:

13 Oct 2021 14:46

Publisher DOI:

10.1038/s41467-021-21300-6

PubMed ID:

33602919

BORIS DOI:

10.48350/159674

URI:

https://boris.unibe.ch/id/eprint/159674

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