|Title||Patient-derived xenografts and organoids model therapy response in prostate cancer.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Karkampouna S, La Manna F, Benjak A, Kiener M, De Menna M, Zoni E, Grosjean J, Klima I, Garofoli A, Bolis M, Vallerga A, Theurillat J-P, De Filippo MR, Genitsch V, Keller D, Booij TH, Stirnimann CU, Eng K, Sboner A, K Y Ng C, Piscuoglio S, Gray PC, Spahn M, Rubin MA, Thalmann GN, de Julio MKruithof-|
|Date Published||2021 02 18|
|Keywords||Androgens, Antineoplastic Agents, Genome, Human, Humans, Male, Models, Biological, Mutation, Neoplasm Metastasis, Organoids, Prostatic Neoplasms, Transcriptome, Xenograft Model Antitumor Assays|
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.
|Alternate Journal||Nat Commun|
|PubMed Central ID||PMC7892572|
Andrea Sboner, Ph.D.