Journal Article

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

Benjak, Andrej, Eng, Kenneth, Rubin, Mark A., Kiener, Mirjam, Bolis, Marco, Zoni, Eugenio, Grosjean, Joël, Sboner, Andrea, Thalmann, George N., Keller, David, Booij, Tijmen H., Spahn, Martin, Klima, Irena, La Manna, Federico, Stirnimann, Christian U., Garofoli, Andrea, Ng, Charlotte K. Y., Vallerga, Arianna, Gray, Peter C., Kruithof-de Julio, Marianna, Karkampouna, Sofia, Genitsch, Vera, De Filippo, Maria R., Piscuoglio, Salvatore, De Menna, Marta, Theurillat, Jean-Philippe

2021

Overview

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. To date, patients still succumb to cancer, due to tumors not responding to therapy or ultimately acquiring resistance. Here the authors show that by exploiting patient derived organoids and a treatment-naïve patient derived xenograft, patient therapy can be personalized.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/100 / 13/106 / 13/31 / 14/1 / 14/19 / 45/23 / 45/91 / 49/47 / 49/56 / 49/88 / 49/90 / 631/532/71 / 631/67/589/466 / 631/67/70 / 64/60 / 692/4028/67/2322 / Androgens - metabolism / Antineoplastic Agents - therapeutic use / BRCA2 protein / Breast cancer / Gene sequencing / Genome, Human / Humanities and Social Sciences / Humans / Inhibitor drugs / Male / Metastases / Metastasis / Microsatellite instability / Models, Biological / multidisciplinary / Mutation / Mutation - genetics / Neoplasm Metastasis / Organoids / Organoids - pathology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Prostatic Neoplasms - therapy / Ribonucleic acid / RNA / Science / Science (multidisciplinary) / Soft tissues / Therapy / Transcriptome - genetics / Transcriptomics / Tumors / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation