Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models.
To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy.
NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models.
Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test.
Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity.
Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms.
In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).
European urology oncology. 2023 Oct 26 [Epub ahead of print]
Ludovic Bigot, Jonathan Sabio, Loic Poiraudeau, Maxime Annereau, Naoual Menssouri, Carole Helissey, Olivier Déas, Marine Aglave, Tony Ibrahim, Cédric Pobel, Catline Nobre, Claudio Nicotra, Maud Ngo-Camus, Ludovic Lacroix, Etienne Rouleau, Lambros Tselikas, Jean-Gabriel Judde, Anne Chauchereau, Alice Bernard-Tessier, Anna Patrikidou, Natacha Naoun, Ronan Flippot, Emeline Colomba, Alina Fuerea, Laurence Albiges, Pernelle Lavaud, Christophe Massard, Luc Friboulet, Karim Fizazi, Benjamin Besse, Jean-Yves Scoazec, Yohann Loriot
Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, Inserm U981, Gustave Roussy Cancer, Université Paris-Saclay, Villejuif, France., Pharmacy, Gustave Roussy, Université Paris-Saclay, Villejuif, France., Clinical Research Unit, Department of Oncology, Military Hospital Begin, Saint-Mandé, France., XenTech, Evry, France., Plateforme de Bioinformatique, Gustave Roussy, Villejuif, France., Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France., Experimental and Translational Pathology Platform (PETRA), Genomic Platform - Molecular Biopathology Unit (BMO) and Biological Resource Center, AMMICA, INSERM, Villejuif, France; Department of Medical Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France., Department of Interventional Radiology, Gustave Roussy Cancer Campus, Villejuif, France., Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France., Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, Inserm U981, Gustave Roussy Cancer, Université Paris-Saclay, Villejuif, France; Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France., Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, Inserm U981, Gustave Roussy Cancer, Université Paris-Saclay, Villejuif, France; Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France; Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. Electronic address: .