The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology.

Abstract

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.

• Authors: Gail P Risbridger, Ashlee K Clark, Laura H Porter, Roxanne Toivanen, Andrew Bakshi, Natalie L Lister, David Pook, Carmel J Pezaro, Shahneen Sandhu, Shivakumar Keerthikumar, Rosalia Quezada Urban, Melissa Papargiris, Jenna Kraska, Heather B Madsen, Hong Wang, Michelle G Richards, Birunthi Niranjan, Samantha O'Dea, Linda Teng, William Wheelahan, Zhuoer Li, Nicholas Choo, John F Ouyang, Heather Thorne, Lisa Devereux, Rodney J Hicks, Shomik Sengupta, Laurence Harewood, Mahesh Iddawala, Arun A Azad, Jeremy Goad, Jeremy Grummet, John Kourambas, Edmond M Kwan, Daniel Moon, Declan G Murphy, John Pedersen, David Clouston, Sam Norden, Andrew Ryan, Luc Furic, David L Goode, Mark Frydenberg, Mitchell G Lawrence, Renea A Taylor
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 5049 (08 19 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34413304 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021. The Author(s).

Topics

• Animals
• Disease Models, Animal
• Drug Evaluation, Preclinical (methods)
• Genome
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Neoplasm Metastasis
• Organoids (metabolism, pathology)
• Prospective Studies
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Tissue Banks
• Transcriptome
• Xenograft Model Antitumor Assays