Patient derived organoids to model rare prostate cancer phenotypes

TLDR

Rare tumors such as neuroendocrine prostate cancer lack preclinical models, limiting research into this aggressive variant. The study generated and characterized organoids from needle biopsies of four metastatic neuroendocrine prostate cancer lesions to probe the role of EZH2 in disease progression. Organoids were derived from the biopsies, profiled genomically, transcriptomically, and epigenomically, and then subjected to high‑throughput drug screening. The organoids recapitulated the patient tumors’ molecular profiles and identified single agents and combinations for repurposing, validating the platform for rare prostate cancer research.

Abstract

Abstract A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes.