New treatments are required for advanced prostate cancer; however, there are fewer preclinical models of prostate cancer than other common tumour types to test candidate therapeutics. One opportunity to increase the scope of preclinical studies of single drugs or combination treatments is to grow tissue from patient-derived xenografts (PDXs) as organoid cultures. Here we report a scalable pipeline for automated seeding, treatment, and analysis of growth and drug synergy in organoids of prostate cancer.
We successfully established organoid cultures from five PDXs with diverse phenotypes of prostate cancer, including castrate-sensitive versus castrate-resistant disease, and adenocarcinoma versus neuroendocrine pathology. We robotically embedded organoids in Matrigel in 384-well plates, and monitored growth via brightfield microscopy, before treatment with the PARP inhibitor talazoparib for up to 12 days. Using bulk and single-organoid readouts of growth, including metabolic activity and live-cell imaging-based features, we showed that most tumours were resistant to talazoparib, as expected. Single-organoid analyses showed significant decreases in organoid area, and Hoechst staining texture and intensity, in a tumour that was sensitive to PARP inhibitors. In addition, we performed combination treatment with talazoparib and CX-5461, a small molecule that induces DNA damage, and measured reductions in organoid size, density (Hoechst intensity), uniformity (Hoechst texture), and metabolic activity. Notably, further analysis with SynergyFinder showed drug synergy across all endpoints.
For the first time, this shows that prostate cancer organoids can reveal drug synergy in high-throughput assays. This increases the scale and scope of organoid experiments, accelerating translation of new treatments for prostate cancer.