Fig. 4: Drug sensitivity of organoids representing different PCa stages and identification of novel compounds for repurposing use, based on medium-throughput organoid screens.
From: Patient-derived xenografts and organoids model therapy response in prostate cancer
a Scheme of experimental protocol for organoid drug screens. Created with BioRender.com. b Organoid drug screen heatmap of log2 fold change viability values (over vehicle, for each PDX model) for PNPCa (N = 4 replicates), BM18 (N = 3), and LAPC9 (N = 3). Negative log2 values (plotted in blue) indicate potential drug candidates with impact on cell viability. Staurosporine was used as positive control. Statistically significant hits (FDR ≤ 0.05) are indicated with an asterisk. Hits with a significant effect on at least one model are reported, listed in alphabetical order and with effective dose indication on the right, in μM. Medium-throughput automated drug screens, using selected FDA-approved compounds, were performed at Nexus Theragnostics platform. c Gene set enrichment analysis (GSEA) of PDXs tissue (PNPCa N = 3, BM18 N = 2, LAPC9 N = 2) and organoids (PNPCa N = 2, BM18 N = 2, LAPC9 N = 2). Enrichment scores of selected Hallmark and KEGG (C2) pathways with FDR < 0.05 derived from differential expression analysis of each group of samples vs. the non-carcinoma control tissue from PNPCa clinical sample (N1). NES normalized enrichment score. d In vivo efficacy by ponatinib treatment in subcutaneous LAPC9 PDX model. Tumor-bearing mice received intraperitoneally (IP) daily injections of vehicle or ponatinib (10 mg/kg) and mean tumor size scoring (×100 mm3) was plotted. Data are presented as mean ± SD, N = 10 independent tumor samples per treatment group); Two-way ANOVA with Sidak correction. *p = 0.029 (day 18), p = 0.012 (day 20), p = 0.016 (day 22). Tumor weight was assessed at endpoint and plotted as mean ± SD, N = 10 independent tumor samples per group; Two-tailed nested t-test. *p = 0.015. e Representative histology of LAPC9 PDX tumors from the vehicle and ponatinib groups, collected at endpoint. HE, hematoxylin and eosin, Ki67 proliferation marker. Scale bars, 0.5 mm.
