Introduction Patient-Derived Organoids (PDOs) are in increasing use as ex-vivo models for high-grade serous ovarian cancer (HGSOC) and other cancers, given their genotypic and phenotypic correlations with in vivo tumour. We aimed to characterise inter- and intrapatient heterogeneity in PDOs from multiple sites in chemo-naïve HGSOC.
Methods Multi-site tumour samples were collected from HGSOC patients undergoing primary cytoreductive surgery and PDOs grown from extracted tumour cells with/without the Wnt agonist R-spondin. PDOs were trialled against chemotherapies and targeted therapeutics using IC50 and AUC for comparison. Transcriptomic differences between PDOs were explored using RNAseq.
Results PDOs were successfully established (≥5 passages) in 8/14 cases (57%), with a mean n=5 sites initially seeded per patient. IC50 and AUC values for platinum compounds and PARP inhibitors varied significantly between patients, and between different sites from the same patient. Cisplatin sensitivity varied 20-fold across 8 different PDO lines (p<0.0001), with carboplatin sensitivity differing by almost 10-fold between different tumour sites in one case (p<0.0001) highlighting HGSOC inter/intrapatient heterogeneity. Rucaparib sensitivity variability was demonstrated between cases and between sites from the same case (p<0.001). Resistance was induced in 2 PDO lines through culturing in low dose conditions, with AUC increments were observed for cisplatin (p<0.01) and rucaparib (p<0.05) compared to controls. Potentially synergistic compounds to overcome platinum and PARPi resistance were trialled.
Conclusion/Implications HGSOC PDOs provide a reliable model for drug screening, incorporating inter and intra-patient heterogeneity. The heterogeneity observed provides rationale for variability in clinical responses and the poor prognosis consistent with advanced HGSOC.
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