The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects (p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K–Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.
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This research was partially funded by the National Cancer Institute, grant number T32 CA160003, and by the National Cancer Institute at the National Institutes of Health including support for the Biostatistics and Bioinformatics Shared Resource Facility, the Cancer Research Informatics, and the Biospecimen Procurement and Translational Pathology Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558).
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to concern for infringement on research subjects’ privacy.
Gorski, Justin W.; Zhang, Zhuwei; McCorkle, J. Robert; DeJohn, Jodi M.; Wang, Chi; Miller, Rachel W.; Gallion, Holly H.; Dietrich, Charles S. III; Ueland, Frederick R.; and Kolesar, Jill M., "Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance" (2021). Obstetrics and Gynecology Faculty Publications. 33.