Abstract
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.
Highlights
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States
Written informed consent was obtained from all subjects, and they were enrolled in the Total Cancer Care Protocol: A Lifetime Partnership with Patients Who Have or May be at Risk of Cancer (MCC 17-MTB-01, UK IRB #44224)
The study was conducted according to the guidelines of the Declaration of Helsinki, and it was approved by the Institutional Review Board of the University of Kentucky
Summary
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. In 2021, it is estimated that 21,410 women will be diagnosed with ovarian cancer and that it will be responsible for 13,770 deaths in the U.S [1]. The current standard of care treatment for advanced stage disease includes surgical debulking, with the goal of removing all macroscopic disease (R0 cytoreduction), in combination with platinum-based neoadjuvant or adjuvant chemotherapy [2]. Despite this aggressive front-line treatment, more than 80% of patients recur [3]. The platinum-free interval (PFI; time from the last dose of front-line adjuvant platinumbased chemotherapy to the detection of recurrence) has been used to classify patients
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