Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance

Authors

Justin W. Gorski, University of KentuckyFollow
Zhuwei Zhang, University of KentuckyFollow
J. Robert McCorkle, University of KentuckyFollow
Jodi M. DeJohn, University of KentuckyFollow
Chi Wang, University of KentuckyFollow
Rachel W. Miller, University of KentuckyFollow
Holly H. Gallion, University of KentuckyFollow
Charles S. Dietrich III, University of KentuckyFollow
Frederick R. Ueland, University of KentuckyFollow
Jill M. Kolesar, University of KentuckyFollow

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.

Document Type

Article

Publication Date

8-16-2021

Notes/Citation Information

Published in Biomedicines, v. 9, issue 8, 1021.

© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.3390/biomedicines9081021

Funding Information

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).

Related Content

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.

Repository Citation

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.
https://uknowledge.uky.edu/obgyn_facpub/33