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

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 i...

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Autores principales: Gorski, Justin W., Zhang, Zhuwei, McCorkle, J. Robert, DeJohn, Jodi M., Wang, Chi, Miller, Rachel W., Gallion, Holly H., Dietrich, Charles S., Ueland, Frederick R., Kolesar, Jill M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394135/
https://www.ncbi.nlm.nih.gov/pubmed/34440225
http://dx.doi.org/10.3390/biomedicines9081021
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author Gorski, Justin W.
Zhang, Zhuwei
McCorkle, J. Robert
DeJohn, Jodi M.
Wang, Chi
Miller, Rachel W.
Gallion, Holly H.
Dietrich, Charles S.
Ueland, Frederick R.
Kolesar, Jill M.
author_facet Gorski, Justin W.
Zhang, Zhuwei
McCorkle, J. Robert
DeJohn, Jodi M.
Wang, Chi
Miller, Rachel W.
Gallion, Holly H.
Dietrich, Charles S.
Ueland, Frederick R.
Kolesar, Jill M.
author_sort Gorski, Justin W.
collection PubMed
description 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 EC(50) values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC(50) 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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spelling pubmed-83941352021-08-28 Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance Gorski, Justin W. Zhang, Zhuwei McCorkle, J. Robert DeJohn, Jodi M. Wang, Chi Miller, Rachel W. Gallion, Holly H. Dietrich, Charles S. Ueland, Frederick R. Kolesar, Jill M. Biomedicines Article 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 EC(50) values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC(50) 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. MDPI 2021-08-16 /pmc/articles/PMC8394135/ /pubmed/34440225 http://dx.doi.org/10.3390/biomedicines9081021 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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/).
spellingShingle Article
Gorski, Justin W.
Zhang, Zhuwei
McCorkle, J. Robert
DeJohn, Jodi M.
Wang, Chi
Miller, Rachel W.
Gallion, Holly H.
Dietrich, Charles S.
Ueland, Frederick R.
Kolesar, Jill M.
Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
title Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
title_full Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
title_fullStr Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
title_full_unstemmed Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
title_short Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
title_sort utilizing patient-derived epithelial ovarian cancer tumor organoids to predict carboplatin resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394135/
https://www.ncbi.nlm.nih.gov/pubmed/34440225
http://dx.doi.org/10.3390/biomedicines9081021
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