Author ORCID Identifier

https://orcid.org/0000-0002-4272-0183

Year of Publication

2021

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Clinical and Translational Science

First Advisor

Dr. Jill M. Kolesar

Abstract

The development of patient-derived tumor organoids (TOs) from 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 utilize 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 organoids from tissue obtained during debulking surgery (2 neoadjuvant carboplatin exposed, 4 chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1 and 0.1µM). Cell viability curves and resultant EC50 values were determined after normalizing to untreated negative controls.

One organoid line, UK1254, was predicted to be resistant to carboplatin based on EC50 value (50.2 µM) above clinically achievable Cmax. UK1254 had a significantly shorter progression free survival (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 linkage of B-cell receptor signaling to the PI3KAkt 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 possibly can be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.392

Funding Information

This research was partially funded by the National Cancer Institute T32: Oncology Research Training for Surgeon Scientists grant (T32 CA160003) in 2018, 2019 and 2020. This research was also supported by the Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558) in 2018, 2019 and 2020 and the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558) in 2019, 2020 and 2021.

Available for download on Sunday, October 23, 2022

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