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Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model

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Authors
Harrington, Brittney S
Ozaki, Michelle K
Caminear, Michael W
Hernandez, Lidia F
Jordan, Elizabeth
Kalinowski, Nicholas J
Goldlust, Ian S
Guha, Rajarshi
Ferrer, Marc
Thomas, Craig
Shetty, Jyoti
Tran, Bao
Wong, Nathan
House, Carrie D
Annunziata, Christina M
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(15 total)
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Abstract
<jats:p>Disease recurrence is the major cause of morbidity and mortality of ovarian cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy, PARP inhibitors significantly improve the overall survival of patients with BRCA mutations but is of little benefit to patients without homologous recombination deficiency (HRD). The stem-like tumor-initiating cell (TIC) population within OC tumors are thought to contribute to disease recurrence and chemoresistance. Therefore, there is a need to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes involved in drug metabolism, oxidative phosphorylation and reactive oxygen species (ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared to adherent cells. The compounds promoted ROS accumulation and oxidative stress and disulfiram, elesclomol and salinomycin increased cell death following carboplatin treatment compared to carboplatin alone. Disulfiram and salinomycin were effective in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that enhancing oxidative stress in TICs can prevent OC recurrence.</jats:p>
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Journal article
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https://hdl.handle.net/10161/26241
Published Version (Please cite this version)
10.3390/cancers12061645
Publication Info
Harrington, Brittney S; Ozaki, Michelle K; Caminear, Michael W; Hernandez, Lidia F; Jordan, Elizabeth; Kalinowski, Nicholas J; ... Annunziata, Christina M (n.d.). Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model. Cancers, 12(6). pp. 1645-1645. 10.3390/cancers12061645. Retrieved from https://hdl.handle.net/10161/26241.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Caminear

Michael Caminear

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