Licofelone enhances the efficacy of paclitaxel in ovarian cancer by reversing drug resistance and tumor stem-like properties

Jeff Hirst, Harsh B. Pathak, Stephen Hyter, Ziyan Y. Pessetto, Thuc Ly, Stefan Graw, Devin C. Koestler, Adam Krieg, Katherine F. Roby, Andrew K. Godwin

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Drug development for first-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anticancer drugs. MCTS exhibited greater resistance to chemotherapeutic agents, showed signs of senescence and hypoxia, and expressed a number of stem cell-associated transcripts including ALDH1A and CD133, also known as PROM1. Using a library of clinically repurposed drugs, we identified candidates with preferential activity in MCTS over 2D cultured cells. One of the lead compounds, the dual COX/LOX inhibitor licofelone, reversed the stem-like properties of ovarian MCTS. Licofelone also synergized with paclitaxel in ovarian MCTS models and in a patient-derived tumor xenograft model. Importantly, the combination of licofelone with paclitaxel prolonged the median survival of mice (>141 days) relative to paclitaxel (115 days), licofelone (37 days), or vehicle (30 days). Increased efficacy was confirmed by Mantel-Haenszel HR compared with vehicle (HR= 0.037) and paclitaxel (HR= 0.017). These results identify for the first time an unappreciated, anti-inflammatory drug that can reverse chemotherapeutic resistance in ovarian cancer, highlighting the need to clinically evaluate licofelone in combination with first-line chemotherapy in primary and chemotherapy-refractory EOC. Significance: This study highlights the use of an in vitro spheroid 3D drug screening model to identify new therapeutic approaches to reverse chemotherapy resistance in ovarian cancer.

Original languageEnglish (US)
Pages (from-to)4370-4385
Number of pages16
JournalCancer Research
Volume78
Issue number15
DOIs
StatePublished - Aug 1 2018

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licofelone
Cellular Spheroids
Paclitaxel
Drug Resistance
Ovarian Neoplasms
Neoplasms
Preclinical Drug Evaluations
Drug Therapy
Drug Repositioning
Cell Culture Techniques
Pharmaceutical Preparations
Primary Cell Culture
Heterografts
Libraries
Cultured Cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Licofelone enhances the efficacy of paclitaxel in ovarian cancer by reversing drug resistance and tumor stem-like properties. / Hirst, Jeff; Pathak, Harsh B.; Hyter, Stephen; Pessetto, Ziyan Y.; Ly, Thuc; Graw, Stefan; Koestler, Devin C.; Krieg, Adam; Roby, Katherine F.; Godwin, Andrew K.

In: Cancer Research, Vol. 78, No. 15, 01.08.2018, p. 4370-4385.

Research output: Contribution to journalArticle

Hirst, J, Pathak, HB, Hyter, S, Pessetto, ZY, Ly, T, Graw, S, Koestler, DC, Krieg, A, Roby, KF & Godwin, AK 2018, 'Licofelone enhances the efficacy of paclitaxel in ovarian cancer by reversing drug resistance and tumor stem-like properties', Cancer Research, vol. 78, no. 15, pp. 4370-4385. https://doi.org/10.1158/0008-5472.CAN-17-3993
Hirst, Jeff ; Pathak, Harsh B. ; Hyter, Stephen ; Pessetto, Ziyan Y. ; Ly, Thuc ; Graw, Stefan ; Koestler, Devin C. ; Krieg, Adam ; Roby, Katherine F. ; Godwin, Andrew K. / Licofelone enhances the efficacy of paclitaxel in ovarian cancer by reversing drug resistance and tumor stem-like properties. In: Cancer Research. 2018 ; Vol. 78, No. 15. pp. 4370-4385.
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abstract = "Drug development for first-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anticancer drugs. MCTS exhibited greater resistance to chemotherapeutic agents, showed signs of senescence and hypoxia, and expressed a number of stem cell-associated transcripts including ALDH1A and CD133, also known as PROM1. Using a library of clinically repurposed drugs, we identified candidates with preferential activity in MCTS over 2D cultured cells. One of the lead compounds, the dual COX/LOX inhibitor licofelone, reversed the stem-like properties of ovarian MCTS. Licofelone also synergized with paclitaxel in ovarian MCTS models and in a patient-derived tumor xenograft model. Importantly, the combination of licofelone with paclitaxel prolonged the median survival of mice (>141 days) relative to paclitaxel (115 days), licofelone (37 days), or vehicle (30 days). Increased efficacy was confirmed by Mantel-Haenszel HR compared with vehicle (HR= 0.037) and paclitaxel (HR= 0.017). These results identify for the first time an unappreciated, anti-inflammatory drug that can reverse chemotherapeutic resistance in ovarian cancer, highlighting the need to clinically evaluate licofelone in combination with first-line chemotherapy in primary and chemotherapy-refractory EOC. Significance: This study highlights the use of an in vitro spheroid 3D drug screening model to identify new therapeutic approaches to reverse chemotherapy resistance in ovarian cancer.",
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