Abstract
ObjectiveThe objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype.MethodsUsing human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy.ResultsLurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies.ConclusionsLurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment.
Highlights
Clear cell carcinoma (CCC) of the ovary is known to be less sensitive to platinum-based firstline chemotherapy and to be associated with a worse prognosis than serous adenocarcinoma (SAC), a more common histological subtype of ovarian cancer [1,2,3,4]
Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined
Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment
Summary
Clear cell carcinoma (CCC) of the ovary is known to be less sensitive to platinum-based firstline chemotherapy and to be associated with a worse prognosis than serous adenocarcinoma (SAC), a more common histological subtype of ovarian cancer [1,2,3,4]. On the basis of previous preclinical and clinical studies suggested that irinotecan is more effective in CCC cells than other anticancer agents [5,6], a phase III study comparing the activity of irinotecan plus cisplatin versus carboplatin plus paclitaxel as a first-line treatment for CCC was conducted by the Japanese Gynecologic Oncology Group (JGOG) (protocol JGOG3017). An elegant study demonstrated that NER-deficient cells (deficient in NER-related genes) exhibited resistance to trabectedin and that their sensitivity to trabectedin was restored by the transfection of the corresponding genes [11]. These findings are in clear contrast with the results obtained for platinum-based agents [12]. Consistent with the promising results obtained in preclinical studies of ovarian CCC [13,14], a phase II study involving recurrent ovarian CCC patients showed that combination therapy with trabectedin and temsirolimus exhibited significant activity, with a response rate of 14.3% and a clinical benefit rate of 42.9% [15]
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