Abstract 1642: Antitumor activity of lurbinectedin toward ovarian clear cell carcinoma

Abstract

Objectives:Lurbinectedin is a marine-derived covalent DNA minor groove binder and is structurally similar to trabectedin except for the C subunit. Lurbinectedin (PM01183) is a newly developed antitumor agent that is currently being investigated in phase I/II clinical trials in patients with solid tumors including ovarian cancer. The objective of this study is to investigate the effectiveness of lurbinectedin as a single agent or as combination with existing antitumor agent against ovarian clear cell carcinoma which is regarded as an aggressive chemoresistant histological subtype. Methods:Using human ovarian clear cell carcinoma cell lines, the anti-tumor effects of lurbinectedin, SN38, topotecan, doxorubicin, cisplatin and paclitaxel as single agent were assessed by MTS assay. Then the cytotoxicities of combination treatments involving lurbinectedin and 1 of the 4 agents were evaluated by isobologram analysis to examine which of these combinations displayed synergistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant ovarian clear cell carcinoma sublines, which were derived from the parental clear cell carcinoma cells by continuously exposing them to cisplatin or paclitaxel. Finally, using nude mice inoculated with clear cell carcinoma cells, we examined the growth-inhibitory effect of lurbinectedin in vivo. Results:Lurbinectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that lurbinectedin significantly inhibits tumor growth. Concurrent exposure to lurbinectedin and SN-38 resulted in synergistic interactions in CCC cell lines. The combination of lurbinectedin plus SN-38 also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Treatment with everolimus significantly enhanced the antitumor activity of single agent lurbinectedin and combination of lurbinectedin plus SN-38. Conclusions:Lurbinectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, lurbinectedin combined with irinotecan may be more efficacious for the management of CCC. Citation Format: Ryoko Takahashi, Seiji Mabuchi, Yuri Matsumoto, Mahiru Kawano, Tomoyuki Sasano, Hiromasa Kuroda, Katsumi Kozasa, Kenjirou Sawada, Tadashi Kimura. Antitumor activity of lurbinectedin toward ovarian clear cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1642. doi:10.1158/1538-7445.AM2015-1642