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The Activity of Trabectedin As a Single Agent Or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary

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The Activity of Trabectedin As a Single Agent Or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary Published OnlineFirst May 27, 2011; DOI: 10.1158/1078-0432.CCR-10-2987 Clinical Cancer Cancer Therapy: Preclinical Research The Activity of Trabectedin As a Single Agent or in Combination with Everolimus for Clear Cell Carcinoma of the Ovary Seiji Mabuchi1, Takeshi Hisamatsu1, Chiaki Kawase1, Masami Hayashi1, Kenjiro Sawada1, Kazuya Mimura1, Kazuhiro Takahashi2, Toshifumi Takahashi2, Hirohisa Kurachi2, and Tadashi Kimura1 Abstract Purpose: The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype. Experimental Design: Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel- resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo. Results: Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin. Conclusion: Trabectedin 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, trabectedin combined with everolimus may be more efficacious for the management of CCC. Clin Cancer Res; 17(13); 4461–72. Ó2011 AACR. Introduction 2–5). The lack of effective chemotherapy for recurrent CCC after frontline treatment is another important problem in Ovarian carcinoma is the fourth most common cause of the clinical management of CCC. Therefore, to improve the cancer death among women in the United States, with survival of patients with CCC, the development of novel more than 21,880 new cases diagnosed and 13,850 deaths treatment strategies in the setting of both first-line treat- estimated to have occurred in 2010 (1). ment and salvage treatment of recurrent disease are needed. Clear cell carcinoma (CCC) of the ovary has been known Trabectedin, which was formerly known as ecteinasci- to show poorer sensitivity to platinum-based frontline din-743 (ET-743), is an antineoplastic agent that was chemotherapy and to be associated with a worse prognosis originally derived from the Caribbean marine tunicate than the more common serous adenocarcinoma (SAC; refs. Ecteinascidia turbinate. It binds covalently to the minor groove of DNA, bending DNA toward the major groove and disrupting transcription, leading to G2–M cell-cycle Authors' Affiliations: 1Department of Obstetrics and Gynecology, Osaka arrest and ultimately apoptosis (6). Although the exact University Graduate School of Medicine, Osaka; and 2Department of mechanism of its action is not clear, it is thought that Obstetrics and Gynecology, Yamagata University, School of Medicine, the cytotoxic activity of trabectedin is based on the inhibi- Yamagata, Japan tion of transcription-dependent nucleotide-excision repair Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). (NER) via the trapping of the proteins responsible for NER, which induces cells to undergo apoptosis (7). S. Mabuchi and T. Hisamatsu contributed equally to this work. In a preclinical study, trabectedin showed significant Corresponding Author: Seiji Mabuchi, Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yama- antitumor activity in vitro and in vivo against a range of daoka, Suita, Osaka 565-0871, Japan. Phone: 81-668-793-354; Fax: 81- solid tumor cells, including soft-tissue sarcoma (STS), 668-793-359; E-mail: smabuchi@gyne.med.osaka-u.ac.jp ovarian, breast, prostate, and renal cancers; melanoma; doi: 10.1158/1078-0432.CCR-10-2987 and non–small-cell lung cancer (8–11). On the basis Ó2011 American Association for Cancer Research. of the promising results of preclinical and clinical studies www.aacrjournals.org 4461 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst May 27, 2011; DOI: 10.1158/1078-0432.CCR-10-2987 Mabuchi et al. Translational Relevance everolimus has been approved for the treatment of renal cell carcinoma (19). In preclinical investigations, everoli- Clear cell carcinoma (CCC) of the ovary is a distinc- mus has been shown to inhibit the proliferation of ovarian tive subtype of epithelial ovarian cancer associated with cancer cells and enhance their sensitivity to cisplatin both a poorer sensitivity to platinum-based chemotherapy in vitro and in vivo (20–22), and its efficacy in ovarian and worse prognosis than the more common serous cancer patients is currently being evaluated in several phase adenocarcinoma. To improve survival, the identifica- I/II trials (23). However, no reports have addressed the role tion of a novel anticancer agent that more effectively of mTOR in the acquisition of resistance to trabectedin. targets CCC is necessary. Our results show that treat- In the current investigation, we evaluated the therapeutic ment with trabectedin significantly inhibited the growth efficacy of trabectedin as a single agent in vitro and in vivo. of CCC in vitro and in vivo. The growth-inhibitory effect We also examined the antitumor activity of trabectedin in of trabectedin on CCC cells was greater than those of both cisplatin-resistant and paclitaxel-resistant CCC cells. cisplatin, paclitaxel, and SN-38, which are clinically Finally, we investigated the role of AKT–mTOR signaling in employed as a part of the first-line chemotherapy for the mechanism of acquired resistance to trabectedin and this disease. This finding may be relevant for the plan- assessed the therapeutic potential of trabectedin in combi- ning of future clinical studies of first-line treatments of nation with everolimus in CCC cells. CCC of the ovary. Moreover, the significant antitumor activity of trabectedin against cisplatin- and paclitaxel- Materials and Methods resistant CCC shown in the current study may represent a novel treatment option for patients with recurrent Reagents/antibodies disease after first-line chemotherapy. Trabectedin was obtained from PharmaMar. Everolimus was obtained from Novartis Pharma AG. Cisplatin, pacli- taxel, and 7-ethyl-10-hydroxycamptothecin (SN-38) were purchased from Sigma. LY294002 was purchased from Cell (10, 12, 13), trabectedin is now approved in Europe for the Signal Technology. Enhanced chemiluminescence (ECL) treatment of STS after anthracycline and ifosfamide failure Western blotting detection reagents were from Perkin and for treating patients who cannot receive these agents Elmer. Antibodies recognizing p70S6K, phospho-p70S6K (14). (Thr389), mTOR, phospho-mTOR (Ser2448), AKT, phos- In ovarian cancer, trabectedin has been studied in several pho-AKT (Ser473), and b-actin were obtained from Cell phase I and II clinical trials, showing a favorable toxicity Signaling Technology. The Cell Titer 96-well proliferation profile and promising activity in recurrent ovarian cancer assay kit was obtained from Promega. patients (15, 16). Following the encouraging results of these studies, a phase III trial investigating the activity of Drug preparation trabectedin plus liposomal doxorubicin versus liposomal Trabectedin was prepared as a 1 mg/mL stock solution doxorubicin in patients with recurrent ovarian cancer has in ethanol. Everolimus was diluted to the appropriate recently been conducted. As this study showed a survival concentration in double-distilled water just before its benefit of trabectedin-based combination chemotherapy, administration by gavage in the animal studies. For the trabectedin has become the focus of attention for research- in vitro analyses, everolimus was prepared in dimethyl ers investigating the treatment of epithelial ovarian cancer sulfoxide (DMSO) before being added to the cell cultures (17). as described previously (20–22). Cisplatin was dissolved As most ovarian cancer cell lines investigated in pre- in sterilized double-distilled water to a final concentra- vious preclinical studies of trabectedin have been from tion of 1 mmol/L. SN-38 and paclitaxel were dissolved in ovarianSAC(6,8,9)andonlyasmallnumberof DMSO to final concentrations of 10 and 100 mmol/L, patients with CCC histology were included in the pre- respectively. vious clinical studies (15–17), the therapeutic potential of trabectedin in patients with CCC is unknown. Because Cell culture of its nature as a newly developed anticancer agent, the The human ovarian CCC cell lines RMG1, RMG2, and mechanism of resistance to trabectedin is largely HAC2 were kindly provided by Dr. H. Itamochi (Tottori unknown. To further improve the prognosis
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