Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary Ovarian Cancer and Us OVARIAN CANCER and US Ovarian Cancer and Us

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Wednesday, April 06, 2016

Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary



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Introduction

Clear cell carcinoma (CCC) of the ovary is known to be less sensitive to platinum-based first-line chemotherapy and to be associated with a worse prognosis than serous adenocarcinoma (SAC), a more common histological subtype of ovarian cancer [14]. 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). However, this study failed to demonstrate the superiority of irinotecan plus cisplatin over carboplatin plus paclitaxel [7]. The lack of an effective chemotherapy for recurrent CCC is another important clinical problem [8]. Therefore, novel treatment strategies for CCC (for both first-line treatment and salvage treatment for recurrent disease) are required.
Trabectedin, an anticancer agent, has recently become the focus of attention for researchers investigating the treatment of CCC. On the basis of the results of a phase III clinical study (the OVA301 study) [9], the use of trabectedin in combination with pegylated liposomal doxorubicin was approved by the European Union in 2009 as a treatment for relapsed platinum-sensitive ovarian cancer. Trabectedin interacts with the nucleotide excision repair (NER) machinery, a versatile DNA repair system that acts against DNA damage induced by platinum-based agents [10], in an unusual manner. 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]. Thus, CCC that display increased NER activity [11], might be the candidates for trabectedin treatment. 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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