Preclinical Activity of Plitidepsin Against Clear Cell Carcinoma of the Ovary

Background/Aim: To evaluate the antitumor effects of Plitidepsin against clear cell carcinoma (CCC) of the ovary. Materials and Methods: The expression of eEF1A2 in ovarian cancer was assessed by immunohistochemistry. Using ovarian CCC cell lines, the antitumor effect of Plitidepsin was assessed both in vitro and in vivo. By over-expressing or knocking down the eEF1A2 expression, we investigated the role of eEF1A2 in the sensitivity of CCC cells to Plitidepsin. Results: Immunoreactivity to eEF1A2 was observed in 76.2% of CCC, which was significantly higher than other histological subtypes of ovarian cancer. Plitidepsin exhibited significant antitumor activity toward chemonaive and chemoresistant CCC cells both in vitro and in vivo. Ectopic expression of eEF1A2 in CCC cells resulted in increased sensitivity to Plitidepsin. In contrast, eEF1A2 knockdown decreased sensitivity of CCC cells to plitidepsin. Conclusion: Plitidepsin, a novel anti-cancer agent that targets eEF1A2, may be a promising agent for treating ovarian CCC.Clear cell carcinoma (CCC) of the ovary is known to be less sensitive to platinum-based frontline chemotherapy, and advanced-stage CCC is known to be associated with a worse prognosis than the more common histological subtype of serous adenocarcinoma (SAC). The lack of an effective chemotherapy for recurrent CCC is another important clinical problem (1). Therefore, novel strategies for both first-line treatment for advanced-stage CCC and salvage treatment for recurrent disease are needed. Plitidepsin (Aplidin®) is a novel anti-cancer agent currently investigated in late phases of clinical development. In 2018, the Australian regulatory agency approved Plitidepsin in combination with dexamethasone for the treatment of multiple myeloma. Plitidepsin was originally isolated from the Mediterranean tunicate Aplidium albicans in 1988: currently it is chemically synthesized by Pharma Mar (Madrid, Spain) (2). According to previous preclinical studies, Plitid