Preclinical Activity of Plitidepsin Against Clear Cell Carcinoma of the Ovary

Abstract

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, Plitidepsin is active against a wide range of malignancies: hematological malignancies such as multiple myeloma, lymphoma, and leukemia, and solid tumors including non-small-cell lung carcinoma, pacncreas, breast, melanoma, sarcoma, gastric, and bladder cancer (3). Importantly, most reports demonstrated in vitro activity of Plitidepsin in a low nanomolar range. Accumulating evidence have suggested that Plitidepsin induces cell cycle arrest and apoptosis in a dose-dependent manner by inducing oxidative stress, decreasing intracellular levels of glutathione, upregulating the JNK and p38 MAPK pathways. In addition to cytotoxic and cytostatic activities, Plitidepsin is known to inhibit tumor-angiogenesis through the inhibition of vascular endothelial growth factor (VEGF) secretion from cancer cells. In ovarian cancer, Plitidepsin exhibited anti-proliferative activity in vitro, and significantly inhibited the growth of a xenograft in athymic mice. However, since most ovarian cancer cell lines used in the previous preclinical studies of Plitidepsin were derived from ovarian SAC, the therapeutic potential of Plitidepsin against ovarian CCC is unknown.

The translation factor eEF1A2 is a tissue-specific variant of the eukaryotic Elongation Factor 1. The expression of eEF1A2 is normally confined to muscles and neurons (4). However, eEF1A2 is frequently over-expressed in various human malignancies and has oncogenic properties. Anand et al. (5) were the first to show that eEF1A2, while not normally expressed in ovary, is expressed in 30% of ovarian tumors. When examined according to histological subtypes, eEF1A2 was highly expressed in clear cell ovarian tumors compared to other histological subtypes of ovarian cancer (6). A recent study demonstrated that approximately 75% of ovarian CCC showed over-expression of eEF1A2 at the protein level (7).

Although detailed mechanisms of action have not been completely investigated, Plitidepsin has been suggested to exert its antitumor activity by directly interacting with eEF1A2. Thus, plitidepsin might be a potential drug candidate for the treatment of CCC showing over-expression of eEF1A2.

In the current study, after investigating the expression rate of eEF1A2 in ovarian cancer specimens, we evaluated the in vitro and in vivo therapeutic efficacy of Plitidepsin as a single agent against both chemonaive and chemorefractory ovarian CCC cells.