Abstract B217: Antitumor activity of the new Bcl-2/Bcl-xl inhibitor S44563 in primary human uveal melanoma xenografts.

Abstract

Abstract Background: Uveal melanoma (UM) is the most common primary malignancy of the eye in adults. Although over 95% of patients have disease limited to the eye at diagnosis, 50% will develop liver metastases and ultimately die of their disease. Because of the limited efficacy of current treatments, new therapeutic strategies need therefore to be developed. Reduced capacity for apoptosis induction is one potential obstacle to therapy but, consequently, regulators of apoptosis may constitute an attractive approach to anticancer therapeutics, such as the Bcl-2 family proteins. Human uveal melanomas are characterized by a high amount of Bcl-2 expression, ranging between 50% and 100% of studied cases. Such an observation has been confirmed in our panel of 16 primary human uveal melanoma xenografts obtained from patient's tumors (Némati et al, CCR 2010). We have therefore investigated the efficacy of the new Bcl-2/Bcl-XL inhibitor S44563 on 4 primary human UM xenografts. Materials and methods: Four well characterized models of primary human UM, obtained from patients after enucleation (MP41 and MP77) or liver metastasis surgery (MM26 and MM66) (Némati et al, CCR 2010), were used for the in vivo experiments. S44563 (50 or 100 mg/kg/day, days 1–5/8–12/22–26/29–33) was administered IP alone or combined with fotemustine, either concomitant (15 or 30 mg/kg days 1 and 22), or after chemotherapy (100 mg/kg) at days 43–47/50–54/64–68/71–75. Tumor Growth Inhibition (TGI) was calculated to measure the efficiency of various tested compounds. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were determined by immunohistochemistry (IHC). Results: The expression of Bcl-2, defined by IHC, was highly positive for the 4 models used (75% to 100% of tumor cells). S44563 administered alone at 50 and 100 mg/kg induced a moderate TGI of about 50% in 1 model (MP41) among all without dose effect. When S44563 was combined to fotemustine, we observed a synergistic activity in 2 models (MP77 and MM66) among the 4 tested, without impact on the proportion of complete remission. Finally, when S44563 was concomitantly and/or administered after fotemustine, we found a delay of tumor growth in 2 among the 3 tested xenografts (MP77, and MM26). IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expressions were not modified after S44563 administration. Conclusion: We have shown that S44563, despite a relative low efficacy when administered alone, increased the efficacy of chemotherapy in concomitant combination or after fotemustine. Such preliminary results therefore underline the therapeutic potential of this new Bcl-2/Bcl-xl inhibitor in human uveal melanoma. Némati et al. Clin Cancer Res 2010;16:2352–2362. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B217.