Antitumor evaluation of the new Bcl-2/Bcl-xl inhibitor S44563 in primary human uveal melanoma xenografts

Purpose Nearly half of primary Uveal melanoma (UM) metastasizes in liver, but there are currently no effective therapies. Human UM are characterized by a high expression of Bcl-2, ranging between 50% and 100%. This observation has been confirmed in our panel of 16 human UM xenografts obtained from patient’s tumors (Nemati et al, CCR 2010). We have investigated the efficacy of the new Bcl-2/Bcl-XL inhibitor S44563 on 4 primary human UM xenografts. Methods Four well characterized primary human UM xenografts were used. S44563 (50 or 100 mg/kg, days 1-5/8-12/22-26/29-33) was administered IP alone or combined with fotemustine, concomitantly (15 or 30 mg/kg days 1 and 22), or after chemotherapy (100 mg/kg, days 43-47/50-54/64-68/71-75). Tumor Growth Inhibition (TGI) was calculated to measure the efficiency of drugs. Bcl-2, Bcl-XL, and Mcl-1 expressions were determined by immunohistochemistry (IHC). Results S44563 administered alone induced a moderate TGI of about 50% in 1 model (MP41). When combined S44563 to fotemustine, we observed a synergistic activity in 2 models (MP77 and MM66), 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 increased the efficacy of chemotherapy in concomitant combination or after fotemustine. Such preliminary results underline the therapeutic potential of this new Bcl-2/Bcl-xl inhibitor in human UM.