Abstract 3446: FL118, a survivin/Mcl-1/XIAP/cIAP2-selective inhibitor, effectively inhibits human mesothelioma xenograft growth in animal models.

We have identified and characterized a novel small chemical molecule (designated FL118). Our in vitro studies showed that FL118 selectively inhibits the expression of survivin, Mcl-1, XIAP and cIAP2, while showing no inhibitory effects on control genes. In an intraperitoneal (i.p.) route, the maximum tolerated dose (MTD) of FL118 was found to be about 1.5 mg/kg at a weekly x 4 schedule in a Tween 80-comtaining formulation, FL118 showed superior antitumor activity in mouse models of human colon and head-&-neck tumor xenografts (PLOS ONE. 2012, 7: e45571). However, we found that actually, the weekly x 4 schedule for FL118 in the Tween 80-containing formulation is the best schedule for showing the maximal antitumor activity for FL118. So further improvement of FL118 antitumor efficacy would have no rooms with this formulation. In this regard, we have developed a Tween 80-free formulation that fits the intravenously (i.v.) injection. Here we report our results with this formulation on human mesothelioma in animal models. Two mesothelioma cell lines (MSTO-211H, NCI-H226) were used to establish human xenograft in SCID mice. After the established human mesothelioma tumor in mice was sub-transplanted 2-3 times, the tumor masses were then used for testing FL118 efficacy and toxicity in a Tween 80-free formulation. We first determined FL118 MTD via i.v. routes in three commonly used schedules in clinical practice - every day for five times (daily x 5), every other day for five times (q2 x 5) and every week for 4 times (weekly x 4). Our result showed that the MTD for FL118 in the Tween 80-free formulation via i.v. increases 3-7 times in comparison with the FL118 MTD in the Tween 80 containing formulation. In the new formulation, FL118 reached 1.5 mg/kg, (daily x 5, q2 x 5) and 5 mg/kg (weekly x 4), respectively. Then we tested the efficacy of FL118 for inhibiting mesothelioma tumor growth and found that FL118 induced tumor regression in all three clinical compatible schedules, while the toxicity profile appears to be improved in comparison with the outcome from FL118 in the Tween 80-containing formulation. Specifically, our data showed that FL118 effectively inhibits MSTO-211H-derived tumor growth, induces tumor regression and even achieved a cure in a percentage of human mesothelioma xenograft, while the tumors in control mice without FL118 treatment reached the maximal size (∼2000 mg/mm3) allowed in less than five weeks. Additionally, FL118 also showed effective inhibition of NCI-H226-established tumor growth. Therefore, we conclude that we developed a clinical suitable formula for FL118 i.v. administration. We also, for the first time, demonstrated that FL118 possesses superior antitumor activity in animal models of human mesothelioma cancer cell line-established tumor xenograft, which provides a hope to use FL118 as a superior option to effectively treat mesothelioma in clinical practice. Citation Format: Fengzhi Li, Shousong Cao, Xiang Ling. FL118, a survivin/Mcl-1/XIAP/cIAP2-selective inhibitor, effectively inhibits human mesothelioma xenograft growth in animal models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3446. doi:10.1158/1538-7445.AM2013-3446