Antitumor activity of Triolimus: a novel multidrug-loaded micelle containing Paclitaxel, Rapamycin, and 17-AAG.

Triolimus is a first-in-class, multidrug-loaded micelle containing paclitaxel, rapamycin, and 17-AAG. In this study, we examine the antitumor mechanisms of action, efficacy, and toxicity of Triolimus in vitro and in vivo. In vitro cytotoxicity testing of Triolimus was conducted using two aggressive adenocarcinomas including the lung cancer cell line, A549, and breast cancer cell line, MDA-MB-231. The three-drug combination of paclitaxel, rapamycin, and 17-AAG displayed potent cytotoxic synergy in both A549 and MDA-MB-231 cell lines. Mechanistically, the drug combination inhibited both the Ras/Raf/mitogen-activated protein kinase and PI3K/Akt/mTOR pathways. Triolimus was advanced into tumor xenograft models for assessment of efficacy, toxicity, and mechanisms of action. In vivo, a three-infusion schedule of Triolimus inhibited A549 and MDA-MB-231 tumor growth far more potently than paclitaxel-containing micelles and effected tumor cures in MDA-MB-231 tumor-bearing animals. Tumor growth delays resulted from a doubling in tumor cell apoptosis and a 50% reduction in tumor cell proliferation compared with paclitaxel-containing micelles. Enhanced antitumor efficacy was achieved without clinically significant increases in acute toxicity. Thus, Triolimus displays potent synergistic activity in vitro and antitumor activity in vivo with comparable toxicity to paclitaxel. These observations provide strong support for further development of Triolimus and an important proof of concept for safe, effective nanoparticle-based delivery of three complementary anticancer agents.

Efficacy of Tie2 receptor antagonism in angiosarcoma.

Angiosarcomas are malignant endothelial cell tumors with few effective systemic treatments. Despite a unique endothelial origin, molecular candidates for targeted therapeutic intervention have been elusive. In this study, we explored the tunica internal endothelial cell kinase 2 (Tie2) receptor as a potential therapeutic target in angiosarcoma. Human angiosarcomas from diverse sites were shown to be universally immunoreactive for Tie2. Tie2 and vascular endothelial growth factor receptor (VEGFR) antagonists inhibited SVR and MS1-VEGF angiosarcoma cell survival in vitro. In the high-grade SVR cell line, Tie2 and VEGF antagonists inhibited cell survival synergistically, whereas effects were largely additive in the low-grade MS1-VEGF cell line. Xenograft modeling using these cell lines closely recapitulated the human disease. In vivo, Tie2 and VEGFR inhibition resulted in significant angiosarcoma growth delay. The combination proved more effective than either agent alone. Tie2 inhibition seemed to elicit tumor growth delay through increased tumor cell apoptosis, whereas VEGFR inhibition reduced tumor growth by lowering tumor cell proliferation. These data identify Tie2 antagonism as a potential novel, targeted therapy for angiosarcomas and provide a foundation for further investigation of Tie2 inhibition, alone and in combinations, in the management of this disease.