Abstract 4502: Eribulin alters vascular function in human triple-negative (TN) breast MX-1 and MDA-MB-231 tumor xenograft models as measured by DCE-MRI.

Objective: Eribulin mesylate( ERI) is a simplified synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin Band an inhibitor of microtubule dynamics. Literature reports have increasingly shown tubulin binding agents have vascular disruptive activity. In this study, we evaluated the effect of eribulinon tumor vasculature using DCE-MRI of TN human breast MX-1 xenografts in nude rats. Methods: The effects of ERIon human TN breast MX-1 and MDA-MB-231 tumor are examined in nude rats and nude mice. ERIwas administered at MTD dose (0.3 mg/kg at Q4D4 in nude rats and 3.0 mg/kg at D1 in nude mice). In nude rats, DCE-MRI was conducted on a Bruker 4.7 T scanner with Magnevist contrast. Imaging was conducted on day -1, 6 hrs, day 2, day 5-6 and day 10. In nude mice, morphology of tumor vasculature was analyzed with immunohistochemistry (IHC) staining with anti-mouse endothelial marker CD31 antibody. Microvessel density ( MVD) and vessel perimeter were analyzed using Aperio Image Scope. Results and discussion: ERIinhibited tumor growth of MX-1 (day 5; 290 +/- 169 vs 1195 +/- 36 mm3, N=5, p trans (1/s) in the tumor rim was decreased in the ERIgroup (MX-1; 0.471 +/- 0.061 vs 0.611 +/- 0.082, p trans in the tumor core was increased in the ERIgroup at later time points (MX-1 day 5; 0.723 +/- 0.155 vs 0.097 +/- 0.073, p trans at 6hrs (confirmed by Hoechst dye perfusion of mouse tumor samples taken at 6 hrs showing a 70% reduction compared to VEH. N=5, p trans at day 5. Results demonstrated that ERItreated tumors had higher MVDcompared to VEH along with decreased vessel perimeter in mice, indicating ERIaffected tumor vascular morphology, suggestive of vascular normalization. Conclusions: ERIaltered tumor vasculature acutely in the tumor rim and increase vascular perfusion in the tumor core 5 days after treatment. In addition to regulation of mitosis, ERImay have induced normalization of tumor vasculature in preclinical TN breast cancer cell models. Further analysis of the mechanism of ERIon vascular normalization will be warranted. Citation Format: Paul J. McCracken, Ken Ito, Mamoru Yanagimachi, Xavier Tizon, Peggy Provent, Shanqin Xu, Namita Kumar, Denice Welsh, Tyler J. Teceno, GalinaKuznetsov, Yasuhiro Funahashi. Eribulinalters vascular function in human triple-negative (TN) breast MX-1 and MDA-MB-231 tumor xenograft models as measured by DCE-MRI. [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 4502. doi:10.1158/1538-7445.AM2013-4502