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.
Authors: McCracken Paul J. , Ito Ken , Yanagimachi Mamoru , Tizon Xavier , Provent Peggy , Xu Shanqin , Kumar Namita , Welsh Denice , Teceno Tyler J. , Kuznetsov Galina , Funahashi Yasuhiro 
Published: August 2014

Objective: Eribulin mesylate (ERI) is a simplified synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and 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 eribulin on tumor vasculature using DCE-MRI of TN human breast MX-1 xenografts in nude rats.

Methods: The effects of ERI on human TN breast MX-1 and MDA-MB-231 tumor are examined in nude rats and nude mice. ERI was 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: ERI inhibited tumor growth of MX-1 (day 5; 290 +/- 169 vs 1195 +/- 36 mm3, N=5, p&lt;0.01) and MDA-MB-231 (day 6; 295 +/- 113 vs 570 +/- 56 mm3, N=5, p&lt;0.05) in nude rats compared to vehicle (VEH). DCE-MRI analysis demonstrated that, at 6 hrs, Ktrans (1/s) in the tumor rim was decreased in the ERI group (MX-1; 0.471 +/- 0.061 vs 0.611 +/- 0.082, p&lt;0.05 vs VEH and MDA-MB-231; 0.290 +/- 0.130 vs 0.537 +/- 0.132, p&lt;0.05 vs VEH). Interestingly, Ktrans in the tumor core was increased in the ERI group at later time points (MX-1 day 5; 0.723 +/- 0.155 vs 0.097 +/- 0.073, p&lt;0.05 vs VEH and MDA-MB-231 day 10; 0.612 +/- 0.187 vs 0.103 +/- 0.090, p&lt;0.01 vs VEH). The effects of ERI on tumor vasculature function were reproduced in a mouse MX-1 xenograft model. The trend towards a decrease in Ktrans 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&lt;0.05) suggests ERI may cause an acute shutdown of vascular function. In endothelial cells, lack of significant change by IHC at 6hrs and no increased apoptosis at 24hrs in vitro indicate the acute activity may be different from vascular disrupting agents. IHC analysis of tumor vasculature morphology was performed to investigate the increase in the tumor core Ktrans at day 5. Results demonstrated that ERI treated tumors had higher MVD compared to VEH along with decreased vessel perimeter in mice, indicating ERI affected tumor vascular morphology, suggestive of vascular normalization.

Conclusions: ERI altered 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, ERI may have induced normalization of tumor vasculature in preclinical TN breast cancer cell models. Further analysis of the mechanism of ERI on 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, Galina Kuznetsov, Yasuhiro Funahashi. Eribulin alters 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