Abstract 5927: Eribulin modulates tumor microenvironment through vascular remodeling for antitumor effect in multiple mouse xenograft models

Eribulin mesilate (Eribulin), a first-in-class halichondrin B-based microtubule dynamics inhibitor, has been reported to remodel tumor vasculature (i.e., improvement of tumor vessels and perfusion) in human breast cancer xenograft models; however, the role of this vascular remodeling in anti-tumor effects is not fully understood. Here, we investigated the effects of eribulin-induced vascular remodeling on anti-tumor activities in multiple human cancer xenograft models. Microvessel densities (MVDs) were evaluated by immunohistochemistry (CD31 staining), and anti-tumor effects were examined in 10 human cancer xenograft models treated with eribulin. Eribulin treatment significantly increased MVDs compared to the corresponding control groups in 7 out of 10 models with a correlation between enhanced MVD levels and anti-tumor effects (R2=0.55). Because of observed increases in MVDs, we next utilized 111In-labeled PEGylated liposomes to examine if eribulin treatment would result in increased tumoral accumulation levels of such liposomes, and indeed, we found that eribulin, unlike vinorelbine another tubulin inhibitor, enhanced them. Since eribulin treatment increased accumulation of 111In-labeled PEGylated liposomes, we postulated that this treatment might enhance anti-tumor effect of Doxil (a liposomal anti-cancer agent). As expected, eribulin enhanced anti-tumor activity of Doxil in the PE-H1650 xenograft model. Then, we evaluated whether eribulin facilitated the recruitment of immune cells into the tumor. Infiltrating CD11b-positive immune cells were significantly increased in the multiple eribulin-treated xenografted tumors, and natural killer (NK) cell depletion reduced anti-tumor effects of eribulin. Collectively, these findings suggested a contribution of the immune cells for anti-tumor activities of eribulin. Taken together, our results obtained from multiple human cancer xenograft models suggested that vascular remodeling induced by eribulin therapy would act as a microenvironment modulator, and contributed to show anti-tumor effects of eribulin. Citation Format: Ken Ito, Shusei Hamamichi, Takanori Abe, Tsuyoshi Akagi, Hiroshi Shirota, Satoshi Kawano, Makoto Asano, Osamu Asano, Akira Yokoi, Junji Matsui, Izumi O. Umeda, Hirofumi Fujii. Eribulin modulates tumor microenvironment through vascular remodeling for antitumor effect in multiple mouse xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017;