Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models

Abstract

We previously reported that eribulin mesylate (eribulin), a tubulin‐binding drug (TBD), could remodel tumor vasculature (i.e. increase tumor vessels and perfusion) in human breast cancer xenograft models. However, the role of this vascular remodeling in antitumor effects is not fully understood. Here, we investigated the effects of eribulin‐induced vascular remodeling on antitumor activities in multiple human cancer xenograft models. Microvessel densities (MVD) were evaluated by immunohistochemistry (CD31 staining), and antitumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased MVD compared to the controls in six out of 10 models with a correlation between enhanced MVD levels and antitumor effects (R 2 = 0.54). Because of increased MVD, we next used radiolabeled liposomes to examine whether eribulin treatment would result in increased tumoral accumulation levels of these macromolecules and, indeed, we found that eribulin, unlike vinorelbine (another TBD) enhanced them. As eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance the antitumor effect of Doxil (a liposomal anticancer agent) and facilitate recruitment of immune cells into the tumor. As expected, eribulin enhanced antitumor activity of Doxil in a post‐erlotinib treatment H1650 (PE‐H1650) xenograft model. Furthermore, infiltrating CD11b‐positive immune cells were significantly increased in multiple eribulin‐treated xenografted tumors, and natural killer (NK) cell depletion reduced the antitumor effects of eribulin. These findings suggest a contribution of the immune cells for antitumor activities of eribulin. Taken together, our results suggest that vascular remodeling induced by eribulin acts as a microenvironment modulator and, consequently, this alteration enhanced the antitumor effects of eribulin.

Elimination of tumor hypoxia by eribulin demonstrated by 18F-FMISO hypoxia imaging in human tumor xenograft models

“…In both animal and clinical studies, recent evidence indicates that eribulin can induce tumor vasculature remodeling [10, 23, 28]. In this study, we found that eribulin could alleviate tumor hypoxia, concordant with the increase in the number of CD31 + microvessels.…”

High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin—but not with treatment of physician’s choice—in the EMBRACE study

“…Eribulin induced the remodelling of the tumour vasculature in a preclinical xenograft model and in patients with breast cancer in several studies [6,[15][16][17]. Additionally, eribulin induced reoxygenation by vascular remodelling in patients with advanced breast cancer and decreased transforming growth factor-beta (TGF-β), which is typically associated with hypoxic conditions [15].…”

Cinobufagin suppresses colorectal cancer angiogenesis by disrupting the endothelial mammalian target of rapamycin/hypoxia‐inducible factor 1α axis

“…CD31 is a widely used angiogenic marker for the measurement of microvessel density (MVD) . Expression of CD31 and vascular area were dose dependently decreased in tumor tissues by cinobufagin treatment (Figure E,F).…”