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

Abstract

Background Eribulin, an inhibitor of microtubule dynamics, shows antitumor potency against a variety of solid cancers through its antivascular activity and remodeling of tumor vasculature. 18 F-Fluoromisonidazole ( 18 F-FMISO) is the most widely used PET probe for imaging tumor hypoxia. In this study, we utilized 18 F-FMISO to clarify the effects of eribulin on the tumor hypoxic condition in comparison with histological findings. Material and methods Mice bearing a human cancer cell xenograft were intraperitoneally administered a single dose of eribulin (0.3 or 1.0 mg/kg) or saline. Three days after the treatment, mice were injected with 18 F-FMISO and pimonidazole (hypoxia marker for immunohistochemistry), and intertumoral 18 F-FMISO accumulation levels and histological characteristics were determined. PET/CT was performed pre- and post-treatment with eribulin (0.3 mg/kg, i.p.). Results The 18 F-FMISO accumulation levels and percent pimonidazole-positive hypoxic area were significantly lower, whereas the number of microvessels was higher in the tumors treated with eribulin. The PET/CT confirmed that 18 F-FMISO distribution in the tumor was decreased after the eribulin treatment. Conclusions Using 18 F-FMISO, we demonstrated the elimination of the tumor hypoxic condition by eribulin treatment, concomitantly with the increase in microvessel density. These findings indicate that PET imaging using 18 F-FMISO may provide the possibility to detect the early treatment response in clinical patients undergoing eribulin treatment.

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].…”

Hypoxia and the phenomenon of immune exclusion

“…18F-FMISO enters cells via passive diffusion, where it is reduced by nitroreductase enzymes under hypoxic conditions. It forms reactive oxygen species, then binds to macromolecular cellular components and conjugates with glutathione, which causes its confinement in the cellular compartment [355][356][357]. 18F-FMISO is the most widely used tracer but is found at a relatively low concentration in tumors.…”

Indices of peripheral leukocytes predict longer overall survival in breast cancer patients on eribulin in Japan

“…It has been hypothesized that the prolonged survival effect of eribulin may be attributable to its immunomodulatory effects; by reversing epithelial-to-mesenchymal transition (EMT), eribulin induces vascular remodeling [ 8 – 12 ] and improves the tumor microenvironment [ 13 ]. Generally, hypoxia suppresses immune regulation by inducing the expression of programmed death-ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β) via the transcription factor hypoxia-inducible factor (HIF)-1.…”