Multiple modes of action of eribulin mesylate: Emerging data and clinical implications

Abstract

Eribulin mesylate (eribulin) is a synthetic analogue of the marine-sponge natural product halichondrin B. Eribulin exhibits potent antiproliferative activities against a variety of human cancer cell types in vitro and in vivo, and is used for the treatment of certain patients with advanced breast cancer or liposarcoma who are refractory to other treatments. The antiproliferative effects of eribulin have long been attributed to its antimitotic activities. Unlike other microtubule-targeting agents, eribulin inhibits microtubule polymerization through specific plus end binding, thus interfering with microtubule dynamic instability. Non-mitotic effects of eribulin on tumor biology have also been established in laboratory settings including: tumor vasculature remodeling, increased vascular perfusion, reduced hypoxia, and phenotypic changes involving reversal of epithelial-to-mesenchymal transition (EMT), resulting in reduced capacities for migration, invasion, and seeding lung metastases in experimental models. Preclinical data suggest that increased perfusion following eribulin treatment improves delivery of subsequent drugs. Supporting evidence for eribulin's non-mitotic effects in the clinical setting include increased tumor oxygen saturation, reduced hypoxia, phenotype changes consistent with EMT reversal, and genotype changes consistent with shifts from nonendocrine-responsive, luminal B, to endocrine-responsive, luminal A, breast cancer subtypes. Finally, potential biomarkers for eribulin response have been established based on tumor-phenotype and gene-expression profiles. Overall, preclinical and clinical data support both antimitotic and non-mitotic mechanisms of eribulin that may underlie the survival benefit observed in various clinical trials.

Utility of the Absolute Lymphocyte Count and Neutrophil/Lymphocyte Ratio for Predicting Survival in Patients with Metastatic Breast Cancer on Eribulin: A Real-World Observational Study

“…Although no significant difference in OS was observed between groups with high and low ALC (c; p = 0.287), those with NLR ≥5.0 had significantly worse OS than those with NLR < 5.0 (d; p < 0.001). antitumor immunity [7,8], while the number of tumorinfiltrating lymphocytes has been known to affect the efficacy of eribulin treatment for breast cancer [23]. Given the difficulty in determining the number of tumor-infiltrating lymphocytes in daily practice, we propose the use of ALC as a predictive marker of the efficacy of eribulin, considering that a significant correlation between tumor-infiltrating lymphocytes and ALC has been already confirmed [18].…”

“…Eribulin is currently in the spotlight for its multiple modes of action [7]. Preclinical studies have shown that, besides inhibiting microtubule growth, eribulin exerts biological effects on the immune system through the suppression of the epithelial-mesenchymal transition, vascular remodeling, and tumor microenvironment improvement [7,8].…”

“…Eribulin is currently in the spotlight for its multiple modes of action [7]. Preclinical studies have shown that, besides inhibiting microtubule growth, eribulin exerts biological effects on the immune system through the suppression of the epithelial-mesenchymal transition, vascular remodeling, and tumor microenvironment improvement [7,8]. In a recent study using cancer tissue samples from patients with breast cancer receiving eribulin, it was revealed that in some patients, eribulin reduced the tumoral expression of PD-L1 and FOXP3, immunological changes which are significantly associated with better treatment response [9].…”

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients

“…Our study patients received Eribulin monotherapy independently of the HR status. Eribulin has multiple modes of action underlying its antiproliferative effect in cancer cells and survival benefit in clinical trials [34]. It is best known for its inhibitory effect on microtubule polymerization, thereby interfering with microtubule dynamics.…”

Oral Capecitabine-Vinorelbine Is Associated with Longer Overall Survival When Compared to Single-Agent Capecitabine in Patients with Hormone Receptor-Positive Advanced Breast Cancer

“…In two prospective, randomized phase III trials, the non-taxane microtubule inhibitor eribulin mesylate was associated with significantly longer OS, or with a trend towards longer OS, when compared to C or other treatments of physician choice, despite the lack of significant benefit in terms of PFS [12,25]. Potential mechanisms to explain these clinical data consist in eribulin's ability to revert epithelial-to-mesenchymal transition (EMT) and metastatic spread of breast cancer cells [26], to enhance immune system activation [27] or to remodel tumor vasculature [28,29]. Since there are no published preclinical data supporting these mechanistic explanations in the case of CV, in this study we preliminarily explored the hypothesis that CV reshapes systemic immune system activation.…”