Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: could the combination with other drugs improve its antitumoral effect?

Abstract

Background Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). Methods In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. Results Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. Conclusions Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

Factors predictive of second‐line chemotherapy in soft tissue sarcoma: An analysis of the National Genomic Profiling Database

“…Eribulin was not highly effective against LMS but had a higher response rate than trabectedin and pazopanib in several, rare sarcomas. STS in the TERT ‐mutated cluster, including MLPS and SFT, had a high response rate that was consistent with the findings of previous in vitro and in vivo studies 48,50,51 . TERT ‐mutation status may be a potential, predictive biomarker for eribulin.…”

“…STS in the TERT ‐mutated cluster, including MLPS and SFT, had a high response rate that was consistent with the findings of previous in vitro and in vivo studies. 48 , 50 , 51 TERT ‐mutation status may be a potential, predictive biomarker for eribulin. In clustering analysis, STS associated with the MDM2 (amp)/ TP53 (WT)/ RB1 (WT) cluster (#6), which generally corresponds to DDLPS, showed a trend toward lower eribulin efficacy.…”

Efficacy of Eribulin Plus Gemcitabine Combination in L-Sarcomas

“…The use of eribulin for LMS has not been supported because, in a subgroup analysis, there was no apparent difference between eribulin and dacarbazine (standard active drug in this pathology) in OS (12.8 months in the eribulin arm and 12.3 months in the dacarbazine arm, respectively) and PFS (2.6 months in both treatment arms) [6]. In our study, we observed that the IC 50 of eribulin for our cell lines is in the nanomolar range, as demonstrated by Hayasaka et al [27], Stehle et al [28], and by Escudero et al in a panel of STS cell lines [29]. Our LMS cell lines are more sensitive to eribulin than LPS cell lines, contrary to what has been published in several clinical trials, so we are providing new data supporting the use of eribulin also for LMS.…”

Preclinical Models of Visceral Sarcomas

“…In this regard, Escudero and colleagues assessed the effect of eribulin (an antitumor agent approved for advanced liposarcoma treatment) on inhibiting the proliferation, migration, and invasion of LPSs and LMSs in 3D spheroid cell cultures. For the first time, they explored erilubin's action under 3D conditions in LMSs and LPSs, demonstrating an increase in the GI 50 (growth inhibitory concentration by 50%) values to a nanomolar range compared to in a 2D cellular context [54].…”