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Published on: September 10, 2018
Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program
E Anders Kolb1, Richard Gorlick, C Patrick Reynolds
1AI duPont Hospital for Children, Wilmington, Delaware 19803, USA.
Background:
Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers.
Procedures:
Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 microM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21.
Results:
In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1-14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR.
Conclusions:
The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine.
Insights
Eribulin shows significant anti-cancer activity in preclinical models of pediatric acute leukemias and solid tumors. This novel antimitotic agent demonstrated potent cytotoxic effects and high response rates, warranting further pediatric evaluation.
Area of Science:
- Oncology
- Pharmacology
- Pediatric Medicine
Background:
- Antimitotic agents are crucial for treating pediatric leukemias and solid tumors.
- Eribulin is a novel agent with a unique tubulin-binding mechanism, distinct from Vinca alkaloids and taxanes.
Purpose of the Study:
- To evaluate the preclinical efficacy of eribulin in pediatric acute leukemias and solid tumors.
- To compare eribulin's activity against established antimitotic agents.
Main Methods:
- In vitro testing against the PPTP cell line panel (0.1 nM to 1.0 microM).
- In vivo testing against PPTP xenograft panels (solid tumors: 1 mg/kg; ALL models: 1.5 mg/kg; q4dx3 schedule).
Main Results:
- Eribulin exhibited potent in vitro cytotoxicity (median IC50: 0.27 nM).
- In vivo, eribulin was well-tolerated and demonstrated significant event-free survival benefits in 83% of solid tumors and 100% of ALL xenografts.
- Objective responses were seen in 51% of solid tumors, with complete responses in Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma models.
Conclusions:
- Eribulin displays high preclinical activity against pediatric acute leukemias and solid tumors.
- Its activity profile in solid tumors is comparable or superior to vincristine, supporting its consideration for pediatric clinical trials.
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