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Dose-response effect of eribulin in preclinical models of osteosarcoma by the pediatric preclinical testing
Jonathan Gill1, Wendong Zhang1, Zhongting Zhang1
1Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract:
The pediatric preclinical testing program previously demonstrated activity of eribulin in osteosarcoma patient-derived xenograft (PDX) models. The phase 2 trial in patients with relapsed osteosarcoma failed to meet response endpoints. Eribulin was evaluated in the original and an expanded set of PDX models and tested at multiple dose levels and schedules to evaluate dose-response. Maximal response was observed at the highest dose, consistent with prior results. The alternative schedule generated similar responses. We demonstrate steep dose-response for eribulin in osteosarcoma PDX models, implying that any deviation from achievement of effective concentrations may have a significant impact on activity.
Insights
Eribulin showed activity in preclinical osteosarcoma models, but a phase 2 trial failed. Further testing confirmed a steep dose-response relationship in patient-derived xenografts, highlighting the importance of effective drug concentrations.
Area of Science:
- Oncology
- Pharmacology
- Preclinical Research
Background:
- Eribulin demonstrated preclinical activity in osteosarcoma patient-derived xenograft (PDX) models.
- A subsequent phase 2 clinical trial in relapsed osteosarcoma did not meet its primary response endpoints.
- This suggests a potential disconnect between preclinical findings and clinical efficacy in osteosarcoma.
Purpose of the Study:
- To re-evaluate the dose-response relationship of eribulin in a comprehensive set of osteosarcoma PDX models.
- To investigate the impact of different dosing schedules on eribulin's efficacy.
- To understand the sensitivity of osteosarcoma to eribulin concentration.
Main Methods:
- Utilized original and expanded osteosarcoma patient-derived xenograft (PDX) models.
- Tested eribulin across multiple dose levels and administration schedules.
- Assessed tumor response to determine dose-response curves.
Main Results:
- Maximal anti-tumor response was observed at the highest tested dose of eribulin.
- Alternative dosing schedules yielded comparable response levels to standard schedules.
- A steep dose-response curve was evident, indicating high sensitivity to drug concentration.
Conclusions:
- Osteosarcoma exhibits a steep dose-response to eribulin in preclinical models.
- Achieving and maintaining effective drug concentrations is critical for eribulin activity.
- These findings underscore the importance of pharmacokinetic/pharmacodynamic considerations in clinical trial design for eribulin in osteosarcoma.
