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Evaluation of ABT-751 against childhood cancer models in vivo
Christopher L Morton1, Edward G Favours, Kimberly S Mercer
1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 North Lauderdale St, Memphis, TN 38105, USA.
Objective:
ABT-751 is a novel antimitotic agent that binds tubulin at the colchicine binding site. ABT-751 is undergoing Phase I trials in children, but has not been evaluated against a range of pediatric tumor models in vivo.
Materials And Methods:
ABT-751 was evaluated against 27 subcutaneously implanted xenograft models of childhood cancer including neuroblastoma [4], osteosarcoma [4], Ewing sarcoma [2] rhabdomyosarcoma [8], medulloblastoma [1] and eight kidney cancer lines (six Wilms tumors, two rhabdoid). ABT-751 was administered at 100 mg/kg P.O. on a schedule of 5 days on, 5 days off, 5 days on, repeating the cycle at 21 days. Tumor diameters were measured at 7 day intervals for a period of 12 weeks. Three measures of antitumor activity were used: (1) clinical response criteria [e.g., partial response (PR), complete response (CR), etc.]; (2) treated to control (T/C) tumor volume at day 21; and (3) a time to event measure based on the median event free survival (EFS) of treated and control lines.
Results:
ABT-751 induced regression in 4 of 25 models (16%) including models of neuroblastoma that are refractory to vincristine and paclitaxel. Other regressions occurred in rhabdomyosarcoma and Wilms tumor models. ABT-751 significantly increased event free survival (EFS > 2.0) in eight models (33%) in addition to those with objective responses.
Conclusions:
ABT-751 demonstrated intermediate activity against this tumor panel. Neuroblastoma models appear somewhat more sensitive to this agent, with objective regressions also in rhabdomyosarcoma and Wilms tumor. ABT-751 was also active in several tumor lines intrinsically refractory to vincristine or paclitaxel.
Insights
ABT-751, an antimitotic agent, showed intermediate activity in pediatric cancer models. It induced regressions in neuroblastoma, rhabdomyosarcoma, and Wilms tumors, including those resistant to other therapies.
Area of Science:
- Oncology
- Pharmacology
Background:
- ABT-751 is a novel antimitotic agent targeting tubulin at the colchicine binding site.
- The agent is currently in Phase I clinical trials for pediatric patients.
- Preclinical evaluation in diverse pediatric tumor models was lacking.
Purpose of the Study:
- To evaluate the in vivo antitumor activity of ABT-751 across a range of pediatric cancer xenograft models.
- To identify specific pediatric tumor types that are sensitive to ABT-751 treatment.
Main Methods:
- ABT-751 was tested against 27 pediatric cancer xenograft models (neuroblastoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma, kidney cancers).
- Administration involved oral dosing (100 mg/kg) on a 5-days-on, 5-days-off schedule, repeated every 21 days.
- Antitumor activity was assessed by clinical response criteria, tumor volume changes (T/C ratio), and event-free survival (EFS).
Main Results:
- ABT-751 induced objective regressions in 16% (4/25) of models, including neuroblastoma refractory to vincristine and paclitaxel.
- Regressions were also observed in rhabdomyosarcoma and Wilms tumor models.
- Event-free survival was significantly increased (EFS > 2.0) in 33% (8/25) of models, including those without objective responses.
Conclusions:
- ABT-751 demonstrated intermediate antitumor activity against the tested panel of pediatric cancer models.
- Neuroblastoma, rhabdomyosarcoma, and Wilms tumor models showed particular sensitivity to ABT-751.
- The agent's activity in tumors refractory to standard chemotherapies like vincristine and paclitaxel is noteworthy.
