Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer

Lowy Cancer Research Centre, Randwick, NSW, Australia.
Pediatric Blood & Cancer (Impact Factor: 2.39). 06/2012; 58(6):916-23. DOI: 10.1002/pbc.23176
Source: PubMed


The centromere kinesin motor protein CENP-E plays a crucial role in mitosis, and is an appealing molecular target in cancer. GSK923295A is an allosteric inhibitor of CENP-E that is undergoing clinical evaluation.
GSK923295A was evaluated against the 23 cell lines in the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposures to concentrations ranging from 1.0 nM to 10.0 µM. GSK923295A was also tested in vivo against the PPTP acute lymphoblastic leukemia (ALL) and solid tumor xenograft panels using a days 1-3 and 8-10 schedule that was repeated at day 21. The agent was administered via the intraperitoneal (i.p.) route at a daily dose of 125 mg/kg.
The median IC(50) for all PPTP cell lines was 27 nM, with the median IC(50) for the ALL panel being the lowest (18 nM) and for the neuroblastoma panel the highest (39 nM). Excessive toxicity was observed for each of the 8 xenografts of the ALL panel in NOD/SCID mice. Thirty-five solid tumor xenograft models were considered evaluable. GSK923295A induced significant differences in event-free survival distribution compared to controls in 32 of 35 evaluable solid tumor xenografts tested. Objective responses were noted in 13 of 35 solid tumor xenografts, including 9 with maintained complete responses, and 3 with complete response (CR).
GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts. These results suggest that CENP-E may be a valuable therapeutic target in pediatric cancer.

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    • "Inhibition of CENP-E in cultured human tumor cells leads to cell cycle arrest in mitosis with bipolar mitotic spindles and misaligned chromosomes and eventual cell death. In the PPTP testing of GSK923295A, two OS xenografts met the criteria for high activity with a CR or MCR (Lock et al., 2012). These results demonstrate that CENP-E may be a valuable target in OS and suggest further in vivo evaluation in the context of tolerable doses achievable in humans. "
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