Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program

Richard B. Lock, Hernan Carol, Christopher L. Morton, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, John M. Maris, Amy W. Wozniak, Richard Gorlick, E. Anders Kolb, Peter J. Houghton, Malcolm A. Smith

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Abstract

Background: 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. Procedures: GSK923295A was evaluated against the 23 cell lines in the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96hr exposures to concentrations ranging from 1.0nM to 10.0μM. 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 125mg/kg. Results: The median IC 50 for all PPTP cell lines was 27nM, with the median IC 50 for the ALL panel being the lowest (18nM) and for the neuroblastoma panel the highest (39nM). 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). Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)916-923
Number of pages8
JournalPediatric Blood and Cancer
Volume58
Issue number6
DOIs
StatePublished - Jun 1 2012

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Keywords

  • Developmental therapeutics
  • GSK923295A
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Lock, R. B., Carol, H., Morton, C. L., Keir, S. T., Reynolds, C. P., Kang, M. H., Maris, J. M., Wozniak, A. W., Gorlick, R., Kolb, E. A., Houghton, P. J., & Smith, M. A. (2012). Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatric Blood and Cancer, 58(6), 916-923. https://doi.org/10.1002/pbc.23176