Skip to main content
Journal cover image

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

Publication ,  Journal Article
Lock, RB; Carol, H; Morton, CL; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Wozniak, AW; Gorlick, R; Kolb, EA; Houghton, PJ; Smith, MA
Published in: Pediatr Blood Cancer
June 2012

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 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. RESULTS: 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). 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.

Duke Scholars

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

June 2012

Volume

58

Issue

6

Start / End Page

916 / 923

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Sarcosine
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice
  • Inhibitory Concentration 50
  • Humans
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lock, R. B., Carol, H., Morton, C. L., Keir, S. T., Reynolds, C. P., Kang, M. H., … Smith, M. A. (2012). Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer, 58(6), 916–923. https://doi.org/10.1002/pbc.23176
Lock, Richard B., Hernan Carol, Christopher L. Morton, Stephen T. Keir, C Patrick Reynolds, Min H. Kang, John M. Maris, et al. “Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program.Pediatr Blood Cancer 58, no. 6 (June 2012): 916–23. https://doi.org/10.1002/pbc.23176.
Lock RB, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, et al. Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Jun;58(6):916–23.
Lock, Richard B., et al. “Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 58, no. 6, June 2012, pp. 916–23. Pubmed, doi:10.1002/pbc.23176.
Lock RB, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, Maris JM, Wozniak AW, Gorlick R, Kolb EA, Houghton PJ, Smith MA. Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer. 2012 Jun;58(6):916–923.
Journal cover image

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

June 2012

Volume

58

Issue

6

Start / End Page

916 / 923

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Sarcosine
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice
  • Inhibitory Concentration 50
  • Humans
  • Female