Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program

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

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Background: Sorafenib is an inhibitor of multiple kinases (e.g., VEGF receptors, PDGFR, FLT3, RET, BRAF, KIT) and is approved by FDA for treatment of two adult cancers. The activity of sorafenib was evaluated against the PPTP's in vitro and in vivo panels. Procedures: Sorafenib was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1.0 nM to 10.0 μM. It was tested against the PPTP in vivo panels at a dose of 60 mg/kg administered by oral gavage daily for 5 days per week, repeated for 6 weeks. Results: In vitro sorafenib demonstrated cytotoxic activity, with a median IC50 value of 4.3 μM. Twenty of 23 cell lines had IC50 values between 1.0 and 10.0 μM. A single cell line (Kasumi-1) with an activating KIT mutation had an IC50 value <1.0 μM (IC50 = 0.02 μM). In vivo sorafenib induced significant differences in event-free survival (EFS) distribution compared to control in 27 of 36 (75%) of the evaluable solid tumor xenografts and in 1 of 8 (12.5%) of the evaluable ALL xenografts. Sorafenib induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C) in 15 of 34 (44%) evaluable solid tumor xenografts. No xenografts achieved an objective response. Conclusions: The primary in vitro activity of sorafenib was noted at concentrations above 1 μM, with the exception of a more sensitive cell line with an activating KIT mutation. The primary in vivo effect for sorafenib was tumor growth inhibition, which was observed across multiple histotypes.

Original languageEnglish (US)
Pages (from-to)1126-1133
Number of pages8
JournalPediatric Blood and Cancer
Volume55
Issue number6
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

Keywords

  • Developmental therapeutics
  • Preclinical testing
  • Tyrosine kinases

ASJC Scopus subject areas

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

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    Keir, S. T., Maris, J. M., Lock, R., Kolb, E. A., Gorlick, R., Carol, H., Morton, C. L., Reynolds, C. P., Kang, M. H., Watkins, A., Houghton, P. J., & Smith, M. A. (2010). Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program. Pediatric Blood and Cancer, 55(6), 1126-1133. https://doi.org/10.1002/pbc.22712