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Initial testing (stage 1) of the multi‐targeted kinase inhibitor sorafenib by the pediatric preclinical testing program
Author(s) -
Keir Stephen T.,
Maris John M.,
Lock Richard,
Kolb E. Anders,
Gorlick Richard,
Carol Hernan,
Morton Christopher L.,
Reynolds C. Patrick,
Kang Min H.,
Watkins Amy,
Houghton Peter J.,
Smith Malcolm A.
Publication year - 2010
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.22712
Subject(s) - sorafenib , in vivo , medicine , ic50 , pharmacology , in vitro , kinase , cancer research , oncology , biology , hepatocellular carcinoma , biochemistry , microbiology and biotechnology
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 IC 50 value of 4.3 µM. Twenty of 23 cell lines had IC 50 values between 1.0 and 10.0 µM. A single cell line (Kasumi‐1) with an activating KIT mutation had an IC 50 value <1.0 µM (IC 50 = 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. Pediatr Blood Cancer. 2010;55:1126–1133. © 2010 Wiley‐Liss, Inc.