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

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 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.

• Authors: 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
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 55 Issue 6 Pg. 1126-33 (Dec 01 2010) ISSN: 1545-5017 [Electronic] United States
• PMID: 20672370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzenesulfonates
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyridines
• Niacinamide
• Sorafenib
• Receptors, Vascular Endothelial Growth Factor

Topics

• Animals
• Benzenesulfonates (therapeutic use)
• Cell Line, Tumor
• Child
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Neoplasms (drug therapy, enzymology, pathology)
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Protein Kinase Inhibitors (therapeutic use)
• Pyridines (therapeutic use)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Sorafenib
• Xenograft Model Antitumor Assays