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. 2010 Dec 1;55(6):1126-33.
doi: 10.1002/pbc.22712.

Initial Testing (Stage 1) of the Multi-Targeted Kinase Inhibitor Sorafenib by the Pediatric Preclinical Testing Program

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Free PMC article

Initial Testing (Stage 1) of the Multi-Targeted Kinase Inhibitor Sorafenib by the Pediatric Preclinical Testing Program

Stephen T Keir et al. Pediatr Blood Cancer. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Sorafenib in vitro activity. Top panel: The median IC50 ratio graph shows the relative IC50 values for the cell lines of the PPTP panel. Each bar represents the ratio of the panel IC50 to the IC50 value of the indicated cell line. Bars to the right represent cell lines with higher sensitivity, while bars to the left indicate cell lines with lesser sensitivity. Bottom panels: Representative dose response curves for B: BT12 (rhabdoid) and C: Kasumi-1 (AML) cell lines.
Figure 2
Figure 2
Sorafenib activity against individual solid tumor xenografts. Kaplan-Meier curves for EFS, median relative tumor volume graphs, and individual tumor volume graphs are shown for selected lines: (A) OS17, and (B) OS33, osteosarcomas, (C) BT28 medulloblastoma and (D) TC-71 Ewing sarcoma xenografts. Controls (gray lines); Treated (black lines).
Figure 3
Figure 3
Sorafenib in vivo objective response activity, left: The colored heat map depicts group response scores. A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥ 2 but < 6, and low activity by a score of < 2. Right: representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.
Figure 4
Figure 4
VEGFA gene expression (Affymetrix U133 Plus 2.0) in PPTP cell lines and xenografts as visualized using GeneSifter software (VizX Labs, Seattle, WA). Gray indicates an absent call from Affymetrix quality control. Gene expression analysis methods are as previously described [47].

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