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Updated: Jun 10, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing
Stephen T Keir1, John M Maris, Richard Lock
1Department of Surgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA. keir0001@mc.duke.edu
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.
Insights
Sorafenib showed cytotoxic effects in vitro, particularly against cell lines with KIT mutations. In vivo, it inhibited tumor growth across various cancer types, demonstrating its potential as an anti-cancer agent.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Sorafenib is a multi-kinase inhibitor approved for adult cancers.
- Its activity was assessed against in vitro and in vivo preclinical cancer models.
Purpose of the Study:
- To evaluate the efficacy of sorafenib in preclinical cancer models.
- To determine the in vitro and in vivo activity spectrum of sorafenib.
Main Methods:
- In vitro: 96-hour exposure of cell lines to sorafenib (1.0 nM to 10.0 µM).
- In vivo: Daily oral gavage of sorafenib (60 mg/kg) for 5 days/week over 6 weeks in xenograft models.
Main Results:
- In vitro: Median IC50 of 4.3 µM; one cell line (Kasumi-1) with KIT mutation showed high sensitivity (IC50 = 0.02 µM).
- In vivo: Sorafenib induced significant event-free survival differences in 75% of solid tumor xenografts and inhibited tumor growth in 44% of evaluable solid tumors.
Conclusions:
- Sorafenib's primary in vitro activity occurred above 1 µM, except for a KIT-mutated cell line.
- In vivo, sorafenib demonstrated tumor growth inhibition across multiple histotypes.
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