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A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo
Samadi, Abbas K. Mukerji, Ridhwi Shah, Anuj Timmermann, Barbara N. Cohen, Mark S.
Samadi, Abbas K.
Mukerji, Ridhwi
Shah, Anuj
Timmermann, Barbara N.
Cohen, Mark S.
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Abstract
Background
Most medullary thyroid carcinomas (MTC) recur or progress despite optimal surgical resection. Current targeted-therapies show promise but lack durable efficacy and tolerability. The purpose of this study was to build upon previous in vitro work and evaluate Withaferin A (WA), a novel RET inhibitor, in a metastatic murine model of MTC.
Methods
5 million DRO-81-1 human MTC-cells injected in the left posterior neck of Nu/Nu mice uniformly generated metastases to the liver, spleen, and/or lungs. Treatment with WA (8mg/kg/day i.p.×21 days) was started for tumors >100 mm3. Endpoints were survival, tumor>1500 mm3, decreased bodyweight, or body score (all measured thrice weekly).
Results
All controls (saline; n=5) died or deteriorated from metastatic disease by 7 weeks post injection. All treated animals were alive,(WA; n=5), having tumor regression and growth-delay without toxicity or weight-loss at 6 wks post treatment; p<0.01. Tumor cells treated with WA demonstrated inhibition of total and phospho-RET levels by Western-Blot analysis in a dose-dependent manner (almost complete inhibition with 5uM WA treatment) as well as potent inhibition of phospho-ERK and phospho-AKT levels.
Conclusions
Withaferin A is a novel natural-product RET-inhibitor with efficacy in a metastatic murine model of MTC. Further long-term efficacy/toxicity studies are warranted to evaluate this compound for clinical translation.
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Date
2010-12
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Elsevier
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Citation
Samadi, Abbas K. et al. “A Novel RET Inhibitor with Potent Efficacy against Medullary Thyroid Cancer in Vivo.” Surgery 148.6 (2010): 1228–1236.