A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo

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.