A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo.
BACKGROUND
Most medullary thyroid carcinomas (MTC) recur or progress despite curative resection. Current targeted therapies show promise but lack durable efficacy and tolerability. The purpose of this study was to build on previous in vitro work and evaluate withaferin A (WA), a novel RET inhibitor, in a metastatic murine model of MTC.


METHODS
A total of 5 million DRO-81-1 human MTC cells injected in the left posterior neck of nu/nu mice generated metastases uniformly to the liver, spleen, and/or lungs. Treatment with WA (8 mg/kg/day, intraperitoneally, for 21 days) was started for neoplasms > 100 mm(3). Endpoints were survival, neoplasm > 15,00 mm(3), decreased body weight, or body score (all measured three times/wk).


RESULTS
All controls (saline; n = 5) died or deteriorated from metastatic disease by 7 weeks postinjection. All treated animals were alive (WA; n = 5), having tumor regression and growth delay without toxicity or weight loss at 6 weeks posttreatment (P < .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 treatment of 5 μM WA) as well as potent inhibition of phospho-ERK and phospho-Akt levels.


CONCLUSIONS
WA 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.
Department of Surgery, The University of Kansas Medical Center, Kansas City, KS, USA.
Abbas K
AK
Samadi
Ridhwi
R
Mukerji
Anuj
A
Shah
Barbara N
BN
Timmermann
Mark S
MS
Cohen
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D044963:Biopsy, Fine-Needle; D002116:Calcitonin / Q000097:blood; D018278:Carcinoma, Neuroendocrine; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009432:Neural Crest / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors*; D013964:Thyroid Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D014183:Transplantation, Heterologous / Q000379:methods / Q000473:pathology; D054358:Withanolides / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D054358:Withanolides; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; C009684:withaferin A