A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo
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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Abbas K Samadi1, Ridhwi Mukerji, Anuj Shah
1Department of Surgery, The University of Kansas Medical Center, Kansas City, KS, USA.
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 microM WA) as well as potent inhibition of phospho-ERK and phospho-Akt levels.
Conclusion:
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.
Insights
Withaferin A (WA), a novel RET inhibitor, effectively treated metastatic medullary thyroid carcinoma (MTC) in mice. This natural compound demonstrated significant tumor regression and growth delay without toxicity, showing promise for future MTC therapies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Medullary thyroid carcinoma (MTC) frequently recurs post-surgery, and current treatments lack lasting efficacy.
- Novel therapeutic strategies are needed to overcome treatment resistance in metastatic MTC.
- Withaferin A (WA), a natural compound, has shown potential as a RET inhibitor.
Purpose of the Study:
- To evaluate the efficacy of Withaferin A (WA) as a novel RET inhibitor in a metastatic murine model of MTC.
- To build upon previous in vitro findings and assess WA's therapeutic potential in a preclinical setting.
Main Methods:
- A metastatic MTC model was established by injecting human MTC cells into immunocompromised mice.
- Treatment with WA (8 mg/kg/day) was initiated for established tumors, with endpoints including survival and tumor growth.
- Western blot analysis was used to assess the inhibition of RET, ERK, and Akt signaling pathways.
Main Results:
- WA treatment led to complete survival and tumor regression in mice with metastatic MTC over a 6-week period.
- Tumor growth was significantly delayed, and no signs of toxicity or weight loss were observed in the WA-treated group.
- WA effectively inhibited total and phospho-RET levels in a dose-dependent manner, alongside potent inhibition of phospho-ERK and phospho-Akt.
Conclusions:
- Withaferin A (WA) demonstrates significant efficacy as a novel natural-product RET inhibitor in a preclinical model of metastatic MTC.
- WA exhibits potent anti-tumor activity and pathway inhibition, suggesting its potential as a therapeutic agent.
- Further long-term studies are warranted to assess the efficacy and toxicity of WA for potential clinical translation in MTC treatment.
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