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Biological Effects of Temsirolimus on the mTOR Pathway in Endometrial Carcinoma: A Pharmacodynamic Phase II Study
Maria Santacana1, Pluvio Coronado, Xavier Matias-Guiu
1*Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLleida, Lleida; †Hospital Clínico Universitario Clínico San Carlos, Madrid; ‡Fundación Instituto Valenciano de Oncología, Valencia; §Hospital Universitari Valle dHebron, Barcelona; ∥Foundation MD Anderson Cancer Centre Madrid, and Department of Biochemistry, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomedicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid; and ¶MedSIR ARO, Barcelona, Spain.
Objective:
The PI3K/AKT/mTOR pathway is frequently aberrantly activated in endometrial carcinoma (EC). Temsirolimus is an mTOR inhibitor that has shown clinical activity in EC. We aimed to characterize the biological effects on mTOR pathway of temsirolimus in treatment-naive patients with primary EC, and to identify potential biomarkers associated with a short-term exposure to temsirolimus.
Materials And Methods:
Patients with EC were treated with 4 doses of temsirolimus previous to surgery. The primary objective was the analysis of paired endometrial aspirates and posttreatment (hysterectomy specimens) tumor tissue samples for mTOR downstream effectors p-S6K1 and p-4BEP1 levels by immunohistochemistry. Secondary objectives included analysis of expression of other mTOR-related biomarkers by immunohistochemistry, as well as analysis of the predictive value of mutations in mTOR-related genes. Toxicity was also assessed.
Results:
Eleven patients were included in the study. p-S6K1 expression was reduced after treatment with temsirolimus in all patients. Variations of the expression of other mTOR-related proteins including p-4BEP1, PTEN, p-AKT, p53, p27, BAD, Bcl-2, Ki67, and cyclin D1 were also observed. Interestingly, the biological effects of the drug were more evident 1 week after the last dose of temsirolimus. Effects were less evident on tumors harboring mutations in NRAS. Toxicity was acceptable, being mucositis the most frequent adverse event.
Conclusions:
Short temsirolimus exposure effectively inhibits mTOR pathway in patients with endometrial cancer. p-S6K1 expression is a promising biomarker of sensitivity. The preoperative window opportunity in EC is a realistic scenario for biological knowledge and target development.
Insights
Short-term temsirolimus effectively inhibits the PI3K/AKT/mTOR pathway in endometrial cancer (EC). Reduced p-S6K1 expression indicates sensitivity, highlighting the potential of preoperative treatment for biomarker development.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Endometrial carcinoma (EC) frequently exhibits aberrant activation of the PI3K/AKT/mTOR pathway.
- Temsirolimus, an mTOR inhibitor, has demonstrated clinical efficacy in EC.
Purpose of the Study:
- To assess the biological impact of short-term temsirolimus exposure on the mTOR pathway in treatment-naive EC patients.
- To identify potential biomarkers predictive of response to temsirolimus therapy.
Main Methods:
- Eleven EC patients received four doses of temsirolimus pre-surgery.
- Paired tumor samples were analyzed for mTOR downstream effectors (p-S6K1, p-4BEP1) via immunohistochemistry.
- Expression of other mTOR-related proteins and gene mutations were evaluated; toxicity was assessed.
Main Results:
- Temsirolimus treatment led to reduced p-S6K1 expression in all patients.
- Variations in other mTOR pathway proteins (p-4BEP1, PTEN, p-AKT, etc.) were observed.
- Biological effects were most pronounced one week post-treatment and less evident in tumors with NRAS mutations; toxicity was acceptable.
Conclusions:
- Short-term temsirolimus effectively inhibits the mTOR pathway in EC.
- p-S6K1 expression serves as a promising biomarker for temsirolimus sensitivity.
- Preoperative treatment offers a viable window for biological insights and target development in EC.
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