Biological Effects of Temsirolimus on the mTOR Pathway in Endometrial Carcinoma: A Pharmacodynamic Phase II Study.

Abstract

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. 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. 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. 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.