Hormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma.

Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesised that mTOR inhibition would enhance sensitivity to hormonal therapy.