Mechanisms of mammalian target of rapamycin inhibition in sarcoma: present and future

The mammalian target of rapamycin (mTOR) is a protein kinase that plays a pivotal role in the control of cell growth and development. A part of the PI3K/Akt pathway, mTOR responds to growth factor stimuli as well as nutrient availability by variations in downstream phosphorylation. Increasing knowledge of the upstream regulators and downstream targets of mTOR has led to the development of anticancer drugs that suppress protein synthesis and metabolism. Rapamycin (sirolimus) and three rapamycin analogues are currently being evaluated in clinical trials: temsirolimus (CCI-779, Wyeth), everolimus (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals Inc.). This review will highlight the role of these inhibitors in the treatment of sarcoma.