The emerging role of mammalian target of rapamycin inhibitors in the treatment of sarcomas.

The mammalian target of rapamycin (mTOR) is a protein kinase that functions as a key regulator of cell growth, proliferation and differentiation, cell-cycle progression, angiogenesis, protein degradation, and apoptosis. Following activation by a number of oncogenic signals such as growth factors, energy and nutrients, mTOR stimulates several downstream effectors including the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4 E binding protein-1 (4 EBP-1), as well as a complex network of regulatory loops. Activation of the mTOR pathway plays a critical role in the development of many tumor types, including renal cell and breast carcinomas, neuroendocrine tumors, and sarcomas. Bone and soft tissue sarcomas are rare, heterogeneous tumors that are curable by local treatments if diagnosed at early stages; however advanced or metastatic sarcomas are rarely curable and very few drugs are efficacious in this setting. Several disruptions in phosphatidylinositol-3 kinase (PI3K)-Akt-mTOR signaling are associated with malignant transformation or progression in various sarcoma sub-types. The PI3K-Akt-mTOR pathway is therefore an exciting target for therapy of sarcomas, and its blockade represents an opportunity to improve outcomes in this poor-prognosis disease. Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments. This article discusses the mTOR signaling pathway and summarizes the clinical experience with mTOR inhibitors in patients with advanced or metastatic sarcoma.