Targeting mTOR Pathways in Human Malignancies

Background: The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-Kinase (PI3K)/AKT signalling pathway with a central role in the control of cell growth, survival and angiogenesis. Multiple and frequent dysregulations of this pathway in human tumors make it a central target in the development of new anticancer treatments. Objective: To review the most significant data on mTOR pathway, role of mTOR inhibitors in cancer treatment, preclinical and clinical data of the three first generation mTOR inhibitors (temsirolimus, everolimus and deferolimus), rationales, preclinical and clinical data of second generation mTOR inhibitors. Methods: Review of published literature on mTOR and related pathways, rapalogs and novel mTOR inhibitors. Results/conclusions: Temsirolimus and everolimus have been approved for the treatment of metastatic Renal Cell Carcinoma (RCC), temsirolimus also for Mantle Cell Lymphoma (MCL) and everolimus will be approved for pancreatic neuroendocrine tumors; all three rapalogs are currently evaluated in phase III studies in several tumors. Only limited published data are available on new mTOR inhibitors; however, in vitro and in vivo in preclinical studies they have shown a significant antiproliferative activity against a broad panel of tumors and a favourable safety profile, with disease stabilization or even tumor regression, either as single agent or in combination.