title: Inhibitors of the mammalian target of rapamycin.
abstract: The mammalian target of rapamycin (mTOR) is a downstream protein kinase of the phosphatidylinositol 3'-kinase-Akt signalling pathway. As a result of its position within this pathway and its central role in controlling cellular growth, mTOR is viewed as an important target for anticancer therapeutics development. Currently, the mTOR inhibitor rapamycin (sirolimus, Wyeth) and its derivatives temsirolimus (CCI-779, Wyeth), everolimus (RAD-001, Novartis Pharma AG) and AP-23573 (Ariad Pharmaceuticals) are being evaluated in cancer clinical trials. Preclinical studies suggest that sensitivity to mTOR inhibition may correlate with aberrant activation of the phosphatidylinositol 3'-kinase pathway and/or with aberrant expression of cell-cycle regulatory or antiapoptotic proteins. Clinical trial results show that mTOR inhibitors are generally well tolerated and may induce prolonged stable disease and even tumour regressions in a subset of patients. Questions remain regarding optimal dose, schedule, patient selection and combination strategies for this novel class of agents.
authors.affiliation: Investigational Drug Branch/CTEP/DCTD, National Cancer Institute, 6130 Executive Boulevard, Room 7131 Rockville, MD 20852, USA. danceyj@ctep.nci.nih.gov
authors.forename: Janet E
authors.initials: JE
authors.lastname: Dancey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D015507:Drugs, Investigational / Q000627:therapeutic use*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases