title: Current and future directions in mammalian target of rapamycin inhibitors development.
abstract: BACKGROUND
  The mammalian target of the rapamycin (mTOR) signalling pathway has a central role in the regulation of cell growth, survival and angiogenesis and the frequent dysregulation of this pathway in tumor cells makes it a crucial target in the treatment of cancer. Temsirolimus and everolimus are approved for use in metastatic renal cell carcinoma and temsirolimus is also approved for mantle cell lymphoma. All three rapalogs, temsirolimus, everolimus and deforolimus, are currently being evaluated in Phase III studies in several tumors.
  
  
  METHODS
  This paper provides a review of the published literature on the mTOR pathway and related pathway signaling, analogs and novel mTOR inhibitors. The most recent and important data on the mTOR pathway, the role of mTOR inhibitors in cancer treatment and the current status of development of second-generation highly potent and selective mTOR inhibitors are overviewed.
  
  
  CONCLUSIONS
  The published data on new mTOR inhibitors are still limited, but the available preclinical results indicate that they have a potent antiproliferative activity against a broad panel of tumor cell lines, have a favorable safety profile, can obtain disease stabilization or even tumor regression and, in some cases, enhance the efficacy of other targeted or standard-of-care anticancer drugs when used in vivo in preclinical studies.
authors.affiliation: Istituto Nazionale dei Tumori, via Venezian 1, Milan, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Fasolo
authors.forename: Cristiana
authors.initials: C
authors.lastname: Sessa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus