Targeting mTOR for cancer treatment.
The mammalian target of rapamycin (mTOR) is involved in the control of cellular growth and proliferation. Abnormal activation of signaling pathways both proximal and distal to this kinase occurs frequently in human cancer, suggesting that mTOR is an attractive target for antineoplastic therapies. Rapamycin and its analogs inhibit mTOR and have demonstrated potent antitumor activity in vitro and in xenograft models. Several phase I and phase II clinical studies with rapamycin-like drugs have been conducted and have demonstrated antitumor activity in various types of refractory neoplasms. To date, mTOR inhibitors have been well tolerated at a wide range of doses, making the selection of phase II trial doses-based solely on toxicity criteria difficult. Assessment of the pharmacodynamic effects in surrogate tumor tissues has been used to determine the pharmacodynamically active doses. The lack of a parallel assessment of tumor tissue effects coupled with the intrinsically high interpatient variability has limited the value of these studies. A better understanding of markers that are predictive of response to mTOR inhibitors could be used for improved patient selection in clinical trials. mTOR inhibitors are promising anticancer agents; however, further studies are required to advance these drugs into the clinic. This review will describe the mTOR pathway and highlight its role as a potential drug target. Several mTOR inhibitors that are currently undergoing clinical development, and the challenges facing the development of inhibitors of this type, will also be discussed.
Rubio-Viqueira
Belen
B
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Baunting and Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, USA.
Hidalgo
Manuel
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D000068338:Everolimus; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus