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 antineoplasm therapies. Rapamycin and its analogs inhibit mTOR, and have showed potent antitumor activity in vitro and in xenograft models. Several phase I and phase II studies with rapamycin-like drug have been performed demonstrating antitumor activity in different types of refractory neoplasms. The clinical development of mTOR inhibitors exemplifies the challenges in developing targeted agents. mTOR inhibitors have been well tolerated at a wide range of doses, making the selection of phase II doses based solely on toxicity criteria difficult. Assessment of pharmacodynamic effects in surrogate tumor tissues has been used to determine pharmacodynamically active doses. Lack of parallel assessment of tumor tissue effects as well as the intrinsically high interpatient variability has limited the value of these studies. A better understanding of determinants of response to mTOR inhibitors could be used for patient selection in clinical trials. In conclusion, mTOR inhibitors are promising anticancer agents. Future studies are needed to properly develop these drugs as current cancer treatment.
Rubio-Viqueira
Belen
B
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University, School of Medicine, Baltimore, MD 21231, USA.
Hidalgo
Manuel
M
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus