Therapeutic potential of target of rapamycin inhibitors.
Target of rapamycin (TOR) functions within the cell as a transducer of information from various sources, including growth factors, energy sensors, and hypoxia sensors, as well as components of the cell regulating growth and division. Blocking TOR function mimics amino acid, and to some extent, growth factor deprivation and has a cytostatic effect on proliferating cells in vivo. Inhibition of TOR in vivo, utilising its namesake rapamycin, leads to immunosuppression. This property has been exploited successfully with the use of rapamycin and its derivatives as a therapeutic agent in the prevention of organ rejection after transplantation with relatively mild side effects when compared to other immunosuppressive agents. The cytostatic effect of TOR on vascular smooth muscle cell proliferation has also recently been exploited in the therapeutic application of rapamycin to drug eluting stents for angioplasty. These stents significantly reduce the amount of arterial reblockage that results from proliferating vascular smooth muscle cells. In cancer, the effect of blocking TOR function on tumour growth and disease progression is currently of major interest and is the basis for a number of ongoing clinical trials. However, different cell types and tumours respond differently to TOR inhibition, and TOR is clearly not cytostatic for all types of cancer cells in vitro or in vivo. As the molecular details of how TOR functions and the targets of TOR activity are further elucidated, tumour and tissue specific functions are being identified that implicate TOR in angiogenesis, apoptosis, and the reversal of some forms of cellular transformation. This review will describe our current understanding of TOR function, describe the current strategies for employing TOR inhibitors in clinical and preclinical development, and outline future strategies for appropriate targets of TOR inhibitors in the treatment of disease.
Easton
John B
JB
St. Jude Childrens Research Hospital, Department of Molecular Pharmacology, 332 N. Lauderdale Street, Memphis, TN 38105-2794, USA.
Houghton
Peter J
PJ
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001157:Arterial Occlusive Diseases / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D002986:Clinical Trials as Topic; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011183:Postoperative Complications / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D015607:Stents; D058570:TOR Serine-Threonine Kinases; D014945:Wound Healing / Q000187:drug effects
D000970:Antineoplastic Agents; D006133:Growth Substances; D007166:Immunosuppressive Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus