Therapeutic potential of target of rapamycin inhibitors

John B. Easton, Peter J Houghton

Research output: Contribution to journalReview article

69 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)551-564
Number of pages14
JournalExpert Opinion on Therapeutic Targets
Volume8
Issue number6
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

Fingerprint

Sirolimus
Therapeutics
Cytostatic Agents
Tumors
Stents
Neoplasms
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Intercellular Signaling Peptides and Proteins
Cells
Drug-Eluting Stents
Sensors
Cell proliferation
Graft Rejection
Cellular Structures
Immunosuppressive Agents
Growth
Transducers
Angioplasty

Keywords

  • Cancer
  • Immunosuppression
  • Mammalian target of rapamycin (mTOR) inhibition
  • Rapamycin
  • Transplantation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Therapeutic potential of target of rapamycin inhibitors. / Easton, John B.; Houghton, Peter J.

In: Expert Opinion on Therapeutic Targets, Vol. 8, No. 6, 01.12.2004, p. 551-564.

Research output: Contribution to journalReview article

@article{a2aa7921c4a94235a446690fdc4521c0,
title = "Therapeutic potential of target of rapamycin inhibitors",
abstract = "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.",
keywords = "Cancer, Immunosuppression, Mammalian target of rapamycin (mTOR) inhibition, Rapamycin, Transplantation",
author = "Easton, {John B.} and Houghton, {Peter J}",
year = "2004",
month = "12",
day = "1",
doi = "10.1517/14728222.8.6.551",
language = "English (US)",
volume = "8",
pages = "551--564",
journal = "Expert Opinion on Therapeutic Targets",
issn = "1472-8222",
publisher = "Informa Healthcare",
number = "6",

}

TY - JOUR

T1 - Therapeutic potential of target of rapamycin inhibitors

AU - Easton, John B.

AU - Houghton, Peter J

PY - 2004/12/1

Y1 - 2004/12/1

N2 - 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.

AB - 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.

KW - Cancer

KW - Immunosuppression

KW - Mammalian target of rapamycin (mTOR) inhibition

KW - Rapamycin

KW - Transplantation

UR - http://www.scopus.com/inward/record.url?scp=11144343679&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=11144343679&partnerID=8YFLogxK

U2 - 10.1517/14728222.8.6.551

DO - 10.1517/14728222.8.6.551

M3 - Review article

C2 - 15584862

AN - SCOPUS:11144343679

VL - 8

SP - 551

EP - 564

JO - Expert Opinion on Therapeutic Targets

JF - Expert Opinion on Therapeutic Targets

SN - 1472-8222

IS - 6

ER -