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Targeting the dysregulated mammalian target of rapamycin pathway in organ transplantation: killing 2 birds with 1 stone.

Abstract
Dysregulation and hyperactivation of the mammalian target of rapamycin (mTOR) pathway define the molecular basis of the hamartoma syndromes, including Cowden syndrome, tuberous sclerosis complex (TSC)/lymphangioleiomyomatosis, and Peutz-Jeghers syndrome. Loss of the tumor suppressors phosphatase and tensin homolog (PTEN), TSC1, TSC2, and LKB1 results in uncontrolled growth of usually benign tumors in various organs that, however, frequently lead to organ failure. Therefore, organ transplantation is a common therapeutic option in distinct patients with hamartoma syndromes, especially those with TSC/lymphangioleiomyomatosis. mTOR inhibitors are currently used in allogeneic transplantation as immunosuppressants and for the treatment of a growing number of cancers with dysregulated mTOR/phosphoinositide 3-kinase pathway. This dual targeting provides the unique opportunity for mTOR inhibitors to affect hamartoma syndromes at the molecular level along with potent immunosuppression in transplanted individuals. Here, we review the molecular mechanisms of hamartoma syndromes and discuss the recent clinical progress in transplant patients with hamartomas. Combining the identification of novel molecular targets of the phosphoinositide 3-kinase/mTOR pathway with insights into the clinical effectiveness of current therapeutic strategies sets the stage for a broader translational potential essential for further progress both in the treatment of cancer and for transplantation.
AuthorsMichael Haidinger, Johannes Werzowa, Thomas Weichhart, Marcus D Säemann
JournalTransplantation reviews (Orlando, Fla.) (Transplant Rev (Orlando)) Vol. 25 Issue 4 Pg. 145-53 (Oct 2011) ISSN: 1557-9816 [Electronic] United States
PMID21419611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
CopyrightCopyright © 2011 Elsevier Inc. All rights reserved.
Chemical References
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
Topics
  • Animals
  • Enzyme Activation
  • Enzyme Inhibitors (therapeutic use)
  • Hamartoma (surgery)
  • Humans
  • Immunosuppressive Agents (therapeutic use)
  • Isoenzymes (metabolism)
  • Organ Transplantation
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphoinositide-3 Kinase Inhibitors
  • Signal Transduction
  • Syndrome
  • TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)

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