J. Cancer Mol. 3: 101-106, 2007

[Review Article]

Targeted mTOR in Human Gynecologic Cancers

Yi-Jen Chen

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan

Abstract:

The protein mammalian Target of Rapamycin (mTOR) is a conserved Serine/Threonine kinase that regulates cell growth and metabolism in response to environmental cues.  When growth conditions are favorable, TOR is active and cells maintain a robust rate of ribosome biogenesis, translation initiation, and nutrient import.  Aberrant high activity of mTOR complexes appears to be an underlying cause of human gynecologic cancers.  In patients with advanced or recurrent gynecologic cancer survival is greatly diminished.  At this time the focus of future research should be on the use of novel targeted agents.  mTOR inhibition represents a promising treatment strategy for endometrial and breast cancer.  The tumor growth-inhibitory properties of rapamycin were recognized early, although it was initially clinically developed for its immunosuppressive properties.  Because rapamycin has an undesirable pharmaceutical profile, including poor water-solubility, some analogues of rapamycin, such as CCI-799 (tensirolimus), RAD001 (everolimus) and AP23573 (ARIAD), have been developed with improved pharmaceutical properties.  mTOR inhibition by theses agents has shown remarkable anti-tumor activity against human gynecologic malignancies in vitro and in vivo, and these drugs are currently under evaluation in Phase I-II clinical trials.  Moreover, mTOR inhibitors enhances chemosensitivity of paclitaxel and cisplatin in ovarian and cervical cancer cells.  mTOR inhibitors may have a major role for the management of malignancies characterized by increased activity of the mTOR pathway.  mTOR is an exciting target, and future research will determine the optimal use of agents directed at this pathway.

(Keywords: mTOR; rapamycin; target therapy; mTORC1; endometrial cancer)

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Received 7/16/07; Revised 8/10/07; Accepted 8/13/07.

¹Correspondence: Dr. Yi-Jen Chen, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, No. 201, Shih-Pai Road Section 2, Taipei 112, Taiwan, Republic of China. E-mail: chenyj@vghtpe.gov.tw

²Abbreviations: TOR, Target of Rapamycin; mTOR, mammalian TOR; TORC, TOR complex; TSC1/2, tuberous sclerosis complex 1/2; S6K1, p70 ribosomal S6 kinase 1; eIF-4E, eukaryotic initiation factor 4E; 4E-BP1, eIF-4E binding protein-1; 5’TOP, 5’ tract of oligopyrimidine; AMPK, AMP-activated protein kinase.

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