title: mTOR inhibitors and their clinical application in cervical, endometrial and ovarian cancers: a critical review.
abstract: OBJECTIVE
  The mechanistic (mammalian) targets of rapamycin (mTOR) inhibitors with known growth Inhibitory effect are currently in clinical trial for treatment of human cancer. The aim of this review is to present current incorporating these new drugs as single agents or in combination with other therapeutic modalities for treatment of gynecologic cancer.
  
  
  METHODS
  A PubMed search was conducted on "mTOR inhibitors" and "human cancer". The relevant studies published between the year 2000 to present were reviewed. Those related to gynecologic cancer (cervical, endometrial and ovarian) were selected for this manuscript. The result of published data and their clinical application in gynecologic malignancies are presented.
  
  
  RESULTS
  mTOR is directly involved in many cell signaling pathways, and mTOR inhibitors have demonstrated anti-tumor activity against a variety of human malignancies, including gynecologic cancers. Combinations of mTOR inhibitors with other treatment modalities, e.g. cytotoxic chemotherapy, hormonal therapies, and other targeted molecular agents, have shown encouraging results particularly in endometrial and ovarian cancer.
  
  
  CONCLUSIONS
  Patients with advanced or recurrent gynecologic cancers who have failed initial treatment are need of new treatment modalities. There is strong evidence that mTOR inhibitors limit tumor proliferation and progression. The PI3k/AKT/mTOR pathway is often deregulated in gynecologic cancer. Patients with PIK3CA mutations are more responsive to PI3K/AKT/mTOR inhibitors than patients without these mutations. Routine screening for PIK3CA mutations warrants further investigation when PI3K/AKT/mTOR inhibitors are considered in treatment of patients with gynecologic cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Cincinnati, 231 Albert Sabin Way Cincinnati, OH 45267-0526, USA. Electronic address: nader.husseinzadeh@uc.edu.
authors.forename: Nader
authors.initials: N
authors.lastname: Husseinzadeh
authors.affiliation: Abramson Cancer Center, Division of Hematology-Oncology, University of Pennsylvania, 200 Penn Tower, 3400 Spruce St., Philadelphia, PA 19104, USA.
authors.forename: Holleh D
authors.initials: HD
authors.lastname: Husseinzadeh
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D000068338:Everolimus; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; C515074:ridaforolimus; C401859:temsirolimus; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Cervical; Endometrial; Gynecologic cancer; Ovarian cancer; mTOR