title: Biologic rationale and clinical activity of mTOR inhibitors in gynecological cancer.
abstract: Advanced recurrent gynecological malignancies have a poor prognosis despite systemic treatment, which is usually cytotoxic chemotherapy. Responses are generally short-lived and more effective treatments are needed. Rationally designed molecularly targeted therapy is an emerging and important option in this setting. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway with a critical role in controlling cancer cellular growth, metabolism and cell cycle progression. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including ovarian, endometrial and cervical cancer. Early clinical studies of first-generation mTOR inhibitors have shown promising clinical activity in endometrial cancer. However, the molecular basis of sensitivity and resistance to these agents remains largely unknown. In this review, we will update the clinical and biological data underlying the development of first generation mTOR inhibitors in the treatment of gynecological tumors. The role of potential new combination regimens with mTOR inhibitors in gynecological cancers will also be discussed.
authors.affiliation: Division of Medical Oncology, Princess Margaret Hospital, University of Toronto, Ontario, Canada. ivan.padilla@uhn.on.ca
authors.forename: Ivan
authors.initials: I
authors.lastname: Diaz-Padilla
authors.forename: Ignacio
authors.initials: I
authors.lastname: Duran
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases