title: Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy.
abstract: BACKGROUND
  Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy.
  
  
  METHODS
  Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin.
  
  
  RESULTS
  Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin.
  
  
  CONCLUSIONS
  The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Mir Alireza
authors.initials: MA
authors.lastname: Hoda
authors.forename: Amir
authors.initials: A
authors.lastname: Mohamed
authors.forename: Bahil
authors.initials: B
authors.lastname: Ghanim
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedus
authors.forename: Masaya
authors.initials: M
authors.lastname: Tamura
authors.forename: Judit
authors.initials: J
authors.lastname: Berta
authors.forename: Bernd
authors.initials: B
authors.lastname: Kubista
authors.forename: Balazs
authors.initials: B
authors.lastname: Dome
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Ulrike
authors.initials: U
authors.lastname: Setinek
authors.forename: Michael
authors.initials: M
authors.lastname: Micksche
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; C401859:temsirolimus; D002945:Cisplatin; D020123:Sirolimus