title: Toll-like receptor 9 agonist IMO cooperates with everolimus in renal cell carcinoma by interfering with tumour growth and angiogenesis.
abstract: BACKGROUND
  Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors.
  
  
  METHODS
  We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau (VHL) gene status, both in vitro and in nude mice. We studied their direct antiangiogenic effects on human umbilical vein endothelial cells.
  
  
  RESULTS
  Both IMO and everolimus inhibited in vitro growth and survival of RCC cell lines, and their combination produced a synergistic inhibitory effect. Moreover, everolimus plus IMO interfered with EGFR-dependent signaling and reduced VEGF secretion in both VHL wild-type and mutant cells. In RCC tumour xenografts, IMO plus everolimus caused a potent and long-lasting cooperative antitumour activity, with reduction of tumour growth, prolongation of mice survival and inhibition of signal transduction. Furthermore, IMO and everolimus impaired the main endothelial cell functions.
  
  
  CONCLUSIONS
  A combined treatment with everolimus and IMO is effective in VHL wild-type and mutant models of RCC by interfering with tumour growth and angiogenesis, thus representing a potentially effective, rationale-based combination to be translated in the clinical setting.
authors.affiliation: Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli Federico II, Naples, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Damiano
authors.forename: R
authors.initials: R
authors.lastname: Rosa
authors.forename: L
authors.initials: L
authors.lastname: Formisano
authors.forename: L
authors.initials: L
authors.lastname: Nappi
authors.forename: T
authors.initials: T
authors.lastname: Gelardi
authors.forename: R
authors.initials: R
authors.lastname: Marciano
authors.forename: I
authors.initials: I
authors.lastname: Cozzolino
authors.forename: G
authors.initials: G
authors.lastname: Troncone
authors.forename: S
authors.initials: S
authors.lastname: Agrawal
authors.forename: B M
authors.initials: BM
authors.lastname: Veneziani
authors.forename: S
authors.initials: S
authors.lastname: De Placido
authors.forename: R
authors.initials: R
authors.lastname: Bianco
authors.forename: G
authors.initials: G
authors.lastname: Tortora
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000068338:Everolimus; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D009841:Oligonucleotides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D011897:Random Allocation; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D009841:Oligonucleotides; D051217:Toll-Like Receptor 9; D000068338:Everolimus; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D020123:Sirolimus