title: Interleukin-6 as a therapeutic target in human ovarian cancer.
abstract: OBJECTIVE
  We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network.
  
  
  METHODS
  We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer.
  
  
  RESULTS
  Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies.
  
  
  CONCLUSIONS
  IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies.
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, UK.
authors.forename: Jermaine
authors.initials: J
authors.lastname: Coward
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.forename: David
authors.initials: D
authors.lastname: Leader
authors.forename: Vessela
authors.initials: V
authors.lastname: Vassileva
authors.forename: D Andrew
authors.initials: DA
authors.lastname: Leinster
authors.forename: Richard
authors.initials: R
authors.lastname: Thompson
authors.forename: Tiziana
authors.initials: T
authors.lastname: Schioppa
authors.forename: Jeffery
authors.initials: J
authors.lastname: Nemeth
authors.forename: Jessica
authors.initials: J
authors.lastname: Vermeulen
authors.forename: Naveena
authors.initials: N
authors.lastname: Singh
authors.forename: Norbert
authors.initials: N
authors.lastname: Avril
authors.forename: Jeff
authors.initials: J
authors.lastname: Cummings
authors.forename: Elton
authors.initials: E
authors.lastname: Rexhepaj
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.forename: Donal J
authors.initials: DJ
authors.lastname: Brennan
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D045744:Cell Line, Tumor; D019295:Computational Biology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors; C504234:siltuximab