title: Inhibition of p-STAT3 enhances IFN-alpha efficacy against metastatic melanoma in a murine model.
abstract: OBJECTIVE
  Melanoma is a common and deadly tumor that upon metastasis to the central nervous system has a median survival duration of <6 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. We hypothesized that WP1193, a novel inhibitor of STAT3 signaling, would enhance the antitumor activity of IFN-alpha against metastatic melanoma.
  
  
  METHODS
  Combinational therapy of STAT3 blockade agents with IFN-alpha was investigated in a metastatic and an established syngeneic intracerebral murine tumor model of melanoma. The immunologic in vivo mechanisms of efficacy were investigated by T-cell and natural killer (NK) cell cytotoxic assays.
  
  
  RESULTS
  IFN-alpha immunotherapy was synergistic with WP1193 showing marked in vivo efficacy against metastatic and established intracerebral melanoma. At autopsy, it was noted that there was a decreased trend in mice with melanoma developing leptomeningeal disease treated with combinational therapy. The combinational approach enhanced both NK-mediated and T-cell-mediated antitumor cytotoxicity.
  
  
  CONCLUSIONS
  The immune modulatory effects of STAT3 blockade can enhance the therapeutic efficacy of IFN-alpha immunotherapy by enhancing both innate and adaptive cytotoxic T-cell activities. This combination therapy has the potential in the treatment of metastatic melanoma that is typically refractory to this type of immune therapeutic approach.
authors.affiliation: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.forename: Alexander
authors.initials: A
authors.lastname: Gelbard
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Chantal
authors.initials: C
authors.lastname: Reina-Ortiz
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Wang
authors.forename: Eric C
authors.initials: EC
authors.lastname: Yang
authors.forename: Yared
authors.initials: Y
authors.lastname: Hailemichael
authors.forename: Izabela
authors.initials: I
authors.lastname: Fokt
authors.forename: Arumugam
authors.initials: A
authors.lastname: Jayakumar
authors.forename: Wei
authors.initials: W
authors.lastname: Qiao
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003487:Cyanoacrylates / Q000737:chemistry / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015151:Immunoblotting; D007155:Immunologic Factors / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology*; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D003487:Cyanoacrylates; D007155:Immunologic Factors; D016898:Interferon-alpha; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C551527:WP 1193
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