title: A novel inhibitor of signal transducers and activators of transcription 3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells.
abstract: OBJECTIVE
  Activation of signal transducers and activators of transcription 3 (STAT3) has been identified as a central mediator of melanoma growth and metastasis. We hypothesized that WP1066, a novel STAT3 blockade agent, has marked antitumor activity, even against the melanoma metastasis to brain, a site typically refractory to therapies.
  
  
  METHODS
  The antitumor activities and related mechanisms of WP1066 were investigated both in vitro on melanoma cell lines and in vivo on mice with subcutaneously syngeneic melanoma or with intracerebral melanoma tumors.
  
  
  RESULTS
  WP1066 achieved an IC(50) of 1.6, 2.3, and 1.5 mumol/L against melanoma cell line A375, B16, and B16EGFRvIII, respectively. WP1066 suppressed the phosphorylation of Janus-activated kinase 2 and STAT3 (Tyr705) in these cells. Tumor growth in mice with subcutaneously established syngeneic melanoma was markedly inhibited by WP1066 compared with that in controls. Long-term survival (>78 days) was observed in 80% of mice with established intracerebral syngeneic melanoma treated with 40 mg/kg of WP1066 in contrast to control mice who survived for a median of 15 days. Although WP1066 did not induce immunologic memory or enhance humoral responses to EGFRvIII, this compound reduced the production of immunosuppressive cytokines and chemokines (transforming growth factor-beta, RANTES, MCP-1, vascular endothelial growth factor), markedly inhibited natural and inducible Treg proliferation, and significantly increased cytotoxic immune responses of T cells.
  
  
  CONCLUSIONS
  The antitumor cytotoxic effects of WP1066 and its ability to induce antitumor immune responses suggest that this compound has potential for the effective treatment of melanoma metastatic to brain.
authors.affiliation: Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.forename: Mohamed K
authors.initials: MK
authors.lastname: Abou-Ghazal
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Arup
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Qiao
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Izabela
authors.initials: I
authors.lastname: Fokt
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grimm
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmittling
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C519885:WP1066
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