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.
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.
Kong
Ling-Yuan
LY
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abou-Ghazal
Mohamed K
MK
Wei
Jun
J
Chakraborty
Arup
A
Sun
Wei
W
Qiao
Wei
W
Fuller
Gregory N
GN
Fokt
Izabela
I
Grimm
Elizabeth A
EA
Schmittling
Robert J
RJ
Archer
Gary E
GE
Sampson
John H
JH
Priebe
Waldemar
W
Heimberger
Amy B
AB
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*
D000970:Antineoplastic Agents; D016207:Cytokines; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C519885:WP1066
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