A novel inhibitor of STAT3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells

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dc.contributor.author Abou-Ghazal, Mohamed K.
dc.contributor.author Kong, Ling-Yuan
dc.contributor.author Wei, Jun
dc.contributor.author Chakraborty, Arup
dc.contributor.author Qiao, Wei
dc.contributor.author Fuller, Gregory N.
dc.contributor.author Fokt, Izabela
dc.contributor.author Grimm, Elizabeth A.
dc.contributor.author Schimttling, Robert J.
dc.contributor.author Archer, Gary E.
dc.contributor.author Sampson, John H.
dc.contributor.author Priebe, Waldemar
dc.contributor.author Heimberger, Amy B.
dc.date.accessioned 2017-11-02T08:48:42Z
dc.date.available 2017-11-02T08:48:42Z
dc.date.copyright 2008 en_US
dc.date.issued 2017-11-02
dc.identifier.uri http://hdl.handle.net/10725/6478
dc.description.abstract urpose Activation of 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. Experimental Design 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 IC50 of 1.6 μM, 2.3 μM, and 1.5 μM against melanoma cell line A375, B16 and B16EGFRvIII, respectively. WP1066 suppressed the phosphorylation of JAK2 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 immunological memory or enhance humoral responses to EGFRvIII, this compound reduced the production of immunosuppressive cytokines and chemokines (TGF-β, RANTES, MCP-1, VEGF), 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. en_US
dc.language.iso en en_US
dc.title A novel inhibitor of STAT3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SOM en_US
dc.author.idnumber 201303847 en_US
dc.author.department N/A en_US
dc.description.embargo N/A en_US
dc.relation.journal Clinical Cancer Research en_US
dc.journal.volume 14 en_US
dc.journal.issue 18 en_US
dc.article.pages 5759 en_US
dc.keywords Melanoma en_US
dc.keywords STAT3 en_US
dc.keywords c-Myc en_US
dc.keywords Regulatory T cells en_US
dc.keywords Central nervous system en_US
dc.identifier.doi http://dx.doi.org/10.1158/1078-0432.CCR-08-0377 en_US
dc.identifier.ctation Kong, L. Y., Abou-Ghazal, M. K., Wei, J., Chakraborty, A., Sun, W., Qiao, W., ... & Archer Jr, G. E. (2008). A novel inhibitor of STAT3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells. Clinical cancer research: an official journal of the American Association for Cancer Research, 14(18), 5759. en_US
dc.author.email mohamed.aboughazal@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583362/ en_US
dc.author.affiliation Lebanese American University en_US

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