Small molecule inhibition of stat3 enhances survival in mice with intracerebral melanoma

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dc.contributor.author Abou-Ghazal, Mohamed
dc.contributor.author Kong, Ling-Yuan
dc.contributor.author Chakraborty, Arup
dc.contributor.author Fuller, Greg
dc.contributor.author Madden, Timothy
dc.contributor.author Qiao, Wei
dc.contributor.author Grimm, Elizabeth
dc.contributor.author Priebe, Waldemar
dc.contributor.author Heimberger, Amy
dc.date.accessioned 2017-11-02T09:35:41Z
dc.date.available 2017-11-02T09:35:41Z
dc.date.copyright 2008 en_US
dc.date.issued 2017-11-02
dc.identifier.uri http://hdl.handle.net/10725/6480
dc.description.abstract Melanoma is a common and deadly tumor that upon metastasis to the brain, survival is less than one year. Development of new, effective therapies for metastatic melanoma that target novel pathways associated with the genesis of metastatic disease is a major unmet clinical need. Constitutive activation of STAT3 has been demonstrated in a variety of human malignancies, including melanoma. We have designed and synthesized a series of potential inhibitors of the JAK2/STAT3 pathway and identified a lead compound displaying high activity within in vivo models. In the study described here, we tested that in mouse models WP1066, a novel STAT3 pathway blockade agent, has marked in vitro and in vivo activity, even with metastasis to the brain, a site typically refractory to therapies. WP1066 achieved an IC50 of 1.6 μM, 2.3 μM, and 1.5 μM against the human melanoma cell line A375, murine melanoma cell line B16, and B16EGFRvIII, respectively. WP1066 suppressed the phosphorylation of JAK2 and phosphorylation (Tyr705) of STAT3 in all three melanoma cell lines. In addition, WP1066 decreased the level of c-Myc and survivin in melanoma cells in a dose- and time-dependent manner. Subcutaneous tumor growth of B16EGFRvIII and B16 in a syngeneic murine model in the C57BL/6J background was markedly inhibited by WP1066 compared to those in the vehicle control group (P<0.05). Long-term survival was observed in 80% of mice with established intracerebral syngeneic melanoma treated with 40 mg/kg of WP1066 in contrast to mice treated with the vehicle control that had a median survival of 15 days (P<0.001). Upon rechallenge, in the animal group that had received WP1066 via o.g., the median survival was 18 days (95% CI: 17, NA), which was significantly different compared to naïve animals challenged at the same time that had a median survival of 11 days (95% CI; 10, NA) (p<0.001); however, there were only 10% long-term survivors suggesting that treatment alone did not generate significant long-term protective immunity. Treatment via o.g. demonstrated minimal toxicity and detailed histological examination of the spleen, kidney, lung, heart, and brain by a pathologist blinded to the treatment group failed to reveal any significant abnormalities in mice treated with WP1066. These results indicate that WP1066 has therapeutic potential for the treatment of melanoma including intracerebral metastasis. Footnotes en_US
dc.language.iso en en_US
dc.publisher AACR Publications en_US
dc.title Small molecule inhibition of stat3 enhances survival in mice with intracerebral melanoma en_US
dc.type Conference Paper / Proceeding 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.identifier.ctation Kong, L. Y., Abou-Ghazal, M., Chakraborty, A., Fuller, G., Madden, T., Qiao, W., ... & Heimberger, A. (2008). Small molecule inhibition of stat3 enhances survival in mice with intracerebral melanoma. en_US
dc.author.email mohamed.aboughazal@lau.edu.lb en_US
dc.conference.date Apr 12-16, 2008 en_US
dc.conference.place San Diego, CA en_US
dc.conference.title AACR Annual Meeting en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url http://cancerres.aacrjournals.org/content/68/9_Supplement/4873.short en_US
dc.author.affiliation Lebanese American University en_US

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