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Laboratory investigate on the therapeutic utility

Tumor-secreted cytokines/growth factors may be critical players in that they can modulate the immune system not only to suppress anti-tumor immunity but also to induce them to become pro-tumorigenic. Accordingly, Dr. Korkaya’s team provided evidence that activation of inflammatory cytokines in tumors is associated with the aggressive EMT/CSC phenotype (Oncogene. 2015, 34:671-80). Tumor-secreted cytokines modulate immune responses by regulating the Jak/Stat3/NF-kB pathway, which is negatively regulated by the suppressor of cytokine signaling 3 (SOCS3). One of the cytokines, IL6, is significantly upregulated in aggressive tumors and correlates with poor patient survival in clinical settings. In collaboration with Dr. Hollingsworth from MedImmune, the Korkaya Laboratory investigated the therapeutic utility of a novel, high-affinity anti-IL6 antibody (MEDI5117) in multiple cancer types. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. In addition, MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Furthermore, these studies demonstrated the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2+ tumor cells, by targeting the CD44+CD24+ cancer stem cell population (Cancer Res. 2016, 76(2):480-90). The Korkaya Laboratory also demonstrated, in collaboration with Dr. D. Sun of The University of Michigan, that sulforaphane (a compound found in cruciferous vegetables such as broccoli and Brussels sprouts) suppresses the growth of trastuzumab-resistant breast cancer in xenograft models by inhibiting the IL6/Stat3/NF-kB signaling pathway. (Sci Rep. 2015, 5:15821).