Inhibition of p-STAT3 enhances IFN-alpha efficacy against metastatic melanoma in a murine model.

Kong LY, Gelbard A, Wei J, Reina-Ortiz C, Wang Y, Yang EC, Hailemichael Y, Fokt I, Jayakumar A, Qiao W, Fuller GN, Overwijk WW, Priebe W, Heimberger AB
Clin Cancer Res. 2010 16 (9): 2550-61

PMID: 20388845 · PMCID: PMC2936966 · DOI:10.1158/1078-0432.CCR-10-0279

PURPOSE - Melanoma is a common and deadly tumor that upon metastasis to the central nervous system has a median survival duration of <6 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. We hypothesized that WP1193, a novel inhibitor of STAT3 signaling, would enhance the antitumor activity of IFN-alpha against metastatic melanoma.

EXPERIMENTAL DESIGN - Combinational therapy of STAT3 blockade agents with IFN-alpha was investigated in a metastatic and an established syngeneic intracerebral murine tumor model of melanoma. The immunologic in vivo mechanisms of efficacy were investigated by T-cell and natural killer (NK) cell cytotoxic assays.

RESULTS - IFN-alpha immunotherapy was synergistic with WP1193 showing marked in vivo efficacy against metastatic and established intracerebral melanoma. At autopsy, it was noted that there was a decreased trend in mice with melanoma developing leptomeningeal disease treated with combinational therapy. The combinational approach enhanced both NK-mediated and T-cell-mediated antitumor cytotoxicity.

CONCLUSIONS - The immune modulatory effects of STAT3 blockade can enhance the therapeutic efficacy of IFN-alpha immunotherapy by enhancing both innate and adaptive cytotoxic T-cell activities. This combination therapy has the potential in the treatment of metastatic melanoma that is typically refractory to this type of immune therapeutic approach.

Copyright 2010 AACR.

MeSH Terms (23)

Animals Brain Neoplasms Cell Line, Tumor Cell Proliferation Cell Survival Cyanoacrylates Cytotoxicity, Immunologic Dose-Response Relationship, Drug Drug Synergism Female Immunoblotting Immunologic Factors Interferon-alpha Kaplan-Meier Estimate Killer Cells, Natural Melanoma, Experimental Mice Mice, Inbred C57BL Neoplasm Metastasis Pyridines STAT3 Transcription Factor T-Lymphocytes Treatment Outcome

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