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

Abstract

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.

• Authors: Ling-Yuan Kong, Alexander Gelbard, Jun Wei, Chantal Reina-Ortiz, Yongtao Wang, Eric C Yang, Yared Hailemichael, Izabela Fokt, Arumugam Jayakumar, Wei Qiao, Gregory N Fuller, Willem W Overwijk, Waldemar Priebe, Amy B Heimberger
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 9 Pg. 2550-61 (May 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20388845 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright 2010 AACR.

Chemical References

• Cyanoacrylates
• Immunologic Factors
• Interferon-alpha
• Pyridines
• STAT3 Transcription Factor
• Stat3 protein, mouse
• WP 1193

Topics

• Animals
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyanoacrylates (chemistry, pharmacology)
• Cytotoxicity, Immunologic (drug effects, immunology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Female
• Immunoblotting
• Immunologic Factors (pharmacology)
• Interferon-alpha (pharmacology)
• Kaplan-Meier Estimate
• Killer Cells, Natural (drug effects, immunology, metabolism)
• Melanoma, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Neoplasm Metastasis
• Pyridines (chemistry, pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Treatment Outcome