Hong Zhou, Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center
Suhendan Ekmekcioglu, Department of Melanoma Medical Oncology, UT M.D. Anderson Cancer Center
John W Marks, Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center
Khalid A Mohamedali, Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center
Kaushal Asrani, Departments of Surgery and Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Keeley K Phillips, Departments of Surgery and Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Sharron A N Brown, Departments of Surgery and Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Emily Cheng, Departments of Surgery and Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Michele B Weiss, Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Walter N Hittelman, Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center
Nhan L Tran, Translational Genomics Research Institute
Hideo Yagita, Department of Immunology, Juntendo University School of Medicine
Jeffrey A Winkles, Departments of Surgery and Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine
Michael G Rosenblum, Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center

Document Type

Article

Publication Date

4-1-2013

Comments

This article has been peer reviewed. It was published in: Journal of Investigative Dermatology.

Volume 133, Issue 4, April 2013, Pages 1052-1062.

The published version is available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600159/. DOI: 10.1038/jid.2012.402

Copyright © 2013 The Society for Investigative Dermatology.

Abstract

Fibroblast growth factor-inducible protein 14 (Fn14), the cell surface receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is overexpressed in various human solid tumor types and can be a negative prognostic indicator. We detected Fn14 expression in ∼60% of the melanoma cell lines we tested, including both B-Raf WT and B-Raf(V600E) lines. Tumor tissue microarray analysis indicated that Fn14 expression was low in normal skin, but elevated in 173/190 (92%) of primary melanoma specimens and in 86/150 (58%) of melanoma metastases tested. We generated both a chemical conjugate composed of the recombinant gelonin (rGel) toxin and the anti-Fn14 antibody ITEM-4 (designated ITEM4-rGel) and a humanized, dimeric single-chain antibody of ITEM-4 fused to rGel (designated hSGZ). Both ITEM4-rGel and hSGZ were highly cytotoxic to a panel of different melanoma cell lines. Mechanistic studies showed that both immunotoxins induced melanoma cell necrosis. In addition, these immunotoxins could upregulate the cellular expression of Fn14 and trigger cell-signaling events similar to the Fn14 ligand TWEAK. Finally, treatment of mice bearing human melanoma MDA-MB-435 xenografts with either ITEM4-rGel or hSGZ showed significant tumor growth inhibition compared with controls. We conclude that Fn14 is a therapeutic target in melanoma and the hSGZ construct appears to warrant further development as a therapeutic agent against Fn14-positive melanoma.

PubMed ID

23190886

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