title: The TWEAK receptor Fn14 is a therapeutic target in melanoma: immunotoxins targeting Fn14 receptor for malignant melanoma treatment.
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.
authors.affiliation: Department of Experimental Therapeutics, UT M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Suhendan
authors.initials: S
authors.lastname: Ekmekcioglu
authors.forename: John W
authors.initials: JW
authors.lastname: Marks
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Mohamedali
authors.forename: Kaushal
authors.initials: K
authors.lastname: Asrani
authors.forename: Keeley K
authors.initials: KK
authors.lastname: Phillips
authors.forename: Sharron A N
authors.initials: SA
authors.lastname: Brown
authors.forename: Emily
authors.initials: E
authors.lastname: Cheng
authors.forename: Michele B
authors.initials: MB
authors.lastname: Weiss
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenblum
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics*; D000922:Immunotoxins / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics*; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology; D000074050:TWEAK Receptor; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D007155:Immunologic Factors; D000922:Immunotoxins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse