The TWEAK receptor Fn14 is a therapeutic target in melanoma: Immunotoxins targeting Fn14 receptor for malignant melanoma treatment

Hong Zhou, Suhendan Ekmekcioglu, John W. Marks, Khalid A. Mohamedali, Kaushal Asrani, Keeley K. Phillips, Sharron A.N. Brown, Emily Cheng, Michele B. Weiss, Walter N. Hittelman, Nhan L. Tran, Hideo Yagita, Jeffrey A. Winkles, Michael G. Rosenblum

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1052-1062
Number of pages11
JournalJournal of Investigative Dermatology
Volume133
Issue number4
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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Immunotoxins
Melanoma
Proteins
Tumors
Therapeutics
Bearings (structural)
Cells
Tissue Array Analysis
Cell signaling
Cell Line
Single-Chain Antibodies
Neoplasms
Fibroblast Growth Factors
TWEAK receptor
Cell Surface Receptors
Microarrays
Heterografts
Skin
Necrosis
Up-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

The TWEAK receptor Fn14 is a therapeutic target in melanoma : Immunotoxins targeting Fn14 receptor for malignant melanoma treatment. / Zhou, Hong; Ekmekcioglu, Suhendan; Marks, John W.; Mohamedali, Khalid A.; Asrani, Kaushal; Phillips, Keeley K.; Brown, Sharron A.N.; Cheng, Emily; Weiss, Michele B.; Hittelman, Walter N.; Tran, Nhan L.; Yagita, Hideo; Winkles, Jeffrey A.; Rosenblum, Michael G.

In: Journal of Investigative Dermatology, Vol. 133, No. 4, 01.01.2013, p. 1052-1062.

Research output: Contribution to journalArticle

Zhou, H, Ekmekcioglu, S, Marks, JW, Mohamedali, KA, Asrani, K, Phillips, KK, Brown, SAN, Cheng, E, Weiss, MB, Hittelman, WN, Tran, NL, Yagita, H, Winkles, JA & Rosenblum, MG 2013, 'The TWEAK receptor Fn14 is a therapeutic target in melanoma: Immunotoxins targeting Fn14 receptor for malignant melanoma treatment', Journal of Investigative Dermatology, vol. 133, no. 4, pp. 1052-1062. https://doi.org/10.1038/jid.2012.402
Zhou, Hong ; Ekmekcioglu, Suhendan ; Marks, John W. ; Mohamedali, Khalid A. ; Asrani, Kaushal ; Phillips, Keeley K. ; Brown, Sharron A.N. ; Cheng, Emily ; Weiss, Michele B. ; Hittelman, Walter N. ; Tran, Nhan L. ; Yagita, Hideo ; Winkles, Jeffrey A. ; Rosenblum, Michael G. / The TWEAK receptor Fn14 is a therapeutic target in melanoma : Immunotoxins targeting Fn14 receptor for malignant melanoma treatment. In: Journal of Investigative Dermatology. 2013 ; Vol. 133, No. 4. pp. 1052-1062.
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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.",
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T2 - Immunotoxins targeting Fn14 receptor for malignant melanoma treatment

AU - Zhou, Hong

AU - Ekmekcioglu, Suhendan

AU - Marks, John W.

AU - Mohamedali, Khalid A.

AU - Asrani, Kaushal

AU - Phillips, Keeley K.

AU - Brown, Sharron A.N.

AU - Cheng, Emily

AU - Weiss, Michele B.

AU - Hittelman, Walter N.

AU - Tran, Nhan L.

AU - Yagita, Hideo

AU - Winkles, Jeffrey A.

AU - Rosenblum, Michael G.

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N2 - 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.

AB - 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.

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