Development of human serine protease-based therapeutics targeting Fn14 and identification of Fn14 as a new target overexpressed in TNBC

Hong Zhou, Khalid A. Mohamedali, Ana Maria Gonzalez-Angulo, Yu Cao, Mary Migliorini, Lawrence H. Cheung, Janine LoBello, Xiudong Lei, Yuan Qi, Walter N. Hittelman, Jeffrey A. Winkles, Nhan L. Tran, Michael G. Rosenblum

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The cytokine TWEAK and its receptor, Fn14, have emerged as potentially valuable targets for cancer therapy. Granzyme B (GrB)-containing Fn14-targeted constructs were generated containing either the Fn14 ligand TWEAK (GrB-TWEAK) or an anti-Fn14 humanized single-chain antibody (GrB-Fc-IT4) as the targeting moieties. Both constructs showed high affinity and selective cytotoxicity against a panel of Fn14-expressing human tumor cells including triple-negative breast cancer (TNBC) lines. Cellular expression of the GrB inhibitor PI-9 in target cells had no impact on the cytotoxic effect of either construct. Cellular expression of MDR1 showed no cross-resistance to the fusion constructs. GrB-TWEAK and GrB-Fc-IT4 activated intracellular caspase cascades and cytochrome c-related proapoptotic pathways consistent with the known intracellular functions of GrB in target cells. Treatment of mice bearing established HT-29 xenografts with GrB-TWEAK showed significant tumor growth inhibition compared with vehicle alone (P < 0.05). Both GrB-TWEAK and GrB-Fc-IT4 displayed significant tumor growth inhibition when administered to mice bearing orthotopic MDA-MB-231 (TNBC) tumor xenografts. The Cancer Genome Atlas analysis revealed that Fn14 mRNA expression was significantly higher in TNBC and in HER2-positive disease (P < 0.0001) compared with hormone receptor-positive breast cancer, and in basal-like 2 tumors (P = 0.01) compared with other TNBC molecular subtypes. IHC analysis of a 101 patient TNBC tumor microarray showed that 55 of 101 (54%) of tumors stained positive for Fn14, suggesting that this may be an excellent potential target for precision therapeutic approaches. Targeting Fn14 using fully human, GrB-containing fusion constructs may form the basis for a new class of novel, potent, and highly effective constructs for targeted therapeutic applications.

Original languageEnglish (US)
Pages (from-to)2688-2705
Number of pages18
JournalMolecular cancer therapeutics
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhou, H., Mohamedali, K. A., Gonzalez-Angulo, A. M., Cao, Y., Migliorini, M., Cheung, L. H., LoBello, J., Lei, X., Qi, Y., Hittelman, W. N., Winkles, J. A., Tran, N. L., & Rosenblum, M. G. (2014). Development of human serine protease-based therapeutics targeting Fn14 and identification of Fn14 as a new target overexpressed in TNBC. Molecular cancer therapeutics, 13(11), 2688-2705. https://doi.org/10.1158/1535-7163.MCT-14-0346