2. Academic Validation
  3. Mitigation of Tumor-Associated Fibroblast-Facilitated Head and Neck Cancer Progression With Anti-Hepatocyte Growth Factor Antibody Ficlatuzumab

Mitigation of Tumor-Associated Fibroblast-Facilitated Head and Neck Cancer Progression With Anti-Hepatocyte Growth Factor Antibody Ficlatuzumab

  • JAMA Otolaryngol Head Neck Surg. 2015 Dec;141(12):1133-9. doi: 10.1001/jamaoto.2015.2381.
Dhruv Kumar 1,  Christopher Kandl 1,  Chase D'Arcy Hamilton 1,  Yelizaveta Shnayder 1,  Terance Ted Tsue 1,  Kiran Kakarala 1,  Levi Ledgerwood 1,  Xiuzhi Susan Sun 2,  Hongzhou John Huang 3,  Douglas Girod 1,  Sufi Mary Thomas 4
Affiliations

Affiliations

  • 1 Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
  • 2 Departments of Grain Science and Industry, and Biological and Agricultural Engineering, Kansas State University, Kansas City.
  • 3 PepGel LLC, Manhattan, Kansas.
  • 4 Department of Otolaryngology, University of Kansas Medical Center, Kansas City4Department of Cancer Biology, University of Kansas Medical Center, Kansas City5Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City6Universi.
PMID: 26540318 DOI: 10.1001/jamaoto.2015.2381
Abstract

Importance: Ficlatuzumab can be used to treat head and neck squamous cell carcinoma (HNSCC) by inhibiting c-Met receptor-mediated cell proliferation, migration, and invasion.

Objective: To understand the effect of ficlatuzumab on HNSCC proliferation, migration, and invasion.

Design, setting, and participants: The effects of ficlatuzumab on HNSCC proliferation, invasion, and migration were tested. Mitigation of c-Met and downstream signaling was assessed by immunoblotting. The tumor microenvironment has emerged as an important factor in HNSCC tumor progression. The most abundant stromal cells in HNSCC tumor microenvironment are tumor-associated fibroblasts (TAFs). We previously reported that TAFs facilitate HNSCC growth and metastasis. Furthermore, activation of the c-Met tyrosine kinase receptor by TAF-secreted hepatocyte growth factor (HGF) facilitates tumor invasion. Ficlatuzumab is a humanized monoclonal antibody that sequesters HGF, preventing it from binding to and activating c-Met. We hypothesized that targeting the c-Met pathway with ficlatuzumab will mitigate TAF-mediated HNSCC proliferation, migration, and invasion. Representative HNSCC cell lines HN5, UM-SCC-1, and OSC-19 were used in these studies.

Exposures for observational studies: The HNSCC cell lines were treated with ficlatuzumab, 0 to 100 µg/mL, for 24 to 72 hours.

Main outcomes and measures: Ficlatuzumab inhibited HNSCC progression through c-Met and mitogen-activated protein kinase (MAPK) signaling pathway.

Results: Ficlatuzumab significantly reduced TAF-facilitated HNSCC cell proliferation (HN5, P < .001; UM-SCC-1, P < .001), migration (HN5, P = .002; UM-SCC-1, P = .01; and OSC-19, P = .04), and invasion (HN5, P = .047; UM-SCC-1, P = .03; and OSC-19, P = .04) through a 3-dimensional peptide-based hydrogel (PGmatrix). In addition, ficlatuzumab also inhibited the phosphorylation of c-Met at Tyr1234/1235 and p44/42 MAPK in HNSCC cells exposed to recombinant HGF.

Conclusions and relevance: We demonstrate that neutralizing TAF-derived HGF with ficlatuzumab effectively mitigates c-Met signaling and decreases HNSCC proliferation, migration, and invasion. Thus, ficlatuzumab effectively mitigates stromal influences on HNSCC progression.

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