title: Efficient targeting of head and neck squamous cell carcinoma by systemic administration of a dual uPA and MMP-activated engineered anthrax toxin.
abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although considerable progress has been made in elucidating the etiology of the disease, the prognosis for individuals diagnosed with HNSCC remains poor, underscoring the need for development of additional treatment modalities. HNSCC is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and an assortment of matrix metalloproteinases (MMPs) that may be expressed by tumor cells, by tumor-supporting stromal cells or by both. Here we explored the use of an intercomplementing anthrax toxin that requires combined cell surface uPA and MMP activities for cellular intoxication and specifically targets the ERK/MAPK pathway for the treatment of HNSCC. We found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis. Interestingly, the human HNSCC cell lines were insensitive to the intercomplementing toxin when cultured ex vivo, suggesting that either the toxin targets the tumor-supporting stromal cell compartment or that the tumor cell requirement for ERK/MAPK signaling differs in vivo and ex vivo. This intercomplementing toxin warrants further investigation as an anti-HNSCC agent.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Schafer
authors.forename: Diane E
authors.initials: DE
authors.lastname: Peters
authors.forename: Thomas
authors.initials: T
authors.lastname: Morley
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000628:therapy*; D002294:Carcinoma, Squamous Cell; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis / Q000378:metabolism; D018307:Neoplasms, Squamous Cell / Q000628:therapy*; D000077195:Squamous Cell Carcinoma of Head and Neck; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases