title: Solid tumor therapy by selectively targeting stromal endothelial cells.
abstract: Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892; shihui.liu@nih.gov sleppla@niaid.nih.gov.
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Qian
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Rasem J
authors.initials: RJ
authors.lastname: Fattah
authors.affiliation: Pathology Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Zuxi
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; shihui.liu@nih.gov sleppla@niaid.nih.gov.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D001427:Bacterial Toxins / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008840:Microfilament Proteins; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015649:Pentostatin / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D000970:Antineoplastic Agents; C523012:Antxr1 protein, mouse; C523013:Antxr2 protein, mouse; D001427:Bacterial Toxins; D014408:Biomarkers, Tumor; D008840:Microfilament Proteins; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C030325:anthrax toxin; D015649:Pentostatin; D003520:Cyclophosphamide; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf
keywords: CMG2; TEM8; angiogenesis; anthrax toxin; tumor targeting