title: The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation.
abstract: Metastatic Ewing Sarcoma carries a poor prognosis, and novel therapeutics to prevent and treat metastatic disease are greatly needed. Recent evidence demonstrates that tumor-associated macrophages in Ewing Sarcoma are associated with more advanced disease. While some macrophage phenotypes (M1) exhibit anti-tumor activity, distinct phenotypes (M2) may contribute to malignant progression and metastasis. In this study, we show that M2 macrophages promote Ewing Sarcoma invasion and extravasation, pointing to a potential target of anti-metastatic therapy. CNI-1493 is a selective inhibitor of macrophage function and has shown to be safe in clinical trials as an anti-inflammatory agent. In a xenograft mouse model of metastatic Ewing Sarcoma, CNI-1493 treatment dramatically reduces metastatic tumor burden. Furthermore, metastases in treated animals have a less invasive morphology. We show in vitro that CNI-1493 decreases M2-stimulated Ewing Sarcoma tumor cell invasion and extravasation, offering a functional mechanism through which CNI-1493 attenuates metastasis. These data indicate that CNI-1493 may be a safe and effective adjuvant agent for the prevention and treatment of metastatic Ewing Sarcoma.
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hesketh
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Department of Surgery, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Maloney
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Department of Surgery, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Behr
authors.affiliation: Department of Pathology and Laboratory Medicine, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York, United States of America.
authors.forename: Morris C
authors.initials: MC
authors.lastname: Edelman
authors.affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York, United States of America.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Glick
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Center for Molecular Innovation, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.
authors.forename: Marc
authors.initials: M
authors.lastname: Symons
authors.affiliation: Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Department of Surgery, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York, United States of America.
authors.forename: Samuel Z
authors.initials: SZ
authors.lastname: Soffer
authors.affiliation: The Elmezzi Graduate School of Molecular Medicine, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, United States of America.|Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.
authors.forename: Bettie M
authors.initials: BM
authors.lastname: Steinberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004727:Endothelium / Q000473:pathology; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000813:Anilides; D006146:Guanidines
chemical_list: D006835:Hydrazones; C097256:semapimod; D000813:Anilides; D006146:Guanidines