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The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation. PLoS One 2015;10(12):e0145197

Date

12/29/2015

Pubmed ID

26709919

Pubmed Central ID

PMC4692435

DOI

10.1371/journal.pone.0145197

Scopus ID

2-s2.0-84957575669 (requires institutional sign-in at Scopus site)   18 Citations

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.

Author List

Hesketh AJ, Maloney C, Behr CA, Edelman MC, Glick RD, Al-Abed Y, Symons M, Soffer SZ, Steinberg BM

Author

Caroline Maloney MD Assistant Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anilides
Animals
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Endothelium
Female
Guanidines
Humans
Hydrazones
Macrophages
Mice
Mice, Nude
Neoplasm Invasiveness
Neoplasm Metastasis
Sarcoma, Ewing
Xenograft Model Antitumor Assays