Harney, Allison S.Karagiannis, George S.Pignatelli, JeanineSmith, Bryan D.Kadioglu, EceWise, Scott C.Hood, Molly M.Kaufman, Michael D.Leary, Cynthia B.Lu, Wei-PingAl-Ani, GadaChen, XiaomingEntenberg, DavidOktay, Maja H.Wang, YarongChun, LawrenceDe Palma, MicheleJones, Joan G.Flynn, Daniel L.Condeelis, John S.2017-08-162017-08-162017-08-16201710.1158/1535-7163.MCT-17-0241https://infoscience.epfl.ch/handle/20.500.14299/139668WOS:000414248500015Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation and metastasis, which can offset the effects of chemotherapy, radiation, and anti-angiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and pro-tumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, anti-angiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2(hi)/VegfA(hi) macrophages in the tumor microenvironment of metastasis (TMEM). The anti-tumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by pro-tumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients.text::journal::journal article::research article