The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors

  • Mol Cancer Ther. 2017 Nov;16(11):2486-2501. doi: 10.1158/1535-7163.MCT-17-0241.
Allison S Harney  1  2  3  4 ,  George S Karagiannis  1  3  4 ,  Jeanine Pignatelli  1  4 ,  Bryan D Smith  5 ,  Ece Kadioglu  6 ,  Scott C Wise  5 ,  Molly M Hood  5 ,  Michael D Kaufman  5 ,  Cynthia B Leary  5 ,  Wei-Ping Lu  5 ,  Gada Al-Ani  5 ,  Xiaoming Chen  1  4 ,  David Entenberg  1  3  4 ,  Maja H Oktay  1  3  7 ,  Yarong Wang  1  3  4 ,  Lawrence Chun  8 ,  Michele De Palma  6 ,  Joan G Jones  1  3  7  9 ,  Daniel L Flynn  10 ,  John S Condeelis  11  3  4
Affiliations
  • 1. Department of Anatomy & Structural Biology, Albert Einstein College of Medicine, New York, New York.
  • 2. Department of Radiology, Albert Einstein College of Medicine, New York, New York.
  • 3. Integrated Imaging Program, Albert Einstein College of Medicine, New York, New York.
  • 4. Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, New York, New York.
  • 5. Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts.
  • 6. ISREC, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland.
  • 7. Department of Pathology Albert Einstein College of Medicine, New York, New York.
  • 8. Emerald Bio, Bainbridge Island, Washington.
  • 9. Department of Epidemiology & Population Health, Albert Einstein College of Medicine, New York, New York.
  • 10. Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts. [email protected] [email protected].
  • 11. Department of Anatomy & Structural Biology, Albert Einstein College of Medicine, New York, New York. [email protected] [email protected].
PMID: 28838996 DOI: 10.1158/1535-7163.MCT-17-0241
Abstract

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral 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, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/VEGF-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor 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 protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in Cancer patients. Mol Cancer Ther; 16(11); 2486-501. ©2017 AACR.

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