1. Academic Validation
  2. Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480

Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480

  • Cancer Res. 2011 Nov 1;71(21):6601-10. doi: 10.1158/0008-5472.CAN-11-1217.
Hong Xin 1 Andreas Herrmann Karen Reckamp Wang Zhang Sumanta Pal Michael Hedvat Chunyan Zhang Wei Liang Anna Scuto Shaobu Weng Deborah Morosini Zhu A Cao Michael Zinda Robert Figlin Dennis Huszar Richard Jove Hua Yu
Affiliations

Affiliation

  • 1 Department of Cancer Immunotherapeutics, Medical Oncology, Molecular Medicine, and Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Abstract

STAT3 has important functions in both tumor cells and the tumor microenvironment to facilitate Cancer progression. The STAT regulatory kinase Janus-activated kinase (JAK) has been strongly implicated in promoting oncogenesis of various solid tumors, including the use of JAK kinase inhibitors such as AZD1480. However, direct evidence that JAK drives STAT3 function and Cancer pathogenesis at the level of the tumor microenvironment is yet to be established clearly. In this study, we show that AZD1480 inhibits STAT3 in tumor-associated myeloid cells, reducing their number and inhibiting tumor metastasis. Myeloid cell-mediated angiogenesis was also diminished by AZD1480, with additional direct inhibition of endothelial cell function in vitro and in vivo. AZD1480 blocked lung infiltration of myeloid cells and formation of pulmonary metastases in both mouse syngeneic experimental and spontaneous metastatic models. Furthermore, AZD1480 reduced angiogenesis and metastasis in a human xenograft tumor model. Although the effects of AZD1480 on the tumor microenvironment were important for the observed antiangiogenic activity, constitutive activation of STAT3 in tumor cells themselves could block these antiangiogenic effects, showing the complexity of the JAK/STAT signaling network in tumor progression. Together, our results indicated that AZD1480 can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10193
    99.91%, JAK1/2 Inhibitor
    JAK