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Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480

Hong Xin1, Andreas Herrmann, Karen Reckamp

  • 1Department 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.

Cancer Research
|September 17, 2011
PubMed

Insights

The JAK inhibitor AZD1480 reduces tumor growth by inhibiting STAT3 signaling in myeloid cells, decreasing angiogenesis and metastasis. This highlights the role of Janus-activated kinase (JAK) in cancer progression.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Signal transducer and activator of transcription 3 (STAT3) signaling is crucial for cancer progression, involving both tumor cells and the tumor microenvironment.
  • Janus-activated kinase (JAK) is implicated in oncogenesis, with inhibitors like AZD1480 being investigated.
  • The precise role of JAK in driving STAT3 function within the tumor microenvironment requires further elucidation.

Purpose of the Study:

  • To investigate the effect of AZD1480 on STAT3 signaling in the tumor microenvironment.
  • To determine if AZD1480 can inhibit myeloid cell function, angiogenesis, and metastasis.
  • To explore the therapeutic potential of targeting JAK/STAT3 signaling in cancer.

Main Methods:

  • Treatment of mouse syngeneic and spontaneous metastatic models with AZD1480.
  • Assessment of STAT3 inhibition in tumor-associated myeloid cells.
  • Evaluation of myeloid cell infiltration, angiogenesis, and pulmonary metastasis.
  • In vitro and in vivo studies on endothelial cell function.
  • Analysis of a human xenograft tumor model.

Main Results:

  • AZD1480 inhibited STAT3 in tumor-associated myeloid cells, reducing their numbers and tumor metastasis.
  • Myeloid cell-mediated angiogenesis was diminished by AZD1480.
  • AZD1480 directly inhibited endothelial cell function.
  • AZD1480 blocked myeloid cell lung infiltration and pulmonary metastasis in mouse models.
  • AZD1480 reduced angiogenesis and metastasis in a human xenograft model.
  • Constitutive STAT3 activation in tumor cells could counteract antiangiogenic effects.

Conclusions:

  • AZD1480 effectively inhibits tumor angiogenesis and metastasis by targeting STAT3 in stromal and tumor cells.
  • Targeting JAK/STAT3 signaling in the tumor microenvironment presents a viable therapeutic strategy.
  • The complexity of the JAK/STAT signaling network influences therapeutic outcomes.

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