Neoplasia: An International Journal for Oncology Research (Jan 2012)

Comparisons of the Efficacy of a Jak1/2 Inhibitor (AZD1480) with a VEGF Signaling Inhibitor (Cediranib) and Sham Treatments in Mouse Tumors Using DCE-MRI, DW-MRI, and Histology

  • Mary E. Loveless,
  • Deborah Lawson,
  • Michael Collins,
  • Murali V. Prasad Nadella,
  • Corinne Reimer,
  • Dennis Huszar,
  • Jane Halliday,
  • John C. Waterton,
  • John C. Gore,
  • Thomas E. Yankeelov

DOI
https://doi.org/10.1593/neo.111478
Journal volume & issue
Vol. 14, no. 1
pp. 54 – 64

Abstract

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Jak1/2 inhibition suppresses STAT3 phosphorylation that is characteristic of many cancers. Activated STAT3 promotes the transcription of factors that enhance tumor growth, survival, and angiogenesis. AZD1480 is a novel small molecule inhibitor of Jak1/2, which is a key mediator of STAT3 activation. This study examined the use of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) biomarkers in assessing early tumor response to AZD1480. Cediranib (AZD2171), a vascular endothelial growth factor signaling inhibitor, was used as a comparator. Thirty mice were injected with Calu-6 lung cancer cells and randomized into the three treatment groups: AZD1480, cediranib, and sham. DW-MRI and DCE-MRI protocols were performed at baseline and at days 3 and 5 after treatment. The percent change from baseline measurements for Ktrans, ADC, and ve were calculated and compared with hematoxylin and eosin (H&E), CD31, cParp, and Ki-67 histology data. Decreases in Ktrans of 29% (P < .05) and 53% (P < .05) were observed at days 3 and 5, respectively, for the cediranib group. No significant changes in Ktrans occurred for the AZD1480 group, but a significant increase in ADC was demonstrated at days 3 (63%, P < .05) and 5 (49%, P < .05). CD31 staining indicated diminished vasculature in the cediranib group, whereas significantly increased cParp staining for apoptotic activity and extracellular space by image analysis of H&E were present in the AZD1480 group. These imaging biomarker changes, and corresponding histopathology, support the use of ADC, but not Ktrans, as a pharmacodynamic biomarker of response to AZD1480 at these time points.