title: 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.
abstract: 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 K(trans), ADC, and v(e) were calculated and compared with hematoxylin and eosin (H&E), CD31, cParp, and Ki-67 histology data. Decreases in K(trans) of 29% (P < .05) and 53% (P < .05) were observed at days 3 and 5, respectively, for the cediranib group. No significant changes in K(trans) 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 K(trans), as a pharmacodynamic biomarker of response to AZD1480 at these time points.
authors.affiliation: Institute of Imaging Science, Vanderbilt University, Nashville, TN 37232-2310, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Loveless
authors.forename: Deborah
authors.initials: D
authors.lastname: Lawson
authors.forename: Michael
authors.initials: M
authors.lastname: Collins
authors.forename: Murali V Prasad
authors.initials: MV
authors.lastname: Nadella
authors.forename: Corinne
authors.initials: C
authors.lastname: Reimer
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.forename: Jane
authors.initials: J
authors.lastname: Halliday
authors.forename: John C
authors.initials: JC
authors.lastname: Waterton
authors.forename: John C
authors.initials: JC
authors.lastname: Gore
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Yankeelov
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; C545606:AZD 1480; C500926:cediranib; D007211:Indoles