title: Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice.
abstract: Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here, we investigated whether the small-molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130(F/F) mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo.
authors.affiliation: Corresponding Author: Matthias Ernst, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia. Matthias.Ernst@wehi.edu.au.
authors.forename: Emma
authors.initials: E
authors.lastname: Stuart
authors.forename: Michael
authors.initials: M
authors.lastname: Buchert
authors.forename: Tracy
authors.initials: T
authors.lastname: Putoczki
authors.forename: Stefan
authors.initials: S
authors.lastname: Thiem
authors.forename: Ryan
authors.initials: R
authors.lastname: Farid
authors.forename: Joachim
authors.initials: J
authors.lastname: Elzer
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.forename: Paul M
authors.initials: PM
authors.lastname: Waring
authors.forename: Toby J
authors.initials: TJ
authors.lastname: Phesse
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: C545606:AZD 1480; D018809:Proliferating Cell Nuclear Antigen; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D053613:Janus Kinase 1; D053614:Janus Kinase 2