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 smallmolecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammationassociated 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 intestinaltype 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. Mol Cancer Ther; 13(2); 468-74. Ó2014 AACR.

Targeted Blockade of JAK/STAT3 Signaling Inhibits Ovarian Carcinoma Growth

“…The work describing AZD1480 (16) evaluated the effects of this compound and similarly showed low or no cytotoxicity in several cultured solid tumor cell lines, but tumor growth inhibition in xenografts. Similar observations of significant tumor growth inhibition of cell line xenografts that exhibited of low in vitro cytotoxicity have been made in several solid tumor models (6, 20-25, 53). The underlying reasons for these seemingly discordant results are unclear, but may be attributed to possible effects specific to conditions of 2D-cell culture or alternatively effects of the tumor microenvironment and/or disruption of a critical cytokine-mediated signaling axis, e.g., IL-6 (6, 21).…”

“…As JAKs are key upstream mediators of STAT3 activation in solid tumors (16), we sought to determine the effects of targeted inhibition of JAKs on STAT3 activation in cell culture and mouse models of OC. To evaluate the effects of JAK/STAT3 pathway inhibition on viability, apoptosis and proliferation of OC cells, the small molecule inhibitor AZD1480 was chosen based on its potent JAK1/2-selective activity and inhibition of STAT3 signaling in several solid tumor models and have been used successfully in models of other solid tumors (6, 20-25). Exposure of human (A1847, OVCAR-5 and OVCAR-8) and murine (MOVCAR-5009 and MOVCAR-5447) OC cells to increasing concentrations of AZD1480 (0, 0.05, 0.1, 1, 5 and 10 μmol/L) for 24 hours resulted in dose dependent inhibition of STAT3 activation, measured by evaluating pSTAT3 Y705 levels by immunoblot analysis (Fig.…”

“…The therapeutic potential of targeting the JAK2/STAT3 pathway with AZD1480, a small molecule ATP-binding inhibitor of JAK1/2 (16), has been investigated in models of several non-ovarian solid tumors, including glioblastoma, breast, small cell lung, prostate and gastrointestinal cancers (6, 20-25). Based on the importance of the IL-6/JAK/STAT3 signaling axis in OC, we sought to explore the therapeutic effects of AZD1480 in the context of OC, using human OC cell lines and a transgenic mouse model that develops spontaneous OC similar to human HGSC with 100% penetrance (26, 27).…”

Molecular Pathways: IL11 as a Tumor-Promoting Cytokine—Translational Implications for Cancers

“…Thus, where adverse (on target) effects were reported for JAK inhibitors, they included anemia, neutropenia, and thrombocytopenia (68). Predictably, JAK1/2 inhibitors, such as AZD1480, impair GP130 signaling, and reduce colitis-associated colon and inflammation-associated GC development in mice (69). We have shown that this occurs through inhibition of STAT3 signaling in the epithelium (69), while others found that AZD1480 also reduced the abundance of tumor-associated myeloid cells and tumor angiogenesis (70).…”

Non-invasive Assessment of the Efficacy of New Therapeutics for Intestinal Pathologies Using Serial Endoscopic Imaging of Live Mice

“…When combined with routine endoscopic monitoring and the intervention strategies outlined here, these protocols will provide powerful pre-clinical insight into the efficacy of therapeutics. Our laboratories routinely use all of these protocols to monitor the success of novel therapeutics 10,23,24 .…”