Abstract 3368: Pre-clinical PK/PD/efficacy characterization of AZD1480, a JAK1/2 kinase inhibitor.

Abstract

Abstract Constitutive activation of the transcription factor STAT3, manifest as Y-705 phosphorylation, is a feature of many hematologically-derived and solid tumor malignancies. Accumulating evidence indicates that JAK kinases are the key mediators of STAT activation in solid tumor models. AZD1480, an inhibitor of Janus kinases 1 and 2 (JAK1/2), is a bioavailable small molecule whose inhibition of the JAK-STAT signalling pathway may provide clinical benefit by suppression of the pleiotropic tumorigenic effects of constitutive STAT3 activation (tumor cell proliferation, motility and survival, tumor angiogenesis, tumor immune suppression). Here we present a pre-clinical population-based effect-compartment pharmacokinetic / pharmacodynamic (PK/PD) model to describe the onset, intensity, and duration of pSTAT3 inhibition as a function of unbound concentration and time in the MDAH-2774 ovarian xenograft mouse model. A mathematical tumor growth inhibition model capturing the relationship between systemic exposure to AZD1480 and tumor growth inhibition was built to provide a pharmacokinetic rationale for tumor growth inhibition. Furthermore, the pSTAT3 inhibition PK/PD relationship for AZD1480 was quantitatively integrated into a tumor growth inhibition model providing a mechanistic pharmacodynamic rationale for tumor growth inhibition pre-clinically. Taken together, these pre-clinical data recommend that increasing inhibition of pSTAT3 correlates with greater tumor growth inhibition and provide a PK/PD/Efficacy platform of evidence for clinical hypothesis testing. Citation Format: Patricia Schroeder. Pre-clinical PK/PD/efficacy characterization of AZD1480, a JAK1/2 kinase inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3368. doi:10.1158/1538-7445.AM2013-3368 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.