Preclinical Development Therapeutic Potential of AZD1480 for the Treatment of Human Glioblastoma

Aberrant activationof the Januskinase (JAK)/signal transducer andactivatorof transcription (STAT)pathway has been implicated in glioblastoma (GBM) progression. To develop a therapeutic strategy to inhibit STAT-3 signaling, we have evaluated the effects of AZD1480, a pharmacologic inhibitor of JAK1 and JAK2. In this study, the in vitro efficacy ofAZD1480was tested inhumanandmurine glioma cell lines.AZD1480 treatment effectively blocks constitutive and stimulus-induced JAK1, JAK2, and STAT-3 phosphorylation in both human and murine glioma cells, and leads to a decrease in cell proliferation and induction of apoptosis. Furthermore, we used human xenograft GBM samples as models for the study of JAK/STAT-3 signaling in vivo, because human GBMsamplespropagatedasxenografts innudemice retainboth thehallmarkgenetic alterationsand the invasive phenotype seen in vivo. In these xenograft tumors, JAK2 and STAT-3 are constitutively active, but levels vary among tumors,which is consistentwith the heterogeneity ofGBMs.AZD1480 inhibits constitutive and stimulusinduced phosphorylation of JAK2 and STAT-3 in these GBM xenograft tumors in vitro, downstream gene expression, and inhibits cell proliferation. Furthermore, AZD1480 suppresses STAT-3 activation in the gliomainitiating cell population in GBM tumors. In vivo, AZD1480 inhibits the growth of subcutaneous tumors and increases survival of mice bearing intracranial GBM tumors by inhibiting STAT-3 activity, indicating that pharmacologic inhibition of the JAK/STAT-3 pathway by AZD1480 should be considered for study in the treatment of patients with GBM tumors. Mol Cancer Ther; 10(12); 2384–93. 2011 AACR.