Glioblastoma (GBM) is a malignancy of the central nervous system that is nearly universally fatal. Constitutive activation of tyrosine phosphorylation signaling pathways is one hallmark of cancers, including GBMs. GBMs show elevated levels and persistent activation of Signal Transducer and Activator of Transcription-3 (STAT-3), a transcription factor that drives expression of genes that regulate anti-apoptotic responses, angiogenesis, cell proliferation and signal transduction. Importantly, STAT-3 was recently shown to be a master regulator of GBM aggressiveness. Janus Kinase 1 (JAK1) and JAK2, tyrosine kinases critical for STAT-3 activation, are also inappropriately activated in GBMs. We have recently demonstrated aberrant expression of endogenous regulators of the JAK/STAT-3 pathway. Protein Inhibitor of Activated STAT-3 (PIAS3), a negative regulator of activated STAT-3, is absent or expressed at very low levels in GBMs, and CK2, a protein kinase important for potentiating JAK1, JAK2 and STAT-3 activation, is over-expressed in GBMs. The premise of this application is that the JAK/STAT-3 signaling axis is inappropriately activated in the context of GBMs, and that therapeutic intervention will be of clinical benefit to patients with GBMs.
Aim 1 will characterize the JAK/STAT-3 Molecular Profiles in Primary GBM Tumors and Impact on Patient Survival. The activational status of this pathway in glioma tissues will be examined, and associations with PIAS3 and/or CK2, with tumor grade, GBM subtypes (classical, mesenchymal, proneural, neural), and overall patient survival analyzed.
Aim 2 will elucidate the Mechanism(s) by Which the JAK/STAT-3 Pathway is activated in GBMs, and test the influence of AZD1480, a potent inhibitor of activated JAK1/JAK2, in glioma xenografts and glioblastoma stem cells (GBM-SC). Analysis of how xenograft and GBM-SC gene expression and/or behavior is affected when PIAS3 or CK2 expression is modulated will also be examined.
Aim 3 will elucidate the Role of Activated JAK/STAT-3 on Gliomagenesis in Vivo, and the Efficacy of the JAK1/JAK2 Inhibitor AZD1480 in preclinical models of malignant gliomas. Changes in survival rates, tumor growth rates, invasion and angiogenesis for human glioma xenografts treated with AZD1480 alone and in conjunction with temozolomide/radiation will be evaluated. Syngeneic GBM models will also be evaluated. The proposed studies are innovative and novel because they are the first comprehensive analysis of the inter- relationships between JAK1, JAK2, STAT-3, PIAS3 and CK2, and whether their expression levels predict patient survival and/or serve as prognostic factors for GBMs. This analysis of GBM tissue samples, TCGA and Oncomine data, human glioma xenografts, GBM-SC, pre-clinical models of glioma and use of AZD1480 will provide the foundation for proposed therapeutic intervention of the JAK/STAT-3 signaling axis in patients with GBMs.

Public Health Relevance

One critically important signaling pathway gaining interest in the context of GBMs is the JAK/STAT-3 pathway, and we hypothesize that JAKs are novel therapeutic targets in GBMs. We will test for the first time the potent JAK1/JAK2 inhibitor AZD1480: by inhibiting the upstream kinases JAK1 and JAK2, AZD1480 treatment will lead to inhibition of STAT-3 activation, gene expression, and the biological functions that promote and sustain gliomagenesis. Collectively, the results from this proposal will provide a compelling rationale for the use of JAK/STAT-3 inhibitors in clinical trials for patients with GBMs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA158534-01A1
Application #
8237478
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Arya, Suresh
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$303,988
Indirect Cost
$96,488
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Gibson, Sara A; Yang, Wei; Yan, Zhaoqi et al. (2018) CK2 Controls Th17 and Regulatory T Cell Differentiation Through Inhibition of FoxO1. J Immunol 201:383-392
Meares, Gordon P; Rajbhandari, Rajani; Gerigk, Magda et al. (2018) MicroRNA-31 is required for astrocyte specification. Glia 66:987-998
Yan, Zhaoqi; Gibson, Sara A; Buckley, Jessica A et al. (2018) Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases. Clin Immunol 189:4-13
Lai, Yun-Ju; Tsai, Jui-Cheng; Tseng, Ying-Ting et al. (2017) Small G protein Rac GTPases regulate the maintenance of glioblastoma stem-like cells in vitro and in vivo. Oncotarget 8:18031-18049
Rowse, Amber L; Gibson, Sara A; Meares, Gordon P et al. (2017) Protein kinase CK2 is important for the function of glioblastoma brain tumor initiating cells. J Neurooncol 132:219-229
Gibson, Sara A; Yang, Wei; Yan, Zhaoqi et al. (2017) Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation. J Immunol 198:4244-4254
Guthrie, Lauren N; Abiraman, Kavitha; Plyler, Emily S et al. (2016) Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses. J Biol Chem 291:15830-40
McFarland, Braden C; Marks, Margaret P; Rowse, Amber L et al. (2016) Loss of SOCS3 in myeloid cells prolongs survival in a syngeneic model of glioma. Oncotarget 7:20621-35
Basu, Rajatava; Whitley, Sarah K; Bhaumik, Suniti et al. (2015) IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance. Nat Immunol 16:286-95
Rajbhandari, Rajani; McFarland, Braden C; Patel, Ashish et al. (2015) Loss of tumor suppressive microRNA-31 enhances TRADD/NF-?B signaling in glioblastoma. Oncotarget 6:17805-16

Showing the most recent 10 out of 18 publications