Glioblastoma (GBM) is the most deadly brain tumor, with median survival of 12-15 months. Aberrant activation of JAK/STAT, NF-?B and PI3K/AKT pathways promotes GBM progression. CK2 is a serine/threonine kinase composed of two catalytic subunits (? and/or ?') and two regulatory ? subunits. CK2 regulates cell cycle progression, apoptosis, angiogenesis, and signaling. CK2 interacts with JAK1/JAK2, thus intensifying JAK/STAT-3 signaling, and is intertwined in other pathways (NF-?B and PI3K/AKT). CSNK2A1, the gene encoding CK2?, is amplified in human GBM (33.7%), while CSNK2B, the gene encoding CK2?, is deleted in 14.1% of GBM. Amplification of CK2? and/or deletion of CK2? lead to heightened CK2 kinase activity. We propose that aberrant CK2 activity contributes to hyper-activation of the JAK/STAT-3, NF-?B and PI3K/AKT pathways in GBM, leading to tumor survival and therapeutic resistance. We demonstrate that CX-4945, a selective CK2 inhibitor, suppresses JAK/STAT-3, NF-?B and PI3K/AKT signaling in GBM xenografts, decreases GBM viability and significantly increases survival time in intracranial GBM xenograft models. Furthermore, the self-renewal properties of brain tumor initiating cells (BTIC) rely on CK2 kinase activity. We hypothesize that targeting the aberrant kinase activity of CK2 will be of therapeutic benefit in the treatment of GBM patients.
Aim 1 will Determine Whether CK2 Inhibition has Efficacy Against GBMs and BTIC to Decrease Growth and Therapeutic Resistance In Vitro. Using our panel of molecularly characterized xenografts, we will assess if sensitivity to CX-4945 correlates with molecular subtype, CK2? amplification, CK2? deletion, or a combination thereof. The effect of CX-4945 on signaling pathways, gene expression profiles, functional parameters, and sensitization to temozolomide (TMZ), ?-irradiation or gefitinib will be examined. Genetic approaches to CK2 modulation will also be tested.
Aim 2 will Determine Whether CK2 Inhibition, Alone and in Combination with Chemo- and Radiotherapy, Suppresses GBM Growth and Tumorigenic Potential In Vivo. Human GBM xenografts will be tested in orthotopic intracranial GBM models, and changes in survival rates, angiogenesis and myeloid cell tumor infiltration in mice treated with CX-4945 examined. The influence of inhibiting CK2 on TMZ, radiation and gefitinib efficacy in vivo will also be determined.
Aim 3 will Evaluate Whether Unbalanced CK2 Subunit Expression Promotes GBM Growth in an Immunocompetent In Vivo Mouse Model. Genetically modified murine GL261 glioma lines that over-express CK2? or are deleted for CK2? will be tested in a syngeneic orthotopic model of glioma. Tumor growth and survival, as well as functional consequences including CK2 target activity, angiogenesis, proliferation, and immune cell infiltration and function (macrophages, myeloid-derived suppressor cells, T-cells) will be evaluated. Lastly, we will evaluate the therapeutic benefit of CX-4945, and determine how CK2 inhibition affects tumor cells as well as immune cells in the tumor microenvironment.
Our results indicate that CX-4945, the first selective orally bioavailable CK2 inhibitor, has a therapeutic benefit of inhibiting CK2 activity in intracranial models of GBM-patient derived cells in vivo. CX-4945 has demonstrated favorable safety, pharmacokinetic characteristics and pharmacodynamics responses in Phase I and II clinical trials; thus, targeting CK2 can have potential clinical utility in the devastating disease of GBM.
| 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 |
| Gibson, Sara A; Benveniste, Etty N (2018) Protein Kinase CK2: An Emerging Regulator of Immunity. Trends Immunol 39:82-85 |
| 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 |
| 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 |
| Bhat, Uppoor G; Jagadeeswaran, Ramasamy; Halasi, Marianna et al. (2011) Nucleophosmin interacts with FOXM1 and modulates the level and localization of FOXM1 in human cancer cells. J Biol Chem 286:41425-33 |
