A key transcriptional factor, the signal transducer and activator of transcription (STAT) 3, drives the tumorigenic components of malignant gliomas and is commonly over expressed. Phosphorylated STATS propagates tumorigenesis, including the glioma cancer stem cell (GSC) contribution, by enhancing proliferation, angiogenesis, invasion, and immunosuppression. We have developed WP1066, a potent orally administered inhibitor of STAT3 with excellent blood-brain-barrier penetration that displays marked efficacy against established intracerebral heterogeneous gliomas in vivo. We have demonstrated that a significant mechanism of WP1066's activity is a combination of both direct anti-tumor effects and the reversal of tumor-mediated immune suppression. In this proposed study, we hypothesize that that in addition to directly inhibiting cell proliferation, angiogenesis, and stemness, targeting p-STATS with the small molecule inhibitor WP1066 results in a therapeutically significant reversal of GBM-mediated immune suppression leading to improved patient survival. To test our hypothesis, our first aim will explore whether the immunological status of the tumor might influence the response to STAT3 blockade. This will involve correlating immune responses to GBM subtypes using The Cancer Genome Atlas and then validating these findings with immunohistochemistry and immune functional assays. This premise will be formally tested in murine models and then in human patients in Specific Aim 2. Given the importance of temozolomide in the treatment of GBM patients, we will then explore the therapeutic effects and immune modulation of the combination of WP1066 and temozolomide on the GSC and within murine models, which may influence, the selected targeted patient population during later clinical trials. Moreover, we will investigate a paradigm shifting concept of whether by simply controlling tumor-mediated immune suppression, sufficient anti-tumor immunity is induced for tumor clearance. Successful completion of this project could result in a novel agent that not only could impact the survival of malignant glioma patients but would also have therapeutic application for a wide variety of other malignancies, including those that metastasis to the brain.

Public Health Relevance

DO NOT EXCEED THE SPACE PROVIDED. The development of new, effective therapies for malignant gliomas that target novel pathways associated with central nervous system malignancies is a major unmet clinical need. This proposal will test a novel, small molecular inhibitor of the signal transduction and activator of transcription, (STAT)-3 pathway, key to tumorigenesis and immune suppression, for implementation in patients with established CNS malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA127001-07
Application #
8753979
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
City
Houston
State
TX
Country
United States
Zip Code
77030
Ji, Haitao; Lee, Jong-Ho; Wang, Yugang et al. (2016) EGFR phosphorylates FAM129B to promote Ras activation. Proc Natl Acad Sci U S A 113:644-9
Hodges, Tiffany R; Ferguson, Sherise D; Heimberger, Amy B (2016) Immunotherapy in glioblastoma: emerging options in precision medicine. CNS Oncol 5:175-86
Zhou, Aidong; Lin, Kangyu; Zhang, Sicong et al. (2016) Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nat Cell Biol 18:954-66
Ohtsuka, Masahisa; Ling, Hui; Ivan, Cristina et al. (2016) H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer. EBioMedicine :
Shah, Maitri Y; Ferrajoli, Alessandra; Sood, Anil K et al. (2016) microRNA Therapeutics in Cancer - An Emerging Concept. EBioMedicine 12:34-42
Lee, J; Jain, R; Khalil, K et al. (2016) Texture Feature Ratios from Relative CBV Maps of Perfusion MRI Are Associated with Patient Survival in Glioblastoma. AJNR Am J Neuroradiol 37:37-43
Gabrusiewicz, Konrad; Rodriguez, Benjamin; Wei, Jun et al. (2016) Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight 1:
Xue, Jianfei; Zhou, Aidong; Wu, Yamei et al. (2016) miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis. Cancer Res 76:4293-304
Chen, Yaohui; Li, Yu; Xue, Jianfei et al. (2016) Wnt-induced deubiquitination FoxM1 ensures nucleus β-catenin transactivation. EMBO J 35:668-84
Park, Soon Young; Piao, Yuji; Thomas, Craig et al. (2016) Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a/p27 in glioblastoma. Oncotarget 7:26793-805

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