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)
Type
Specialized Center (P50)
Project #
5P50CA127001-07
Application #
8753979
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
City
Houston
State
TX
Country
United States
Zip Code
77030
Gressot, Loyola V; Doucette, Tiffany A; Yang, Yuhui et al. (2015) Signal transducer and activator of transcription 5b drives malignant progression in a PDGFB-dependent proneural glioma model by suppressing apoptosis. Int J Cancer 136:2047-54
Chen, James C; Alvarez, Mariano J; Talos, Flaminia et al. (2014) Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell 159:402-14
Schrand, Brett; Berezhnoy, Alexey; Brenneman, Randall et al. (2014) Targeting 4-1BB costimulation to the tumor stroma with bispecific aptamer conjugates enhances the therapeutic index of tumor immunotherapy. Cancer Immunol Res 2:867-77
Lang, Frederick F; Barker 2nd, Fred G (2014) A history of the AANS/CNS Section on Tumors Biennial Satellite Symposium. J Neurooncol 119:593-600
Olar, Adriana; Aldape, Kenneth D (2014) Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol 232:165-77
Singh, Mamata; Leasure, Justin M; Chronowski, Christopher et al. (2014) FANCD2 is a potential therapeutic target and biomarker in alveolar rhabdomyosarcoma harboring the PAX3-FOXO1 fusion gene. Clin Cancer Res 20:3884-95
Congdon, Kendra L; Gedeon, Patrick C; Suryadevara, Carter M et al. (2014) Epidermal growth factor receptor and variant III targeted immunotherapy. Neuro Oncol 16 Suppl 8:viii20-5
Conrad, Charles A; Fueyo, Juan; Gomez-Manzano, Candelaria (2014) Intratumoral heterogeneity and intraclonal plasticity: from warburg to oxygen and back again. Neuro Oncol 16:1025-6
Zhao, Jun; Wallace, Michael; Melancon, Marites P (2014) Cancer theranostics with gold nanoshells. Nanomedicine (Lond) 9:2041-57
Jiang, Hong; Clise-Dwyer, Karen; Ruisaard, Kathryn E et al. (2014) Delta-24-RGD oncolytic adenovirus elicits anti-glioma immunity in an immunocompetent mouse model. PLoS One 9:e97407

Showing the most recent 10 out of 70 publications