The median survival of patients with glioblastoma (GBM) is 12-15 months. Extending the life of individuals with this disease is a critical unmet need. Clearly more effective therapies are needed and the identification of new targets is a key strategy to accelerate progress towards this goal. This application is based on our unique discovery of a new candidate kinase target for GBM called STK17A. STK17A is a novel member of the DAP family of serine/threonine protein kinases. Our preliminary data directly links STK17A to survival of GBM patients. STK17A is highly overexpressed in GBM. STK17A overexpression and increased copy number is associated with a significant survival disadvantage for patients with glioma. Knockdown of STK17A in established and primary human GBM results in a decrease in proliferation and sensitized cells to nutritional stress. Knockdown of STK17A is associated with a marked decrease in ULK1, a critical rate-limiting component of autophagy and STK17A knockdown represses autophagy in response to cytotoxic and nutritional stress. Small molecular weight inhibitors of STK17A also inhibit the growth/survival of GBM cells. STK17A is an entirely new candidate kinase target for GBM that our lab has uncovered. The broad, long-term goal of this project is to determine the role of STK17A in promoting GBM proliferation and survival and to discover whether targeting STK17A is a promising strategy to combat GBM which is resistant to current forms of therapy. Our hypothesis is that STK17A is an exciting and new therapeutic target and prognostic biomarker in GBM and that overexpression of STK17A promotes progression and growth of GBM and promotes autophagy-mediated tumor cell survival upon nutrient deprivation and therapy-induced genotoxic stress. Translational studies using clinical samples and in vitro and in vivo models will mechanistically test our hypothesis. This application is innovative since it is based on new data generated by our laboratory on a novel serine/threonine kinase that has not previously been linked to cancer or tumor cell chemosensitivity. The proposed aims are significant since they have the potential to introduce the field to an entirely new GBM target that could lead to development of new therapies for GBM and other cancers and provide a new strategy to sensitize cancers to existing therapies. This project will also lead to findings to support targetig autophagy as a general strategy to combat cancer and provides a target in which to do so in GBM. Through the unique resources available and expert collaborators we are poised to make significant contributions to our understanding of STK17A as a prognostic marker and therapeutic target for GBM.
Glioblastoma is a deadly cancer that cannot be cured with current available therapies. We have discovered that a novel serine/threonine kinase called STK17A is overexpressed in glioblastoma patients and this overexpression correlates with poor clinical outcome and the ability of glioblastoma tumor cells to resist chemotherapy and starvation. This previously unrecognized pathway that we have discovered to be frequently overexpressed in glioblastoma cells may be exploited as a novel therapeutic strategy to treat and chemosensitize the tumors of glioblastoma patients.
|Sonnenburg, Daniel; Spinella, Michael J; Albany, Costantine (2016) Epigenetic Targeting of Platinum Resistant Testicular Cancer. Curr Cancer Drug Targets 16:789-795|
|Yim, Christina Y; Sekula, David J; Hever-Jardine, Mary P et al. (2016) G0S2 Suppresses Oncogenic Transformation by Repressing a MYC-Regulated Transcriptional Program. Cancer Res 76:1204-13|
|Mao, Pingping; Hever-Jardine, Mary P; Rahme, Gilbert J et al. (2013) Serine/threonine kinase 17A is a novel candidate for therapeutic targeting in glioblastoma. PLoS One 8:e81803|