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A large-scale siRNA screen to study the role of kinases in Androgen Receptor activation (ARKSS)
Start date: Mar 1, 2012, End date: Feb 28, 2015 PROJECT  FINISHED 

"Prostate cancer is one of most commonly diagnosed cancer in European men and a leading cause of cancer-related death. If the cancer is diagnosed early, it is frequently curable by surgery or radiotherapy. However, locally advanced, recurrent or metastatic prostate cancer is much more difficult to control. These patients are commonly treated with androgen withdrawal therapy that is designed to inhibit the activation of the androgen receptor (AR). While initially successful, the effectiveness of this type of treatment is usually temporary and the surviving tumour cells almost always progress to a “castrate-resistant ” state. The treatment options for these patients are very limited and the median patient survival is 1-2 years. Despite this resistance, there is considerable evidence that the inappropriate activation of AR is linked to recurrent cancer growth. The AR therefore, remains the most effective therapeutic target to treat castrate-resistant prostate cancer.Phosphorylation of the AR by kinases has been demonstrated to induce transcriptional activation in low-androgen environments. This kinase-mediated pathway is believed to be one of the main causes of AR activation in castrate-resistant cancer patients. While various kinases have been identified to be involved in AR signaling, those tested only represent a small fraction of the total kinases present in the eukaryotic genome. Therefore, to better understand the role of kinases in AR activation, I am proposing to conduct a high-throughput siRNA screen against almost every kinase in the genome. This study will allow for the identification of those kinases that are critical for AR signaling. Importantly, this functional genomic screen will be conducted in multiple cell lines to give a deeper understanding of this heterogeneous disease. Given the importance of kinases of AR activation, the “hits” identified from this screen will offer novel drug targets for the treatment of prostate cancer."

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