Prostate cancer is the second leading cause of cancer deaths in North American men. For patients presenting with disseminated prostate cancer, the tumor is typically dependent on androgen for growth and is therefore responsive to therapies that take advantage of surgical and/or pharmacological depletion of circulating androgens. However, this type of therapeutic success is temporary. The disease almost invariably recurs, even in the face of low levels of circulating androgens, and progresses to a metastatic and lethal disease. The Androgen Receptor (AR) is essential for the growth and survival of castration-resistant prostate cancer (CRPC). The recent FDA approval of the CYP17 inhibitor abiraterone and the novel anti-androgen MDV3100 emphasize the clinical importance of targeting AR function in CRPC. Despite the justifiable excitement over these new therapies, the response to anti-androgens does not endure: the AR becomes reactivated with lethal consequences. It is essential to understand the mechanisms leading to AR reactivation, as they present targets for developing the combination therapies that will be required for effective deployment of next-gen anti-androgens. In this project, we propose studying a mechanism of resistance to anti-androgens that represents a prime opportunity for therapeutic co-targeting: AR regulation by signaling molecules. We recently discovered through a kinome wide RNA interference screen in prostate cancer cells that checkpoint kinase 2 (CHK2) knockdown significantly increased prostate cancer cell growth. This observation is clinically relevant since CHK2 inactivating mutations arise in over 10% of prostate cancer patients and CHK2 expression decreases as prostate cancer progresses to a castration- resistant disease. These data strongly suggest that CHK2 functions as a negative regulator or tumor suppressor in prostate cancer. We have determined that CHK2 knockdown increases AR transcriptional activity and that the growth increase resulting from CHK2 knockdown can be blocked with anti- androgens. This provides evidence that the CHK2 effect on prostate cancer cell growth functions, at least in part, through the AR. Moreover, we have discovered that CDK1, a downstream effector of CHK2 activity, can directly phosphorylate the AR on S308 in G2/M, and that androgen regulates a unique subset of genes in G2/M. This has significant clinical implications since CDK1 activity is elevated in CRPC. In this project we propose to determine the mechanism of CHK2 regulation of AR activity and CRPC cell growth. Specifically, we hypothesize that a reduction in CHK2 signaling increases AR activity and facilitates cell proliferation through AR S308 phosphorylation, thereby driving progression of prostate cancer to castration-resistance. Several CHK inhibitors and second-generation CDK1 inhibitors are now in clinical trials. Moreover, the CHK2 signaling pathway is activated in response to DNA damage such as that generated by radiation. Thus, delineating how CHK2 impinges on AR activity will provide important insights into how to more effectively combine radiation therapy with androgen blockade.
There is currently no effective therapy for castration-resistant prostate cancer. In order to develop therapies to treat this lethal form of prostate cancer we must understand the molecular events that contribute to progression to castration resistant disease. This project focuses on the mechanisms of androgen receptor function, a critical regulator of prostate cancer progression. Thus, this work will yield significant insights into how o more effectively treat castration-resistant prostate cancer.
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