Prostate cancer (PCa) is the second leading cause of cancer-related deaths for men in the United States. Prostatectomy and radiation are standard front line therapies, but a significant portion of these patients will recur and eventually develop metastatic disease. The primary means of treatment for patients with recurrent/metastatic PCa is blockade of androgen receptor (AR) or the use of androgen- deprivation therapy (ADT) through surgical and/or pharmacological depletion of circulating androgens. Nevertheless, these types of treatment only last for 1 or 2 years. The disease will almost always recur, even with low levels of circulating androgens in the blood, and progress toward becoming a castration resistant prostate cancer (CRPC) that usually is fatal. Therapeutic failure of ADT is often accompanied by molecular alterations of the AR, including AR overexpression and mutation. In addition, the abnormal activation of other survival pathways through compensatory mechanisms following androgen depletion and AR inhibition is also essential for CRPC progression and therapeutic resistance. Through mass spectrometry analysis, we have found that IkappaB kinase beta (IKKbeta), one of the two catalytic subunits of the IKK complex that controls NF-κB activity, associates with and phosphorylates androgen receptor in CRPC cells. IKKbeta activity is significantly elevated in CRPC cells and knockdown of IKKbeta leads to a dramatic decrease in AR signaling. Furthermore, the novel IKKβ inhibitor, CmpdA, when used as either a single agent or in combination with a FDA approved AR inhibitor MDV3100, leads to a significant inhibition of CRPC cell proliferation and survival. The overall objective of this project is to determine the role of IKKβ in regulating CRPC growth and to test the therapeutic efficacy of the IKKbeta inhibitor CmpdA in CRPC. We hypothesize that IKKbeta is a critical driver for CRPC and that inhibition of IKKbeta, in combination with AR inhibitors, could lead to regression of CRPC. To test this, we will determine whether IKKbeta is required for CRPC growth in vitro and in vivo in established cells, characterize the mechanism and significance of IKKbeta regulation of AR in CRPC and determine the therapeutic potential of dual targeting of IKKbeta and AR in CRPC. Completion of this project will provide important insight into how to effectively treat CRPC through a combination of IKKbeta inhibitor and androgen blockade.