Protein kinase CK2 (CK2) regulates several biological features that are hallmarks of cancer. Its consistent dysregulation in various cancers has led to the suggestion that it is a master regulator of malignant cells, further highlighted by its potential as a therapy target. This CSR&D research proposal is designed to investigate the mechanism of function of CK2 in prostate cancer (PCa) pathobiology; specifically, to define how nuclear elevation of CK2 is involved in transcriptional mechanisms of castration resistant PCa (CRPC) tumor signaling and relation to progression-free survival (PFS) in CRPC patients. Our preliminary data demonstrate the association of androgen axis therapies with elevation of intra- and extra-cellular CK2 levels and PCa progression, prompting our current focus on roles for CK2 in CRPC transcriptional regulation. Our hypothesis is that elevation of CK2 levels caused by androgen axis therapies enables treatment resistance through altered transcriptional programming and CK2-associated nuclear protein complexes. Further, higher tumor-released CK2 mRNA in PCa patient blood results in worse progression-free survival. Two specific aims (Aims 1 and 2) address the basic science mechanism questions in the project while Aim 3 links the expression of CK2 in CRPC disease to patient outcomes. Specific Aim 1: determine how elevated CK2 activity alters the AR-related transcriptional program under androgen axis treatment stress and develop a CK2 gene signature to assess CK2 activity in clinical datasets. Specific Aim 2: elucidate CK2-regulated nuclear protein interactions and their contribution to enhanced CRPC survival under androgen axis treatment stress. Specific Aim 3: in a prospective study, measure CK2 mRNA serum levels in a CRPC cohort and correlate baseline CK2 levels with PFS. This aim has two further sub-studies. The first is a prospective study to compare CK2 mRNA levels in serum of patients pre- and post-prostatectomy. The second is a retrospective study to correlate CK2 mRNA and protein in metastatic CRPC biopsies with CK2 mRNA in matching patient serum. The mechanisms of how elevated nuclear CK2 is involved in PCa have remained unclear thus far. The present investigations will provide, for the first time, mechanistic data related to CK2- regulated transcriptional programming and nuclear protein interactions in CRPC disease. These studies will also provide the first novel proof-of-concept evidence for association of CK2 serum mRNA with tumor levels and disease progression, providing cross-validation between patient and model data and the scientific basis for including a drug to block CK2 activity. There is a direct path to clinical translation of this work by incorporating into PCa treatment a clinical grade inhibitor of CK2 (CX-4945/Silmitasertib) that is being pursued for phase II clinical trials in other cancers. High incidence of PCa in the VA and military personnel warrants identification of novel and effective strategies...