Principal Investigator/Program Director (Last, First, Middle): Chinni, Sreenivasa, R Castrate resistant prostate cancer (CRPC) is a debilitating disease and currently resistant to available therapies. Bone metastasis is predominant in these patients and understanding the molecular pathways driving CRPC progression constitutes a fundamental gap in knowledge. Our previous work focused on CXCL12/CXCR4 signaling promoting homing of prostate cancer (PC) cells to bone and found that phosphoinositide signaling (PI4KIII and Sac1) cross talk with CXCL12/CXCR4 in PC cells. The long-term goal is to understand the biological and molecular mechanisms governing CRPC develop- ment. The objective of this application is to identify how the CXCR4-PI4KIII axis promotes PC bone tumor growth by their function in cancer cells. The central hypothesis is that CXCR4-PI4KIII crosstalk confers PC cell invasion and that CXCR4 induced cellular changes in bone metastasis pro- mote growth and structural changes in bone via tumor induced bone modification. Guided by novel preliminary data, this hypothesis will be tested by pursuing by following specific aims: 1) Characterize interaction between CXCR4 and PI4KIII and impact of interaction in prostate cancer cell invasion, and 2) Determine the biological and clinical significance of PI4KIII signaling in intraosseous expan- sion of prostate tumors. The specific aims will be carried out using molecular biology, confocal imag- ing, in vitro lipid kinase activity, in vivo intra-tibial bone tumor growth assay and gene expression analysis of human prostate metastatic biopsy specimens. Known function of GPCRs is to cleave PI(4,5)P2 in cell membrane through phospholipase C activation and thus dependent on high levels of PI(4,5)P2 in PM for cellular signaling. Our data points to a novel GPCR function in generating PI4P in plasma membrane through recruitment and activation of PI4KIII We will crucially address the relevance of CXCR4- PI4KIII in prostate cancer cell invasion and metastatic growth in bone. Summary