Men of African ancestry (AA) have a higher incidence and mortality from prostate cancer (PCa) than men of European ancestry (EA). These disparities are driven by the interplay between socioeconomic, lifestyle, environmental, and biological/genetic factors. Growing evidence indicates that AA and EA men have differences in their PCa immunobiology resulting in the differential expression of inflammatory gene pathways. These differences may impact the anti-tumor immune response including the immune targeting of cell surface tumor associated antigens (TAAs). There is an urgency to understand the molecular mechanisms underlying these race-related differences and to harness them for identifying novel therapeutic targets. In this multi-PI exploratory application, we propose to investigate differences in anti-tumor autoantibody responses to the glycolytic enzyme enolase (ENO) in AA and EA men with PCa and exploit these differences for guiding the development of small molecules targeting this protein as novel theranostics agents for advanced PCa. The rationale for the proposed studies is supported by several key observations: 1) ENO, particularly the ENO1 isoform, is emerging as a cell surface TAA with characteristics of an ideal theranostics target, whereas the ENO2 isoform could be a theranostic biomarker for NEPC tumors; 2) AA and EA men with PCa produce a differential autoantibody response to ENO; 3) this response has a distinctive impact on the migration of chemoresistant PCa cells; 4) the expression of ENO2, a cell surface NEPC marker, but not that of ENO1, is lost in PCa cells with NEPC markers as they transition to taxane resistance; and 5) we have initiated the design and characterization of novel boron- based ENO1-targeting small molecules that will be evaluated for their antitumor activity and theranostics potential in pre-clinical models of chemoresistant AA and EA PCa. These observations support the hypothesis that EA and AA patients with PCa have distinctive immune responses to ENO that differentially affect tumor cell properties, and that these responses may reveal tumor vulnerabilities that could be exploited for the development of novel PCa theranostics agents. Aim 1 will determine the mechanisms underlying the differential reactivity and antitumor effects of anti-ENO autoantibodies in AA and EA men with PCa. Aim 2 will synthesize and functionally characterize novel boron-based small molecule ENO1 compounds as potential therapeutics for PCa. The proposed study has high relevance as it will uncover the biological basis for the race-related differential anti- ENO immunoreactivity. This will provide key insights into immune determinants contributing to PCa mortality disparities. The study will also establish ENO as a potential theranostic target for advanced PCa, which could lead to innovative clinical strategies to reduce overall PCa mortality and its racial disparities.