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.
