Abstract C063: Enolase-1 as a candidate theranostics target for neuroendocrine prostate cancer

Abstract Prostate cancer (PCa) is the second most common cancer in American men, with men of African ancestry (AA) having twice the mortality of men of European ancestry (AA). Although taxane-based chemotherapy is the last line of defense in men with advanced PCa, it ultimately fails due to chemoresistance. The protein-specific membrane antigen (PSMA) has been an effective target for the imaging and therapy of advanced PCa. Specifically, PSMA radioligand therapy (PSMA-RLT) is a theranostics (therapy + diagnostics) option for men with advanced PCa. However, about 30% of men with advanced PCa have limited response to PSMA-RLT due to the presence of neuroendocrine-like PCa (NEPC), which lacks PSMA expression. A promising alternative to PSMA targeting is the glycolytic enzyme enolase (ENO), which localizes to the cell surface in advanced tumors. There are three enolases with similar functions, with ENO-1 and ENO-2 implicated in PCa. Previously, we showed that AA and EA men with PCa show differential serum antibody reactivity to ENO. While circulating serum antibodies from EA-PCa patients recognized ENO in both docetaxel (DTX)-sensitive and -resistant PCa cell lines, sera from AA-PCa men only recognized ENO in DTX-sensitive cells, with loss of immunoreactivity in the resistant cells. Here, we demonstrate, using immunoblotting and specific monoclonal antibodies, that chemosensitive NEPC cells express both ENO-1 and ENO-2; however, DTX-resistant cells only express ENO-1 with a clear loss of ENO-2. This pattern is identical to that produced by the AA-PCa serum antibodies, suggesting the possibility that AA-PCa patients may generate a preferential antibody response to ENO-2, with EA-PCa patients preferentially targeting ENO-1. This differential immunoreactivity may reflect differences between AA and EA PCa patients in tumor immunobiology, consistent with emerging literature. The loss of ENO-2 in chemoresistant PCa cells also generates a metabolic vulnerability due to the loss of ENO redundancy. We hypothesize that ENO-1 is expressed on the surface of NEPC cell lines and can be targeted with small molecule inhibitors (SMIs) that could be used as potential theranostics agents. Current studies are identifying ENO-1 surface expression on NEPC cell lines using monoclonal antibodies as well as AA and EA patient antibodies, via immunofluorescence microscopy, membrane fractionation analysis, and flow cytometry. We also initiated the testing of small molecule inhibitors (SMIs) targeting ENO-1 in chemoresistant NEPC cells. Our long-term goal is to identify an alternative treatment for patients with NEPC by establishing ENO-1 as a novel theranostics target. This could benefit AA-PCa patients, which may not mount a strong antitumor ENO-1 immune response. Citation Format: Krystal R. Santiago, Alfonso M. Duran, Carlos A. Casiano, Frankis G. Almaguel, Bhaskar Das. Enolase-1 as a candidate theranostics target for neuroendocrine prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C063.