Abstract 387: 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 (EA). 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-differentiated 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. Here, we demonstrate, using immunoblotting, confocal microscopy, and cell fractionation studies with specific monoclonal antibodies, that chemosensitive NEPC cells express both ENO-1 and ENO-2; however, docetaxel (DTX)-resistant PC3-DR and DU145-DR cells only express ENO-1 with clear loss of ENO-2. Loss of ENO-2 in chemoresistant PCa cells generates a metabolic vulnerability due to loss of ENO redundancy. We also initiated the testing of small molecule inhibitors (SMIs) targeting ENO-1 in chemoresistant and chemosensitive NEPC cells, showing that these inhibitors have cytotoxic activity against these cells, with IC50 values in the low micromolar range. These results support the hypothesis that ENO-1 is expressed in the surface of NEPC cell lines and can be targeted with SMIs that could be modified as potential theranostics agents. Our long-term goal is to identify an alternative treatment for patients with NEPC by establishing ENO-1 as a novel cell surface theranostics target. Citation Format: Krystal Rubi Santiago Torres, Alfonso Duran. Enolase-1 as a candidate theranostics target for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 387.