Abstract C029: Surface localization and targeting of enolase-1 (ENO1) as a novel theranostic approach for docetaxel-resistant neuroendocrine prostate cancer

Abstract Prostate cancer (PCa) is American men's second most common cancer. This cancer exhibits the most significant racial disparities among all cancer types, with elevated incidence and mortality in men of African ancestry. Although taxane-based chemotherapy with docetaxel (DTX) and cabazitaxel is the last line of defense for metastatic Castration Resistant Prostate Cancer (mCRPC), it invariably fails due to the development of chemoresistance. The protein-specific membrane antigen (PSMA) is currently an effective target for the imaging and therapy of mCRPC. However, although PSMA radioligand therapy (PSMA-RLT) is a theranostic option for men with advanced PCa, about 30% have a limited response to this treatment, particularly those that lack PSMA. In addition, some reports indicate that PSMA is suppressed in neuroendocrine PCa (NEPC), making it an unreliable theranostic target for this aggressive subtype. The glycolytic enzyme Enolase (ENO) is a promising theranostic alternative due to its cell surface localization in many human tumors. We hypothesized that ENO1 is abundant on the surface of NEPC-like cell lines and can be targeted with small molecule inhibitors (SMIs) that could potentially be used as theranostic agents. Western blotting (WB) analysis revealed that DTX-sensitive PCa cell lines expressing NEPC markers express both ENO1 and ENO2. By contrast, DTX-resistant NEPC-like cells only express ENO1 and therefore have a metabolic vulnerability due to the loss of ENO2. Additionally, we observed by WB and confocal microscopy changes in the expression and localization of ENO1 in NEPC-like cell lines under different glucose concentrations. Our results showed that under high glucose conditions, found on metabolically active metastatic tumors, ENO1 is highly abundant on the cell surface, making it a promising candidate target for theranostics. However, standard glucose conditions resulted in ENO1 downregulation, most likely due to inhibition of the activity of the c-MYC oncogene and upregulation of MBP1, the small splice variant of ENO1 that blocks the transcriptional activity of c-MYC. We also evaluated the cytotoxicity of SMIs designed to target ENO1 in chemoresistant NEPC-like cell lines using MTT viability assays, clonogenic assays, and Hoffman Modulation microscopy imaging. We observed that these inhibitors can significantly impair, with IC50 values at low micromolar concentrations, the proliferation and clonogenicity of NEPC cell lines. These results support our long-term goal to identify an alternative theranostic option for patients with NEPC by establishing ENO1 as a novel theranostic target. Citation Format: Krystal R. Santiago Torres, Kristen Whitley, Alfonso Duran, Bhaskar Das, Carlos Casiano, Frankis Almaguel. Surface localization and targeting of enolase-1 (ENO1) as a novel theranostic approach for docetaxel-resistant neuroendocrine prostate cancer abstract. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C029.