Abstract 56: Multi-omic profiling of PSMA heterogeneity in prostate cancer liver metastases identifies new metabolomic targets

Abstract Background: Prostate-specific membrane antigen (PSMA) is a metabolic enzyme involved in glutamate and folate pathways. Being a cell surface protein, PSMA serves as a theranostic target in castration-resistant prostate cancer (CRPC) with PSMA-radioligand therapy (PSMA-RLT). However, not all patients with PSMA-PET positive tumors respond to PSMA-RLT, partly due to heterogeneous expression of PSMA. We hypothesize that the metabolic features of the tumor microenvironment contribute to PSMA expression and function. Methods: We profiled CRPC autopsy tumors from five patients and a series of orthotopic PSMA-positive metastatic CRPC models using mass spectrometry (MS), H3K27ac ChIP-seq, and spatial whole transcriptomics by Visium CytAssist platform. Results: Spatial transcriptomic mapping indicated enrichment of amino acid transport and biosynthesis pathways in PSMA-suppressed liver metastases versus other sites of disease. Similarly, MS metabolomics revealed elevated levels of neutral amino acids, such as L-Leucine, in liver metastases. H3K27ac ChIP-seq showed that only liver metastatic tumors in the 22Rv1 CRPC model exhibited an H3K27ac peak at the SLC7A5 (LAT1) gene locus, correlating with low PSMA expression, not seen in primary tumors. A PSMA-suppressed 22Rv1 liver metastasis-derived cell line demonstrated sensitivity to LAT1 inhibition (V-9302), suggesting its potential as a therapeutic target. Conclusions: Multi-omic profiling of patient tumors and prostate cancer models point to PSMA-suppression and heterogeneity in liver metastases associated with potentially targetable epigenetic and metabolomic alterations. Citation Format: Martin K. Bakht, Yasutaka Yamada, Sheng-Yu Ku, Anthony P. Belanger, Quang-De Nguyen, Himisha Beltran. Multi-omic profiling of PSMA heterogeneity in prostate cancer liver metastases identifies new metabolomic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 56.