Introduction: Not all prostate cancer (PCa) is detected by prostate-specific membrane antigen (PSMA)-based imaging or responsive to PSMA-based radiopharmaceuticals. We sought to define the molecular processes associated with PSMA expression. Methods: Using multiple datasets (n=5 Homo sapiens; n=2 mouse xenograft models; n=1 cell line), we correlated PSMA gene expression (FOLH1) with biological processes and treatments. Results: In an exploratory analysis of a prospective cohort of 7,000 tumors from radical prostatectomy, tumors with high PSMA RNA expression (one standard deviation above mean) tended to demonstrate more androgen receptor activity, high genomic risk scores (Decipher), more markers of homologous recombination deficiency, less immune content, lower predicted response to radiotherapy (“PORTOS”), and enrichment for P13K/AKT/mTOR pathways (Figure). In a validation cohort, adenocarcinoma tumors (n=49) expressed more PSMA than benign tissue (n=12; Wilcoxon p=0.020) and castration resistant tumors (n=27; p=0.015). An additional cohort showed adenocarcinoma (n=110) expressed more PSMA than neuroendocrine tumors (n=20; p=4.4e-6). In a mouse xenograft model (n=1) of high-grade adenocarcinoma, PSMA expression declined as the model underwent conversion to castration resistance and subsequent neuroendocrine transformation following castration. From both mouse and human data, treatment with androgen deprivation was associated with an initial increase in PSMA expression. From TCGA (n=491), tumors with high PSMA expression also tended to have a higher mutational burden and fewer tumor infiltrating lymphocytes in a subset with immunohistochemistry data (n=330). To assess the association between PSMA and P13K/AKT/mTOR, we used data from a cell line exposed to the MAPK inhibitor trametinib which upregulates P13K/AKT/mTOR pathways. VCaP cells treated with both enzalutamide and trametinib expressed two-fold more PSMA compared to those treated with the individual medications or neither. Conclusions: PCa with high PSMA expression is characterized by relevant differences in biological processes. If corroborated with PSMA-PET avidity, these results could optimize precision PCa care by informing adjunctive molecular testing or treatment paradigms for low or high PSMA expressing tumors. SOURCE OF Funding: None
