Hepsin, a type II transmembrane serine protease, is commonly overexpressed in a variety of epithelial cancers, where its overexpression and concurrent proteolytic activity correlate with tumor progression. Recent studies indicate that Hepsin undergoes activation via autocatalysis and subsequent ectodomain shedding, thus highlighting its potential as a serum-based biomarker. Using transgenic mouse models of prostate adenocarcinoma, Hepsin overexpression has previously been implicated in disease progression and, notably, metastases that are neuroendocrine in nature. Collectively, these findings led us to explore the potential diagnostic utility of Hepsin expression in prostate cancer progression, inclusive of metastatic variants. Here, we reanalyzed pre-existing, publicly available gene expression datasets (2 datasets, 326 patient samples), which revealed a significant upregulation of Hepsin gene expression in tumor tissue versus benign tissue and further pronounced upregulation in androgen-dependent and -independent metastatic lesions. To further examine the potential correlation of Hepsin overexpression to androgen-independence, we reanalyzed in vitro data comparing LNCaP parental versus androgen-independent LNCaP subclones. This analysis revealed a stepwise increase in Hepsin expression over the course of androgen deprivation, which was accompanied by a concomitant decrease in PSA expression. Lastly, to evaluate circulating hepsin protein levels as they occur in patient serum, a total of 424 subjects suspected of prostate cancer were analyzed for circulating Hepsin levels from 2015 to 2018 at the time of biopsy and followed for recurrence or survival until the end of the study. Serum Hepsin levels, as determined by enzyme-linked immunosorbent assay, rendered a specificity of 89% (Gleason < 6 (3+3); Hepsin positive, >100 ng/mL). Within this cohort, 18 patients presented with biochemical recurrence, of which 44% were Hepsin positive and exhibited a 22-month accelerated clinical path to recurrence versus Hepsin negative patients. Collectively, these results highlight the longitudinal diagnostic potential of circulating Hepsin levels in the prostate cancer setting.

Citation Format: John Beard, Sam Eddington, Noah Bowman, Adam Cole, Timothy O'Brien, Blake P. Johnson. Circulating hepsin as a novel serum biomarker in prostate cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6450.