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Abstract Introduction: Prostate cancer (PCa) is the most common non-skin malignancy and the second leading cause of cancer related death in men. Prostate cancer is a heterogeneous disease with diverse clinical outcomes ranging from indolent asymptomatic cases to very aggressive and potentially lethal metastatic forms of the disease. Early detection of PCa is predominantly through determination of serum PSA levels and digital rectal examinations (DRE). Subsequently, biopsy based Gleason Grade Scores and TNM staging, tumor size or mpMRI are used to assess disease severity and progression. However, due to the low specificity of PSA concentration in diagnosis and prognosis, biopsy complications, and high mpMRI costs, there is still a critical need to identify and develop novel noninvasive biomarkers that discriminate indolent from aggressive PCa upon diagnosis. Our long-term objective is to discover biomarkers for aggressive PCa, develop and to implement them into robust clinical testing minimally invasive assays for PCa risk stratification at diagnosis. The current focus is on Prostate-Specific Membrane Antigen (PSMA), a membrane bound glycoprotein, that is significantly over-expressed in aggressive and metastatic prostate carcinomas and with poor patient prognosis. The role of its glycosylation status and composition in disease progression and its glycoforms on biomarker development and therapeutics is unknown. Aberrant glycosylation of glycoproteins occurs in many cancers, and it influences disease progression. We rationalize that differential glycosylation of PSMA correlate with progression to aggressive PCa and that PSMA glycopeptides and glycoforms can be used as diagnostics and prognosticators for aggressive disease. Methods/Results: PSMA was isolated from risk Grade Group stratified post-DRE urines, seminal plasma and prostate cancer cell lines with different metastatic phenotypes cell line lysates. Intact glycopeptides were isolated, purified and analyzed by qualitative and quantitative mass spectrometry to identify site specific glycoforms. Our data demonstrate differential expression of unique PSMA glycoforms that correlate with disease risk and severity. Conclusions: Differential glycosylation of PSMA correlates with PCa disease progression to aggressive phenotypes and may have utility in disease stratification. Ongoing studies focus on determining if these qualitative and quantitative changes have diagnostic/prognostic value and if these be integrated with other PCa biomarkers to improve their prognostic power in discriminating aggressive PCa. Acknowledgements: This work was supported by the DOD, USAMRAA, through the Prostate Cancer Research Program under Award No. W81XWH18-1-0228. Opinions, interpretations, and conclusions are those of the author and are not necessarily endorsed by the USAMRAA. Citation Format: Stephen Mackay, Ian O. Oduor, Tanya Burch, Dean A. Troyer, Oliver J. Semmes, Julius O. Nyalwidhe. Prostate specific membrane antigen (PSMA) glycoforms and prostate cancer progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1853.
Mackay et al. (Fri,) studied this question.