KEY TAKEAWAYS
- The early phase I trial aimed to investigate the potential of PSMA expression levels in PC to guide personalized molecular testing and treatment decisions.
- The results demonstrated the pathways linked to PSMA expression in primary prostate cancer, suggesting potential for precision medicine via PSMA PET optimization but requiring further validation with richer PET data and protein levels.
Prostate cancer (PC) is both highly prevalent and biologically diverse, leading to significant variability in treatment efficacy among patients. To enhance the characterization of PC, new molecular imaging approaches, such as positron emission tomography (PET) targeting the cell membrane protein prostate-specific membrane antigen (PSMA), have emerged.
Despite the increasing clinical use of PSMA PET, its efficacy is influenced by variable PSMA expression, indicative of diverse tumor biology. Leveraging information from PSMA expression holds potential for individualizing targeted molecular tumor testing and optimizing treatment selection.
Adam B. Weiner and his research team conducted the study that aimed to explore the role of PSMA expression via PET in tailoring molecular tumor testing and treatment selection for diverse PC patients.
The study compared molecular profiles of tumors with high and low PSMA RNA expression (FOLH1). Initially, PSMA RNA expression was correlated with SUVmax in a prospective surgery cohort (NCT03392181; n=55).
Subsequently, a dataset of 7,000 primary prostate tumors from the GRID database (NCT02609269) was analyzed, matching tumors from the lowest and highest PSMA expression pentiles (n=918 each) in a 1:1 ratio based on grade and stage. Utilizing Hallmark gene set differential expression (n=50), the findings were validated in The Cancer Genome Atlas (TCGA; n=491). Multivariable logistic regression, accounting for grade, stage, PSA, and patient age, was applied to all differentially expressed signatures. Publicly available datasets were assessed to validate correlated pathways.
The reported outcome showed that PSMA RNA expression had moderate correlation with SUVmax (Spearman ρ = 0.41). Across GRID and TCGA cohorts, 26 hallmark pathways correlated with PSMA expression in multivariable analyses .
High PSMA tumors were enriched for androgen response, fatty acid metabolism, and DNA repair pathways, whereas low PSMA tumors exhibited increased immune-related and hypoxia pathways. Validation included lower PSMA expression in tumors from patients treated with two months of hormone therapy (GEO series: GSE102124).
In TCGA, the analysis confirmed a negative association between PSMA and tumor-infiltrating lymphocytes and a positive association with genomic markers of DNA damage. In LNCaP cells (GSE114016), increasing exposure to a fatty acid synthesis inhibitor resulted in lower PSMA expression, while PSMA negatively correlated with upregulation in hypoxia pathways (GSE195571).
The study identified and validated multiple pathways linked to PSMA expression in primary prostate cancer. These insights hold potential for refining precision management strategies, particularly in optimizing the interpretation of PSMA PET. Given the moderate correlation observed between PSMA RNA expression and SUVmax, future validation in a cohort with additional PET metrics and PSMA protein levels is recommended. The research is sponsored by Northwestern University and GenomeDx Biosciences Corp.
Source: https://suo-abstracts.secure-platform.com/a/gallery/rounds/18/details/2814
Clinical Trial: https://clinicaltrials.gov/study/NCT03392181
https://clinicaltrials.gov/study/NCT02609269
Weiner AB, Wang N, Agrawal R, et al.(2023) ’’MOLECULAR CORRELATES WITH PSMA EXPRESSION IN PRIMARY PROSTATE CANCER.’’ Presented at SUO 2023 (Poster #201)
