Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer

Abstract

BackgroundProstate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility.ObjectiveTo elucidate PC PSMA expression and associate this with defective DNA damage repair (DDR).Design, setting, and participantsMembranous PSMA (mPSMA) expression was scored immunohistochemically from metastatic castration-resistant PC (mCRPC) and matching, same-patient, diagnostic biopsies, and correlated with next-generation sequencing (NGS) and clinical outcome data.Outcome measurements and statistical analysisExpression of mPSMA was quantitated by modified H-score. Patient DNA was tested by NGS. Gene expression and activity scores were determined from mCRPC transcriptomes. Statistical correlations utilised Wilcoxon signed rank tests, survival was estimated by Kaplan-Meier test, and sample heterogeneity was quantified by Shannon's diversity index.Results and limitationsExpression of mPSMA at diagnosis was associated with higher Gleason grade (p = 0.04) and worse overall survival (p = 0.006). Overall, mPSMA expression levels increased at mCRPC (median H-score [interquartile range]: castration-sensitive prostate cancer [CSPC] 17.5 [0.0–60.0] vs mCRPC 55.0 [2.8–117.5]). Surprisingly, 42% (n = 16) of CSPC and 27% (n = 16) of mCRPC tissues sampled had no detectable mPSMA (H-score <10). Marked intratumour heterogeneity of mPSMA expression, with foci containing no detectable PSMA, was observed in all mPSMA expressing CSPC (100%) and 37 (84%) mCRPC biopsies. Heterogeneous intrapatient mPSMA expression between metastases was also observed, with the lowest expression in liver metastases. Tumours with DDR had higher mPSMA expression (p = 0.016; 87.5 [25.0–247.5] vs 20 [0.3–98.8]; difference in medians 60 [5.0–95.0]); validation cohort studies confirmed higher mPSMA expression in patients with deleterious aberrations in BRCA2 (p < 0.001; median H-score: 300 [165–300]; difference in medians 195.0 [100.0–270.0]) and ATM (p = 0.005; 212.5 [136.3–300]; difference in medians 140.0 [55.0–200]) than in molecularly unselected mCRPC biopsies (55.0 [2.75–117.5]). Validation studies using mCRPC transcriptomes corroborated these findings, also indicating that SOX2 high tumours have low PSMA expression.ConclusionsMembranous PSMA expression is upregulated in some but not all PCs, with mPSMA expression demonstrating marked inter- and intrapatient heterogeneity. DDR aberrations are associated with higher mPSMA expression and merit further evaluation as predictive biomarkers of response for PSMA-targeted therapies in larger, prospective cohorts.Patient summaryThrough analysis of prostate cancer samples, we report that the presence of prostate-specific membrane antigen (PSMA) is extremely variable both within one patient and between different patients. This may limit the usefulness of PSMA scans and PSMA-targeted therapies. We show for the first time that prostate cancers with defective DNA repair produce more PSMA and so may respond better to PSMA-targeting treatments.

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

“…A similar correlation between Gleason score, tumor stage and prognosis was found for patients with DRMs (28,29). One recent work (relying on immunohistochemistry) found higher PSMA-expression in BRCA2 and ATM deficient than in unselected tumor samples (30). Thus, a somehow increased overlap between PSMA-PET positive patients and DRM carriers would be reasonable.…”

Preparation of the alpha‐emitting prostate‐specific membrane antigen targeted radioligand [212Pb]Pb‐NG001 for prostate cancer

“…The prostate‐specific membrane antigen (PSMA) is highly expressed in metastatic castrate‐resistant prostate cancer (mCRPC) with limited expression in healthy tissues and correlates with a dismal prognosis . The majority of bone, visceral, and lymph‐node metastases highly express PSMA, making PSMA an ideal target for radioligand therapy (RLT) of mCRPC . A variety of low molecular weight PSMA‐targeting ligands have been synthesized, labelled with radionuclides, and tested in both preclinical and clinical trials .…”

Design and Evaluation of 223Ra-Labeled and Anti-PSMA Targeted NaA Nanozeolites for Prostate Cancer Therapy–Part I

“…PSMA is a well-characterized target that is overexpressed selectively on prostate cancer cells and in the neovasculature of several types of solid tumors but has limited expression in normal non-prostatic tissues [ 6 , 7 , 8 , 9 ]. Its expression increases progressively with higher-grade prostate cancer, metastatic disease, and mCRPC [ 10 ]. PSMA seems also to drive oncogenic signaling in prostate cancer cells and, therefore, to have a role in PCa aggressiveness [ 11 , 12 ].…”