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Comparison of prostate-specific membrane antigen ligands in clinical translation research for diagnosis of prostate cancer.

ABSTRACT:

Background

Prostate-specific membrane antigen (PSMA), overexpressed on prostate cancer (PCa), is a well-characterized cell surface protein to selectively diagnose PCa. PSMA's unique characteristics and its 1000-fold higher expression in PCa compared with other tissues renders it as a suitable biomarker for detection of PCa in its early stage. In this report, we critically analyze and recommend the requirements needed for the development of variety of PSMA-targeted molecular imaging agents based on antibodies, small molecule ligands, peptides, and aptamers. The targeting moieties are either conjugated to radionuclear isotopes or near-infrared agents for efficient diagnosis of PCa.

Recent findings

From the analysis, it was found that several small molecule-derived PCa imaging agents are approved for clinical trials in Europe and the United States, and few are already in the clinical use for diagnosis of PCa. Even though ¹¹¹In-labeled capromab pendetide was approved by the Food and Drug Administration (FDA) and other engineered antibodies are available for detection of PCa, but high production cost, low shelf life (less than 1 month at 4°C), possibility of human immuno reactions, and low blood clearance rate necessitated a need for developing new imaging agents, which are serum stable, cost-effective, and possesses longer shelf life (6 months), have fast clearance rate from nontargeted tissues during the diagnosis process. It is found that small molecule ligand-derived imaging agents possesses most of the desired properties expected for an ideal diagnostic agent when compared with other targeting moieties.

Conclusion

This report discusses in detail the homing moieties used in the development of targeted diagnostic tools for detection of PCa. The merits and demerits of monoclonal antibodies, small molecule ligands, peptides, and aptamers for imaging of PCa and intraoperative guided surgery are extensively analyzed. Among all, urea-based ligands were found to be most successful in preclinical and clinical trials and show a major promise for future commercialization.

SUBMITTER: Sengupta S

PROVIDER: S-EPMC7941450 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveDespite a multitude of detection and treatment advances in the past 2 decades, prostate cancer remains the second leading cause of deaths due to cancer among men in the United States. Technological evolution and expanding knowledge of tumor biomarkers have invigorated exploration in prostate cancer therapeutics. Prostate-specific membrane antigen (PSMA) was one of the first prostate cancer biomarkers successfully cloned. Since then, it has been characterized as the prototypical cell-surface marker for prostate cancer and has been the subject of intense clinical inquiry. In this article, we review the relevant research in PSMA on the 20th anniversary of its cloning.Methods and materialsA PubMed search using the keywords "prostate-specific membrane antigen" or "glutamate carboxypeptidase II" provided 1019 results. An additional 3 abstracts were included from scientific meetings. Articles were vetted by title and abstract with emphasis placed on those with clinically relevant findings.ResultsSixty articles were selected for inclusion. PSMA was discovered and cloned in 1993. Its structure and function were further delineated in the ensuing decade. Consensus sites of expression in normal physiology are prostate, kidney, nervous system, and small intestine. PSMA has been implicated in the neovasculature of several tumors including urothelial and renal cell carcinomas. In prostate cancer, expression of PSMA is directly related to the Gleason grade. PSMA has been tested both in imaging and therapeutics in a number of prostate cancer clinical trials. Several recent approaches to target PSMA include the use of small molecule inhibitors, PSMA-based immunotherapy, RNA aptamer conjugates, and PSMA-targeted prodrug therapy. Future study of PSMA in prostate cancer might focus on its intracellular functions and possible role in tumor neurogenesis.ConclusionsTwenty years from its discovery, PSMA represents a viable biomarker and treatment target in prostate cancer. Research to delineate its precise role in prostate carcinogenesis and within the therapeutic armamentarium for patients with prostate cancer remains encouraging.

Project description:Simple Summary Multiparametric magnetic-resonance imaging (mpMRI) is a routinely used imaging modality for diagnosing prostate cancer but misses 10–20% of prostate tumours. Recently, prostate-specific membrane antigen positron-emission tomography (PSMA PET) has been proposed as an alternative to mpMRI for diagnosis. Our systematic review and meta-analysis aimed to compare the diagnostic performance between mpMRI and PSMA PET modalities prior to biopsy. Ten articles directly comparing the performance of both modalities in the same patient cohort were investigated. PSMA PET/CT was superior in diagnosing patients with prostate cancer over mpMRI, but not in defining the location of the cancer. Early evidence suggests that the addition of PSMA PET within the diagnostic pathway may enhance the detection of clinically significant prostate cancer. Abstract Multiparametric magnetic-resonance imaging (mpMRI) has proven utility in diagnosing primary prostate cancer. However, the diagnostic potential of prostate-specific membrane antigen positron-emission tomography (PSMA PET) has yet to be established. This study aims to systematically review the current literature comparing the diagnostic performance of mpMRI and PSMA PET imaging to diagnose primary prostate cancer. A systematic literature search was performed up to December 2021. Quality analyses were conducted using the QUADAS-2 tool. The reference standard was whole-mount prostatectomy or prostate biopsy. Statistical analysis involved the pooling of the reported diagnostic performances of each modality, and differences in per-patient and per-lesion analysis were compared using a Fisher’s exact test. Ten articles were included in the meta-analysis. At a per-patient level, the pooled values of sensitivity, specificity, and area under the curve (AUC) for mpMRI and PSMA PET/CT were 0.87 (95% CI: 0.83–0.91) vs. 0.93 (95% CI: 0.90–0.96, p < 0.01); 0.47 (95% CI: 0.23–0.71) vs. 0.54 (95% CI: 0.23–0.84, p > 0.05); and 0.84 vs. 0.91, respectively. At a per-lesion level, the pooled sensitivity, specificity, and AUC value for mpMRI and PSMA PET/CT were lower, at 0.63 (95% CI: 0.52–0.74) vs. 0.79 (95% CI: 0.62–0.92, p < 0.001); 0.88 (95% CI: 0.81–0.95) vs. 0.71 (95% CI: 0.47–0.90, p < 0.05); and 0.83 vs. 0.84, respectively. High heterogeneity was observed between studies. PSMA PET/CT may better confirm the presence of prostate cancer than mpMRI. However, both modalities appear comparable in determining the localisation of the lesions.