The era of prostate-specific membrane antigen for the diagnosis and treatment of prostate cancer: A novel horizon.
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ABSTRACT:
SUBMITTER: Song B
PROVIDER: S-EPMC10172049 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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The era of prostate-specific membrane antigen for the diagnosis and treatment of prostate cancer: A novel horizon.
Song Byeongdo B Hong Sung Kyu SK
Investigative and clinical urology 20230501 3
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Project description:Theranostics, a combination of therapy and diagnostics, is a field of personalized medicine involving the use of the same or similar radiopharmaceutical agents for the diagnosis and treatment of patients. Prostate-specific membrane antigen (PSMA) is a promising theranostic target for the treatment of prostate cancers. Diagnostic PSMA radiopharmaceuticals are currently used for staging and diagnosis of prostate cancers, and imaging can predict response to therapeutic PSMA radiopharmaceuticals. While mainly used in the setting of metastatic, castrate-resistant disease, clinical trials are investigating the use of PSMA-based therapy at earlier stages, including in hormone-sensitive or hormone-naïve prostate cancers, and in oligometastatic prostate cancers. This review explores the use of PSMA as a theranostic target and investigates the potential use of PSMA in earlier stage disease, including hormone-sensitive metastatic prostate cancer, and oligometastatic prostate cancer.
| S-EPMC8621856 | biostudies-literature
Project description:Background and objectiveWe characterized tumor prostate-specific membrane antigen (PSMA) levels as a reflection of cancer biology and treatment sensitivities for treatment-naïve prostate cancer.MethodsWe first correlated PSMA positron emission tomography (PET) maximum standardized uptake values (SUVmax) in primary prostate cancer with tumor FOLH1 (PSMA RNA abundance) to establish RNA as a proxy (n = 55). We then discovered and validated molecular pathways associated with PSMA RNA levels in two large primary tumor cohorts. We validated those associations in independent cohorts (18 total; 5684 tumor samples) to characterize the pathways and treatment responses associated with PSMA.Key findings and limitationsPSMA RNA abundance correlates moderately with SUVmax (ρ = 0.41). In independent cohorts, androgen receptor signaling is more active in tumors with high PSMA. Accordingly, patients with high PSMA tumors experienced longer cancer-specific survival when managed with androgen deprivation therapy for biochemical recurrence (adjusted hazard ratio [AHR] 0.54 [0.34-0.87]; n = 174). PSMA low tumors possess molecular markers of resistance to radiotherapy. Consistent with this, patients with high PSMA tumors experience longer time to recurrence following primary radiotherapy (AHR 0.50 [0.28-0.90]; n = 248). In the SAKK09/10 trial (n = 224), patients with high PSMA tumors who were managed with salvage radiotherapy experienced longer time to progression in the 64-Gy arm (restricted mean survival time [RMST] +7.60 [0.05-15.16]), but this effect was mitigated in the 70-Gy arm (RMST 3.52 [-3.30 to 10.33]). Limitations include using PSMA RNA as a surrogate for PET SUVmax.Conclusions and clinical implicationsPSMA levels in treatment-naïve prostate cancer differentiate tumor biology and treatment susceptibilities. These results warrant validation using PET metrics to substantiate management decisions based on imaging.
| S-EPMC11637967 | biostudies-literature
Project description:The rising incidence rate of the cancer in the prostate gland has increased the demand for improved diagnostic, imaging, and therapeutic approaches. Prostate-specific membrane antigen (PSMA), with folate hydrolase and carboxypeptidase and, internalization activities, is highly expressed in the epithelial cells of the prostate gland and is strongly upregulated in prostatic adenocarcinoma, with elevated expression correlating with, metastasis, progression, and androgen independence. Recently, PSMA has been an active target of investigation by several approaches, including the successful utilization of small molecule inhibitors, RNA aptamer conjugates, PSMA-based immunotherapy, and PSMA-targeted prodrug therapy. Future investigations of PSMA in prostate cancer (PCa) should focus in particular on its intracellular activities and functions. The objective of this contribution is to review the current role of PSMA as a marker for PCa diagnosis, imaging, and therapy.
| S-EPMC6308151 | biostudies-literature
Project description:BackgroundProstate-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 findingsFrom 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.ConclusionThis 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.
| S-EPMC7941450 | biostudies-literature
Project description:Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand-drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule-drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body-drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.
| S-EPMC7865627 | biostudies-literature
Project description: Not available
| S-EPMC9434807 | biostudies-literature
Project description:All cells release extracellular vesicles (EVs) to communicate with adjacent and distant cells. Consequently, circulating EVs are found in all bodily fluids, providing information applicable for liquid biopsy in early cancer diagnosis. Studies observed an overexpression of the membrane-bound prostate-specific membrane antigen (PSMA) on prostate cancer cells. To investigate whether EVs derived from communicating prostate cells allow for reliable conclusions on prostate cancer development, we isolated PSMA-positive, as well as CD9-positive, EVs from cell-free urine with the use of magnetic beads. These populations of EVs were subsequently compared to CD9-positive EVs isolated from female urine in Western blotting, indicating the successful isolation of prostate-derived and ubiquitous EVs, respectively. Furthermore, we developed a device with an adapted protocol that enables an automated immunomagnetic enrichment of EVs of large sample volumes (up to 10 mL), while simultaneously reducing the overall bead loss and hands-on time. With an in-house spotted antibody microarray, we characterized PSMA as well as other EV surface markers of a prostate cohort of 44 urine samples in a more simplified way. In conclusion, the automated and specific enrichment of EVs from urine has a high potential for future diagnostic applications.
| S-EPMC9221222 | biostudies-literature
Project description:Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration-resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron-dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate-specific membrane antigen (PSMA)-targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane-coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M-gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA-specific, CRPC-targeting platform for ferroptosis induction with increased efficacy and safety.
| S-EPMC11434221 | biostudies-literature
Project description:Prostate cancer is one of the most common cancers and among the leading causes of cancer deaths in the United States. Men diagnosed with the disease typically undergo radical prostatectomy, which often results in incontinence and impotence. Recurrence of the disease is often experienced by most patients with incomplete prostatectomy during surgery. Hence, the development of a technique that will enable surgeons to achieve a more precise prostatectomy remains an open challenge. In this contribution, we report a theranostic agent (AuNP-5kPEG-PSMA-1-Pc4) based on prostate-specific membrane antigen (PSMA-1)-targeted gold nanoparticles (AuNPs) loaded with a fluorescent photodynamic therapy (PDT) drug, Pc4. The fabricated nanoparticles are well-characterized by spectroscopic and imaging techniques and are found to be stable over a wide range of solvents, buffers, and media. In vitro cellular uptake experiments demonstrated significantly higher nanoparticle uptake in PSMA-positive PC3pip cells than in PSMA-negative PC3flu cells. Further, more complete cell killing was observed in Pc3pip than in PC3flu cells upon exposure to light at different doses, demonstrating active targeting followed by Pc4 delivery. Likewise, in vivo studies showed remission on PSMA-expressing tumors 14 days post-PDT. Atomic absorption spectroscopy revealed that targeted AuNPs accumulate 4-fold higher in PC3pip than in PC3flu tumors. The nanoparticle system described herein is envisioned to provide surgical guidance for prostate tumor resection and therapeutic intervention when surgery is insufficient.
| S-EPMC6392200 | biostudies-literature
Project description: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.
| S-EPMC6853166 | biostudies-literature