Patients with metastatic castration-resistant prostate cancer (mCRPC) face poor prognoses due to tumor heterogeneity and drug resistance. Antibody-drug conjugates (ADCs) have been under development for over two decades for mCRPC treatment. Several clinical trials have demonstrated promising antitumor activity and acceptable safety profiles for ADCs in this setting. Among prostate-specific membrane antigen (PSMA)-targeted ADCs, ARX517 demonstrates superior safety and more significant prostate-specific antigen (PSA) reductions compared to earlier agents such as MLN2704, PSMA-ADC, and MEDI3726. ADCs targeting B7-H3, such as MGC018 and DB-1311, have also shown antitumor activity. ADCs targeting other antigens, including six-transmembrane epithelial antigen of the prostate (STEAP)1 (DSTP3086S), trophoblast cell surface antigen (TROP)2 (sacituzumab govitecan), and solute carrier (SLC) 44A4 (ASG-5ME), have shown preliminary antitumor activity in early trials but face challenges with insufficient efficacy or toxicity. Tisotumab vedotin (targeting tissue factor) has shown no significant therapeutic response in mCRPC. Meanwhile, disitamab vedotin (HER2-targeted), ABBV-969 and DXC008 (both dual PSMA/STEAP1-targeted) are currently under evaluation. Notably, an international multicenter phase Ⅲ clinical trial (NCT06925737) for mCRPC has been initiated in May 2025 for evaluating B7-H3-targeted ADC ifinatamab deruxtecan. This review summarizes recent advances in ADCs targeting key antigens in mCRPC (including PSMA, B7-H3, STEAP1, TROP2, SLC44A4, and others) and explores combination strategies, offering insights to inform the clinical management of mCRPC.
Humans ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Male ; Immunoconjugates/therapeutic use* ; Glutamate Carboxypeptidase II/immunology* ; Antibodies, Monoclonal, Humanized/therapeutic use* ; B7 Antigens/immunology* ; Neoplasm Metastasis ; Prostate-Specific Antigen ; Antigens, Neoplasm/immunology* ; Antigens, Surface ; Camptothecin/analogs & derivatives* ; Oxidoreductases

Prostate cancer (PCa) is the second leading cause of cancer-related death among men. Prostate-specific antigen (PSA) testing is used in screening programs for early detection with a consequent reduction of PCa-specific mortality at the cost of overdiagnosis and overtreatment of the nonaggressive PCa. Recently, several assays have been commercially developed to implement PCa diagnosis, but they have not been included in both screening and diagnosis of PCa. This review aims to describe the actual and novel commercially available molecular biomarkers that can be used in PCa management to implement and tailor the screening and diagnosis of PCa.
Humans ; Prostatic Neoplasms/genetics* ; Male ; Biomarkers, Tumor/genetics* ; Early Detection of Cancer/methods* ; Prostate-Specific Antigen/blood* ; Molecular Diagnostic Techniques/methods* ; Glutamate Carboxypeptidase II/metabolism*

Prostate cancer is one of the most common malignant tumors in men and posing a serious threat to men's health. Detection methods such as prostate-specific antigen (PSA), prostate biopsy, and magnetic resonance imaging are widely used for prostate cancer screening, but they have low specificity, high cost, and significant risks. Therefore, there is an urgent need to develop highly specific, low-cost, easily obtained, stable, and reliable biomarkers, and use them as the basis to establish non-invasive screening and diagnostic methods for prostate cancer. This paper reviewed the recent advances in the use of prostate cancer biomarkers and combined detection methods for prostate cancer diagnosis and prognosis assessment and provides an in-depth analysis and comparison of different biomarkers and combined detection methods, as well as points out the directions and challenges for future research. The paper emphasizes the importance of developing efficient, cost-effective and easy-to-implement biomarkers to increase the early diagnosis rate of prostate cancer, improve patient prognosis, and reduce the waste of healthcare resources. This paper provides an important theoretical basis and technical guidance for early diagnosis, precise treatment and prognostic evaluation of prostate cancer, and has important reference value for promoting clinical research and practice of prostate cancer.
Humans ; Male ; Prostatic Neoplasms/diagnosis* ; Biomarkers, Tumor/blood* ; Early Detection of Cancer/methods* ; Prognosis ; Prostate-Specific Antigen/blood* ; Glutamate Carboxypeptidase II/metabolism* ; Antigens, Neoplasm/blood* ; Antigens, Surface ; Serine Endopeptidases

Objective: To investigate the safety and effectiveness of radical retropubic prostatectomy (RRP) with adjuvant androgen deprivation or external radiotherapy in the treatment of prostate cancer (PCa) with pelvic lymph node metastasis (PLNM). METHODS: Twenty PCa patients underwent bilateral pedal lymphangiography (PLG) preoperatively, and 11 of them received lymph node aspiration for examination of the mRNA expressions of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) in the lymph fluid by real-time RT-PCR. All the patients were treated by RRP with extended dissection of pelvic lymph nodes, and 3 of them by external radiotherapy in addition after recovery from urinary incontinence because of positive surgical margins, followed by adjuvant androgen deprivation therapy. RESULTS: Real-time RT-PCR showed positive mRNA expressions of PSA and PSMA in the lymph fluid of the 11 patients, all pathologically confirmed with PLNM. The median intraoperative blood loss was 575 ml, with blood transfusion for 5 cases. Positive surgical margin was found in 3 cases, lymphorrhagia in 2 and urinary leakage in another 2 each. There were no such severe complications as vascular injury and rectum perforation. The patients were followed up for 6－48 (mean 42) months, during which, biochemical recurrence was observed in 12 cases at a median of 12 months postoperatively and 2 patients died at 12 and 48 months respectively. CONCLUSIONS Bilateral PLG and lymph node aspiration for examination of the mRNA expressions of PSA and PSMA in the lymph fluid help to confirm PLNM preoperatively. Radical retropubic prostatectomy with adjuvant androgen deprivation or external radiotherapy is safe and effective for the treatment of PCa with PLNM, but it should be chosen cautiously for those with Gleason 5+5.
Androgen Antagonists ; therapeutic use ; Antigens, Surface ; metabolism ; Chemotherapy, Adjuvant ; Glutamate Carboxypeptidase II ; metabolism ; Humans ; Lymph Node Excision ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Male ; Pelvis ; Postoperative Period ; Prostate-Specific Antigen ; metabolism ; Prostatectomy ; methods ; Prostatic Neoplasms ; drug therapy ; metabolism ; surgery

Prostate cancer is one of the most common malignant tumors in the male urinary system as well as the second leading cause of cancer death in men. Prostate specific antigen (PSA) screening is the main method for the early diagnosis of prostate cancer, but has a low specificity for its detection. In recent years, a variety of tumor markers with high sensitivity and specificity have been found. This review focuses on some of the more promising tumor biomarkers such as prostate cancer antigen 3, early prostate cancer antigen, prostate-specific membrane antigen, alpha-methylacyl-CoA racemase, and vascular endothelial growth factor.
Antigens, Neoplasm ; blood ; Antigens, Surface ; blood ; Biomarkers, Tumor ; blood ; Early Detection of Cancer ; GPI-Linked Proteins ; blood ; Glutamate Carboxypeptidase II ; blood ; Humans ; Male ; Neoplasm Proteins ; blood ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; diagnosis ; Racemases and Epimerases ; blood ; Sensitivity and Specificity ; Vascular Endothelial Growth Factor A ; blood

BACKGROUNDProstate specific membrane antigen (PSMA) can facilitate the growth, migration, and invasion of the LNCaP prostate cancer cell lines, but the underlying molecular mechanisms have not yet been clearly defined. Here, we investigated whether PSMA serves as a novel regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling by employing PSMA knockdown model and PI3K pharmacological inhibitor (LY294002) in LNCaP prostate cancer cells.

METHODSPSMA knockdown had been stably established by transfecting with lentivirus-mediated siRNA in our previous study. Then, LNCaP cells were divided into interference, non-interference, and blank groups. We first testified the efficacy of PSMA knockdown in our LNCaP cell line. Then, we compared the expression of PSMA and total/activated Akt by Western blotting in the above three groups with or without LY294002 treatment. Furthermore, immunocytochemistry was performed to confirm the changes of activated Akt (p-Akt, Ser473) in groups. Besides, cell proliferation, migration, and cell cycle were measured by CCK-8 assay, Transwell analysis, and Flow cytometry respectively.

RESULTSAfter PSMA knockdown, the level of p-Akt (Ser473) but not of total-Akt (Akt1/2) was significantly decreased when compared with the non-interference and blank groups. However, LY294002 administration significantly reduced the expression of p-Akt (Ser473) in all the three groups. The results of immunocytochemistry further confirmed that PSMA knockdown or LY294002 treatment was associated with p-Akt (Ser473) down-regulation. Decrease of cell proliferation, migration, and survival were also observed upon PSMA knockdown and LY294002 treatment.

CONCLUSIONSTaken together, our results reveal that PI3K/Akt signaling pathway inhibition may serve as a novel molecular mechanism in LNCaP prostate cancer cells of PSMA knockdown and suggest that Akt (Ser473) may play a critical role as a downstream signaling target effector of PSMA in this cellular model.

Antigens, Surface ; genetics ; metabolism ; Cell Line, Tumor ; Glutamate Carboxypeptidase II ; genetics ; metabolism ; Humans ; Male ; Phosphatidylinositol 3-Kinases ; metabolism ; Prostatic Neoplasms ; enzymology ; genetics ; therapy ; Proto-Oncogene Proteins c-akt ; metabolism ; RNA Interference ; Signal Transduction ; genetics ; physiology

OBJECTIVETo construct, express and purify human fusion proteins composed of a single-chain antibody fragment scFv that recognizes the prostate specific membrane antigen (PSMA) protein, Fdt, HA2 and tp, and to analyze the binding activity of the expressed fusion proteins.

METHODSThe fusion protein genes scFv, scFv-tp, and scFv-Fdt-HA2-tp were amplified by PCR, and the genes obtained were then cloned into the expression vector pET28 and expressed in E. coli BL21. The expressed products were identified by SDS-PAGE and Western blot and purified with Ni(2+)-NTA chelating agarose. The antigen-binding activity of the fusion proteins was determined by ELISA.

RESULTSThe human anti-PSMA fusion gene was successfully constructed and expressed in M15 as the inclusion body after induced with IPTG. All the target proteins expressed could bind the PSMA antigen.

CONCLUSIONFusion proteins can specifically bind the PSMA antigen. This finding contributes to the study of the targeted delivery of siRNA.

Antigens, Surface ; immunology ; Cloning, Molecular ; Electrophoresis, Polyacrylamide Gel ; Escherichia coli ; genetics ; immunology ; Glutamate Carboxypeptidase II ; immunology ; Humans ; Male ; Polymerase Chain Reaction ; RNA, Small Interfering ; administration & dosage ; immunology ; Recombinant Fusion Proteins ; genetics ; immunology ; Single-Chain Antibodies ; genetics ; immunology

Antigens, Neoplasm ; metabolism ; Antigens, Surface ; metabolism ; Autoantibodies ; metabolism ; Biomarkers, Tumor ; metabolism ; Carrier Proteins ; metabolism ; Glutamate Carboxypeptidase II ; metabolism ; Humans ; Kallikreins ; metabolism ; Male ; MicroRNAs ; metabolism ; Oncogene Proteins, Fusion ; metabolism ; PTEN Phosphohydrolase ; metabolism ; Prostate-Specific Antigen ; metabolism ; Prostatic Neoplasms ; metabolism ; Receptor, Epidermal Growth Factor ; metabolism ; Trypsin Inhibitor, Kazal Pancreatic ; Urokinase-Type Plasminogen Activator ; metabolism

OBJECTIVETo detect and compare the transcriptional activities of prostate-specific membrane antigen (PSMA) promoter and enhancer and survivin promoter in different human prostate cancer cell lines, and to search for some evidence for the targeting gene therapy of human prostate cancer.

METHODSThe fragments of the PSMA promoter and enhancer and survivin promoter were amplified by PCR and inserted into pGL3-Basic. The recombinant plasmids were transiently transfected into human prostate cancer cell lines and normal Chang liver cells, and, their transcriptional activities in various cells were determined by measuring the expression of luciferase.

RESULTSThe survivin promoter exhibited a higher transcriptional activity than PSMA promoter and enhancer in tumor cell lines, and the S2pro promoter showed the highest activity, reaching one third of that of the CMV promoter.

CONCLUSIONThe survivin promoter is highly activated in prostate cancer cell lines and may serve as a new tool for the transcriptional targeting gene therapy of prostate cancer.

Antigens, Surface ; genetics ; Cell Line, Tumor ; Glutamate Carboxypeptidase II ; genetics ; Humans ; Inhibitor of Apoptosis Proteins ; genetics ; Male ; Plasmids ; Promoter Regions, Genetic ; Prostatic Neoplasms ; genetics ; therapy ; Transcription Initiation Site ; Transcriptional Activation ; Transfection

OBJECTIVETo explore the transgenic efficiency of non-viral vector Tf-PEG-PEI and the cell specific silencing effect of plasmid pPSMAe/p-shNS-ploy(A) on prostate cancer cells.

METHODSPolyethyleneimine (PEI) was modified by using polyethylene glycol and transferrin to synthesize the non-viral vector Tf-PEG-PEI. NS-specific plasmids pPSMAe/p-shNS-ploy(A) and Tf-PEG-PEI were used to transfect prostate cancer LNCap and PC-3 cells. The changes of cell morphology, proliferation ability and cell cycle were studied after down-regulating the NS gene level.

RESULTSTf-PEG-PEI was successfully modified. After transfection, the PSMA-expressing LNCaP cells became larger and showed more pseudopodia, having a tendency to differentiate. Their cell proliferation ability was reduced, and the detection of cell cycle showed a decrease of S phase and an increase of G(1) phase after knocking down NS gene. These targets were not changed in non-PSMA-expresing PC-3 cells.

CONCLUSIONSThe non-viral vector Tf-PEG-PEI has a high ability to transfer targeted gene into target cells. The cellular specificity of short-hairpin RNA transcription driven by PSMAe/p is confirmed by silencing NS gene. The use of cell specific promoter may be an effective strategy of gene therapy for prostate cancer.

Antigens, Surface ; genetics ; metabolism ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; GTP-Binding Proteins ; genetics ; metabolism ; Genetic Vectors ; Glutamate Carboxypeptidase II ; genetics ; metabolism ; Humans ; Male ; Nuclear Proteins ; genetics ; metabolism ; Plasmids ; Polyethylene Glycols ; Polyethyleneimine ; analogs & derivatives ; Promoter Regions, Genetic ; Prostatic Neoplasms ; pathology ; RNA Interference ; RNA, Messenger ; metabolism ; RNA, Small Interfering ; genetics ; Transfection ; Transferrin ; genetics