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International Journal of Molecular... Nov 2023extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits...
Auraptene Enhances AMP-Activated Protein Kinase Phosphorylation and Thereby Inhibits the Proliferation, Migration and Expression of Androgen Receptors and Prostate-Specific Antigens in Prostate Cancer Cells.
extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation.
Topics: Male; Humans; AMP-Activated Protein Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Prostate-Specific Antigen; Receptors, Androgen; Prostate; HEK293 Cells; AMP-Activated Protein Kinase Kinases; TOR Serine-Threonine Kinases; Prostatic Neoplasms; Cell Proliferation; Cell Line, Tumor
PubMed: 37958994
DOI: 10.3390/ijms242116011 -
Frontiers in Immunology 2023In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and...
INTRODUCTION
In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics.
METHODS
Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration.
RESULTS
Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm.
DISCUSSION
These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.
Topics: Male; Humans; Prostate; Root Cause Analysis; Prostate-Specific Antigen; Antibodies; Antigens, Surface; T-Lymphocytes; Biological Products
PubMed: 37942314
DOI: 10.3389/fimmu.2023.1261070 -
In Vivo (Athens, Greece) 2021Lack of interchangeability between prostate-specific antigen (PSA) assays could have a clinical impact. We compared PSA assays from different manufacturers and... (Comparative Study)
Comparative Study
BACKGROUND/AIM
Lack of interchangeability between prostate-specific antigen (PSA) assays could have a clinical impact. We compared PSA assays from different manufacturers and calibrations.
PATIENTS AND METHODS
A total of 233 men who underwent prostate biopsy (PSA: 2-10 ng/ml; Beckman Coulter Access Hybritech as reference) were enrolled. Total (tPSA) and free PSA (fPSA) were also measured using the Roche cobas and the Abbott Architect methods.
RESULTS
Roche tPSA values were ≈1% higher than Beckman, while Abbott values were ≈5% lower. Roche had the highest diagnostic sensitivity (92%) compared to Beckman Coulter (87%) and Abbott (85%). Roche fPSA was ≈3% lower and Abbott ≈17% higher than that of Beckman. For the percentage of fPSA, Roche had the highest sensitivity (98%).
CONCLUSION
Roche cobas and Beckman Coulter Access Hybritech tPSA were almost interchangeable. While the agreement was acceptable for tPSA, this did not happen with fPSA and greater efforts for harmonization are required.
Topics: Calibration; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Reference Standards; World Health Organization
PubMed: 34697179
DOI: 10.21873/invivo.12643 -
International Journal of Molecular... Aug 2023Prostate-specific membrane antigen (PSMA)-based imaging improved the detection of primary, recurrent and metastatic prostate cancer. However, in certain patients, a low...
Prostate-specific membrane antigen (PSMA)-based imaging improved the detection of primary, recurrent and metastatic prostate cancer. However, in certain patients, a low PSMA surface expression can be a limitation for this promising diagnostic tool. Pharmacological induction of PSMA might be useful to further improve the detection rate of PSMA-based imaging. To achieve this, we tested dutasteride (Duta)-generally used for treatment of benign prostatic enlargement-and lovastatin (Lova)-a compound used to reduce blood lipid concentrations. We aimed to compare the individual effects of Duta and Lova on cell proliferation as well as PSMA expression. In addition, we tested if a combination treatment using lower concentrations of Duta and Lova can further induce PSMA expression. Our results show that a treatment with ≤1 μM Duta and ≥1 μM Lova lead to a significant upregulation of whole and cell surface PSMA expression in LNCaP, C4-2 and VCaP cells. Lower concentrations of Duta and Lova in combination (0.5 μM Duta + 0.5 μM Lova or 0.5 μM Duta + 1 μM Lova) were further capable of enhancing PSMA protein expression compared to a single compound treatment using higher concentrations in all tested cell lines (LNCaP, C4-2 and VCaP).
Topics: Male; Humans; Dutasteride; Prostate; Lovastatin; Glutamate Carboxypeptidase II; Antigens, Surface; Prostatic Neoplasms; Prostate-Specific Antigen; Cell Line, Tumor
PubMed: 37569712
DOI: 10.3390/ijms241512338 -
European Journal of Cancer (Oxford,... Mar 2023The relationship between prostate-specific antigen (PSA) and prostate cancer (PCa) grade was traditionally thought to be linear but recent reports suggest this is not...
OBJECTIVE
The relationship between prostate-specific antigen (PSA) and prostate cancer (PCa) grade was traditionally thought to be linear but recent reports suggest this is not true in high-grade cancers. We aimed to compare the association between PSA and PCa-specific mortality (PCSM) in clinically localised low/intermediate and high-grade PCa.
SUBJECTS/PATIENTS AND METHODS
Retrospective cohort study using the National Prostate Cancer Audit database in England of men treated with external beam radiotherapy (EBRT), EBRT and brachytherapy boost (EBRT + BT), radical prostatectomy or no radical local treatment between 2014 and 2018. Multivariable competing-risk regression was used to examine the association between PSA, Gleason, and PCSM. Multivariable restricted cubic spline regression was used to explore the non-linear associations of PSA and PCSM.
RESULTS
102,089 men were included, of whom 71,138 had low/intermediate-grade and 22,425 had high-grade PCa. In high-grade, 4-year PCSM was higher with PSA ≤5 than PSA 5.1-10 for men treated with EBRT (hazard ratio 1.96 (95% confidence interval 1.15-3.34) or no radical local treatment (hazard ratio 1.99 (95% confidence interval 1.33-2.98). Restricted cubic spline regression showed that PSA and PCSM have a non-linear association in high-grade but a linear association in low/intermediate-grade PCa.
CONCLUSION
The low-PSA/high-grade combination in M0 PCa treated with EBRT has a higher PCSM than those with high-grade and intermediate PSA levels. In high-grade disease, the PSA association was non-linear; by contrast, low/intermediate-grade had a linear relationship. This confirms a more aggressive biology in low PSA secreting high-grade PCa and a worse outcome following treatment.
Topics: Male; Humans; Prostate-Specific Antigen; Retrospective Studies; Prostatic Neoplasms; Prostatectomy; Brachytherapy
PubMed: 36641896
DOI: 10.1016/j.ejca.2022.12.017 -
Journal of Clinical Laboratory Analysis Jan 2022This study aimed to identify parameters with a higher diagnostic value for early screening of prostate cancer (PCa) at different ages.
PURPOSE
This study aimed to identify parameters with a higher diagnostic value for early screening of prostate cancer (PCa) at different ages.
MATERIALS AND METHODS
A total of 294 patients were included and divided into two groups according to the age of patients (≤66 and >66 years). Receiver operating characteristic (ROC) curves of total prostate-specific antigen (TPSA), free PSA (FPSA), (F/T)PSA, PSA density (PSAD), PSA-AV score, the ratio of patients' age to prostate volume (AVR) and (F/T)/PSAD were constructed. The area under the ROC curve (AUC) was calculated, and differences in the AUC values among the above-mentioned parameters were compared.
RESULTS
There were 121 patients in the ≤66 years age group (benign prostatic hyperplasia BPH, 103 patients; PCa 18 patients) and 173 patients in the >66 years age group (BPH, 100 patients; PCa, 73 patients). In the ≤66 years age group, the AUC value of AVR for PCa diagnosis was the highest; however, there was no statistically significant difference compared with the AUC values of PSAD and (F/T)/PSAD; compared with TPSA, FPSA, (F/T)PSA and PSA-AV, the differences were statistically significant. In the >66 years age group, the AUC values of PSAD and PSA-AV for PCa diagnosis were higher than those of TPSA, FPSA, (F/T)PSA and (F/T)/PSAD, and the difference was statistically significant; however, the difference was not statistically significant when compared with the AUC value of AVR.
CONCLUSION
In different age groups, screening indices for PCa diagnosis should be selected according to the age of patients.
Topics: Age Factors; Aged; Early Detection of Cancer; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; ROC Curve
PubMed: 34816496
DOI: 10.1002/jcla.24098 -
JAMA Network Open May 2021The diagnostic activity for prostate cancer has increased during the past decades. However, the benefit and harm of the increased diagnostic activity have not been...
IMPORTANCE
The diagnostic activity for prostate cancer has increased during the past decades. However, the benefit and harm of the increased diagnostic activity have not been quantified in detail for a country or a large region.
OBJECTIVE
The aim of this study was to evaluate and quantify the association between increases in diagnostic activity driven by prostate-specific antigen testing and incidence of prostate cancer diagnosis, treatment, and mortality.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used the Proxy-Based Risk-Stratified Incidence Simulation Model-Prostate Cancer to examine observed data on all Swedish men with prevalent prostate cancer and compare them with a corresponding, hypothetical, simulated scenario with more restrictive diagnostic activity. All men aged 40 to 100 years living in Sweden during the time period 1996 to 2016 with incident and prevalent prostate cancer were included. The second scenario is the corresponding, hypothetical, simulated scenario where diagnostic activity remained constant as of 1996 (the beginning of the prostate-specific antigen testing era) throughout the study period.
EXPOSURES
High or low diagnostic activity for prostate cancer.
MAIN OUTCOMES AND MEASURES
Incidence of prostate cancer diagnosis, treatment (deferred treatment, curative treatment, and hormonal treatment), and prostate cancer mortality.
RESULTS
During the study period from 1996 to 2016, 188 884 men were diagnosed with prostate cancer at a median (interquartile range) age of 71 (64-77) years. Compared with the low-diagnostic activity scenario, in the high-diagnostic activity scenario, the number of men diagnosed with prostate cancer was 48% higher (423 vs 286 [95% CI, 271-302] per 100 000 men per year), 148% more men were diagnosed with low- or intermediate-risk cancer (221 vs 89 [95% CI, 73-105] per 100 000 men per year), and 108% more men received curative treatment (152 vs 73 [95% CI: 66-85] per 100 000 men per year). There were up to 15% fewer prostate cancer deaths in the scenario with high-diagnostic activity (incidence rate ratio, 0.85; 95% CI, 0.82-0.88).
CONCLUSIONS AND RELEVANCE
This study's results suggest that increased prostate-specific antigen testing and diagnostic activity are associated with a larger number of men being diagnosed with prostate cancer, predominately with low- and intermediate-risk disease. The increased diagnostic activity was associated with a 2-fold increase in curative treatment and a modest decrease in mortality.
Topics: Aged; Aged, 80 and over; Early Detection of Cancer; Humans; Incidence; Male; Middle Aged; Models, Statistical; Prevalence; Prostate-Specific Antigen; Prostatic Neoplasms; Sweden; Treatment Outcome
PubMed: 33999165
DOI: 10.1001/jamanetworkopen.2021.9444 -
Advances in Clinical and Experimental... Aug 2020Previous studies have suggested that prostate-specific antigen (PSA) plays a role in the etiology of prostate cancer (PCa), and that polymorphisms of KLK3 may be... (Meta-Analysis)
Meta-Analysis Review
Previous studies have suggested that prostate-specific antigen (PSA) plays a role in the etiology of prostate cancer (PCa), and that polymorphisms of KLK3 may be associated with PCa. However, these results were conflicting. Therefore, we performed a meta-analysis to illuminate this problem. We searched the PubMed and Web of Science databases. Ten single nucleotide polymorphisms (SNPs) were involved in this meta-analysis. The pooled results showed that the minor alleles of rs1058205, rs2735839, rs174776, rs17632542, rs266849, rs266878, and rs2569735 were significantly associated with PCa. Compared to genotypes of the common homozygotes, the heterozygous genotypes of rs1058205, rs2735839, rs174776, rs17632542, rs266849, and rs266878 were significantly associated with PCa, as well as the homozygous genotypes of rs1058205, rs2735839, rs17632542, rs266878, rs266876, and rs2569735. Only rs2735839 was involved in the Gleason score (GS). The pooled results showed that when compared with GS ≥ 8 PCa, the A-allele was the protective factor for GS < 7 PCa. It was also a protective factor for GS ≥ 4+3 when compared to GS ≤ 3+4 PCa. A strong association was observed between PCa and rs1058205, rs2735839, rs266882, rs174776, rs17632542, rs266849, rs266878, rs266876, rs1058274, and rs2569735. The G-allele of rs2735839 was a risk factor for GS < 7 PCa when compared with the GS ≥ 8 PCa, as well as for the GS ≥ 4+3 when compared to the GS ≤ 3+4 PCa. Therefore, these SNPs may be valuable as biomarkers for PCa in the future.
Topics: Genetic Predisposition to Disease; Humans; Kallikreins; Male; Neoplasm Grading; Polymorphism, Single Nucleotide; Prostate-Specific Antigen; Prostatic Neoplasms
PubMed: 32869960
DOI: 10.17219/acem/121521 -
Clinical Chemistry and Laboratory... Nov 2021
Topics: Bias; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Research Design
PubMed: 34751521
DOI: 10.1515/cclm-2021-1125 -
Journal of the Formosan Medical... Jan 2021In advanced or high-grade prostate cancer (PCa), prostate-specific antigen (PSA) is usually elevated, however, some patients may present with low initial PSA (iPSA)...
PURPOSE
In advanced or high-grade prostate cancer (PCa), prostate-specific antigen (PSA) is usually elevated, however, some patients may present with low initial PSA (iPSA) levels. The objective of this study was to evaluate whether different iPSA levels were associated with dissimilar clinical outcomes among men with high-grade PCa and advanced disease after robot-assisted laparoscopic radical prostatectomy (RaLRP).
METHODS
This study enrolled 69 PCa patients with initial Gleason score ≥8 and pathologic T-stage ≥3a from April 2012 to December 2018. Patients were stratified into 3 groups based on iPSA levels at diagnosis: <5.0, 5.0-9.9, and ≥10.0. The patients' related parameters were compared among these groups.
RESULTS
The median follow-up period was 33.1 months (IQR: 12.1-48.1). There was no difference in biochemical recurrence (BCR) between the 3 groups (Log-rank test, p = 0.484). We found a higher risk of biochemical recurrence in patients with positive surgical margins (HR: 5.04, 95% CI: 1.64-15.50, p = 0.005). In addition, patients with low iPSA levels (<5.0 ng/mL) had poor radiographic progression-free survival (Log-rank test, p = 0.001) and a higher risk of disease progression (HR: 12.2, 95% CI: 1.18-1260.99, p = 0.036) compared with patients with higher iPSA levels (≥10 ng/mL).
CONCLUSION
In patients with high-grade locally-advanced PCa, a low iPSA level was associated with a higher risk of disease progression, but not with biochemical recurrence. In this unique population, serum PSA may not be a reliable marker to detect disease progression. Monitoring of these patients may warrant other biomarkers or imaging.
Topics: Disease Progression; Humans; Male; Neoplasm Grading; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms
PubMed: 32591157
DOI: 10.1016/j.jfma.2020.06.021