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The Journal of Clinical Investigation Nov 2023Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid...
Half of all men with advanced prostate cancer (PCa) inherit at least 1 copy of an adrenal-permissive HSD3B1 (1245C) allele, which increases levels of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) and promotes intracellular androgen biosynthesis. Germline inheritance of the adrenally permissive allele confers worse outcomes in men with advanced PCa. We investigated whether HSD3B1 (1245C) drives resistance to combined androgen deprivation and radiotherapy. Adrenally permissive 3βHSD1 enhanced resistance to radiotherapy in PCa cell lines and xenograft models engineered to mimic the human adrenal/gonadal axis during androgen deprivation. The allele-specific effects on radiosensitivity were dependent on availability of DHEA, the substrate for 3βHSD1. In lines expressing the HSD3B1 (1245C) allele, enhanced expression of DNA damage response (DDR) genes and more rapid DNA double-strand break (DSB) resolution were observed. A correlation between androgen receptor (AR) expression and increased DDR gene expression was confirmed in 680 radical prostatectomy specimens. Treatment with the nonsteroidal antiandrogen enzalutamide reversed the resistant phenotype of HSD3B1 (1245C) PCa in vitro and in vivo. In conclusion, 3βHSD1 promotes prostate cancer resistance to combined androgen deprivation and radiotherapy by upregulating DNA DSB repair. This work supports prospective validation of early combined androgen blockade for high-risk men harboring the HSD3B1 (1245C) allele.
Topics: Humans; Male; Androgen Antagonists; Androgens; DNA; Genotype; Hydroxysteroid Dehydrogenases; Multienzyme Complexes; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 37966114
DOI: 10.1172/JCI165718 -
Theranostics 2024Radical prostatectomy (RP) combined with pelvic lymph node dissection (PLND) is the first step in multimodal treatment of prostate cancer (PCa) without distant... (Review)
Review
Radical prostatectomy (RP) combined with pelvic lymph node dissection (PLND) is the first step in multimodal treatment of prostate cancer (PCa) without distant metastases. For a long time, the surgical resection range has been highly dependent on the surgeon's visualization and experience with preoperative imaging. With the rapid development of prostate-specific membrane antigen positron emission tomography and single-photon emission computed tomography (PSMA-PET and PSMA-SPECT), PSMA-targeted surgery has been introduced for a more accurate pathological diagnosis and complete resection of positive surgical margins (PSMs) and micro-lymph node metastases (LNMs). We reviewed PSMA-targeted surgeries, including PSMA-PET-guided prostatic biopsy (PSMA-TB), PSMA-targeted radio-guided surgery (PSMA-RGS), PSMA-targeted fluorescence-guided surgery (PSMA-FGS), and multi-modality/multi-targeted PSMA-targeted surgery. We also discuss the strengths and challenges of PSMA-targeted surgery, and propose that PSMA-targeted surgery could be a great addition to existing surgery protocols, thereby improving the accuracy and convenience of surgery for primary and recurrent PCa in the near future.
Topics: Humans; Male; Prostatic Neoplasms; Glutamate Carboxypeptidase II; Antigens, Surface; Prostatectomy; Surgery, Computer-Assisted; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon; Lymph Node Excision
PubMed: 38773975
DOI: 10.7150/thno.95039 -
Archivos Espanoles de Urologia Nov 2023Prostate cancer remains a significant global health challenge. Traditionally anchored by the Gleason score/Grade Group (GS/GG), the landscape of prostate cancer... (Review)
Review
Prostate cancer remains a significant global health challenge. Traditionally anchored by the Gleason score/Grade Group (GS/GG), the landscape of prostate cancer diagnosis is undergoing transformative steps, particularly in the domain of biopsy procedures. GS/GG continues to be pivotal in malignancy grading, but recent technological strides have augmented the diagnostic relevance of biopsies. Integral to this progression is the adoption of advanced imaging techniques, especially magnetic resonance imaging, which has refined biopsy accuracy and efficiency. A deep understanding of prostate cancer pathology reveals a cribriform pattern and intraductal carcinoma of the prostate as independent forms of malignancy, suggesting a potentially aggressive disease course. Furthermore, the distinct behaviour of ductal adenocarcinoma and small cell carcinoma of the prostate, compared with acinar adenocarcinoma, necessitates their accurate differentiation during biopsy. The genomic era ushers in a renewed emphasis on tissue samples obtained from prostate biopsies, especially as mutations in genes, such as /, and paves the way for precision medicine. This review encapsulates the evolving dynamics of prostate biopsy, from technological advancements to the profound implications on prostate cancer management and therapy.
Topics: Male; Humans; Prostate; BRCA1 Protein; BRCA2 Protein; Prostatic Neoplasms; Biopsy; Carcinoma, Intraductal, Noninfiltrating; Neoplasm Grading
PubMed: 38053418
DOI: 10.56434/j.arch.esp.urol.20237609.78 -
Journal of Enzyme Inhibition and... Dec 2023Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine...
Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) and histone deacetylase 2 (HDAC2) could potentially be a novel strategy against PCa. Herein, we identified seven compounds simultaneously targeting CARM1 and HDAC2 through structure-based virtual screening. These compounds possessed potent inhibitory activities at the nanomolar level . Among them, CH-1 was the most active inhibitor which exhibited excellent and balanced inhibitory effects against both CARM1 (IC = 3.71 ± 0.11 nM) and HDAC2 (IC = 4.07 ± 0.25 nM). MD simulations presented that CH-1 could stably bind the active pockets of CARM1 and HDAC2. Notably, CH-1 exhibited strong anti-proliferative activity against multiple prostate-related tumour cells (IC < 1 µM). assessment indicated that CH-1 significantly inhibited tumour growth in a DU145 xenograft model. Collectively, CH-1 could be a promising drug candidate for PCa treatment.
Topics: Male; Humans; Histone Deacetylase 2; Antineoplastic Agents; Protein-Arginine N-Methyltransferases; Prostatic Neoplasms; Histone Deacetylase Inhibitors
PubMed: 37528657
DOI: 10.1080/14756366.2023.2241118 -
Journal of Translational Medicine Jul 2023The genetic risk of aggressive prostate cancer (PCa) is hard to be assessed due to the lack of aggressiveness-related single-nucleotide polymorphisms (SNPs). Prostate...
BACKGROUND
The genetic risk of aggressive prostate cancer (PCa) is hard to be assessed due to the lack of aggressiveness-related single-nucleotide polymorphisms (SNPs). Prostate volume (PV) is a potential well-established risk factor for aggressive PCa, we hypothesize that polygenic risk score (PRS) based on benign prostate hyperplasia (BPH) or PV-related SNPs may also predict the risk of aggressive PCa or PCa death.
METHODS
We evaluated a PRS using 21 BPH/PV-associated SNPs, two established PCa risk-related PRS and 10 guideline-recommended hereditary cancer risk genes in the population-based UK Biobank cohort (N = 209,502).
RESULTS
The BPH/PV PRS was significantly inversely associated with the incidence of lethal PCa as well as the natural progress in PCa patients (hazard ratio, HR = 0.92, 95% confidence interval [CI]: 0.87-0.98, P = 0.02; HR = 0.92, 95% CI 0.86-0.98, P = 0.01). Compared with men at the top 25th PRS, PCa patients with bottom 25 PRS would have a 1.41-fold (HR, 95% CI 1.16-1.69, P = 0.001) increased PCa fatal risk and shorter survival time at 0.37 yr (95% CI 0.14-0.61, P = 0.002). In addition, patients with BRCA2 or PALB2 pathogenic mutations would also have a high risk of PCa death (HR = 3.90, 95% CI 2.34-6.51, P = 1.79 × 10; HR = 4.29, 95% CI 1.36-13.50, P = 0.01, respectively). However, no interactive but independent effects were detected between this PRS and pathogenic mutations.
CONCLUSIONS
Our findings provide a new measurement of PCa patients' natural disease outcomes via genetic risk ways.
Topics: Male; Humans; Prostatic Hyperplasia; Genetic Predisposition to Disease; Prostatic Neoplasms; Risk Factors; Risk Assessment
PubMed: 37415201
DOI: 10.1186/s12967-023-04316-y -
Matrix Biology : Journal of the... Dec 2023Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy,...
Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVβ3 ligands. Moreover, we describe for the first time co-fractionation of αVβ3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients' plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. The monocytes incubated with small extracellular vesicles do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as "adhesion competent". Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Signal Transduction; Antibodies, Monoclonal; Integrins; Integrin alphaVbeta3; Cell Line, Tumor
PubMed: 37956856
DOI: 10.1016/j.matbio.2023.11.003 -
Interaction between smoking status and dietary selenium intake affects PSA: A cross-sectional study.Urologic Oncology Dec 2023Conflicting results regarding the impact of selenium on reducing prostate cancer have been reported. The current analysis aimed to understand whether there are potential...
BACKGROUND
Conflicting results regarding the impact of selenium on reducing prostate cancer have been reported. The current analysis aimed to understand whether there are potential factors affecting the relationship between selenium and prostate cancer.
OBJECTIVE
To clarify the relationship between dietary selenium intake and prostate cancer, we evaluated the correlation between dietary selenium intake and prostate-specific antigen (PSA) based on the National Health and Nutrition Examination Survey (NHANES) database.
METHODS
After screening the NHANES survey data from 2005 to 2010, data for 3,614 of 31,034 participants were considered suitable to include in our study. Dietary selenium intake was the independent variable of our study, while PSA was the dependent variable. We stratified participants into current, former, and never smokers and performed an interaction test on the relationship between selenium intake and PSA using multivariable logistic regression for each smoking-status subgroup.
RESULTS
For our subgroup analysis, we grouped participants based on smoking status and investigated the association between dietary selenium intake and PSA levels. Among the 242 participants with a PSA level of 4 or higher, the mean age was 58.5 years (±12.1). After adjusting for covariates, we did not find a significant association between dietary selenium and the odds of having a high PSA level. However, we observed a significant interaction between smoking status and dietary selenium in relation to PSA levels (P = .007). Specifically, smokers had lower odds of having high PSA levels, while nonsmokers had higher odds. This suggests that smoking status may modify the effect of dietary selenium on PSA levels.
CONCLUSION
Our findings suggest that smoking status affects the relationship between dietary selenium intake and PSA and that smokers are at lower odds of having a high PSA level.
Topics: Humans; Male; Middle Aged; Cross-Sectional Studies; Nutrition Surveys; Prostate-Specific Antigen; Prostatic Neoplasms; Selenium; Smoking
PubMed: 37940471
DOI: 10.1016/j.urolonc.2023.07.009 -
JNCI Cancer Spectrum Aug 2023Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score,...
BACKGROUND
Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer.
METHODS
Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy-tested cohort and postoperative radiotherapy in the GC-tested cohort as well as adverse pathological findings after prostatectomy.
RESULTS
A total of 572 545 patients were included in the analysis, of whom 8927 patients underwent GC testing. GC biopsy-tested patients were more likely to undergo active active surveillance or watchful waiting than untested patients (odds ratio [OR] =2.21, 95% confidence interval [CI] = 2.04 to 2.38, P < .001). The highest use of active surveillance or watchful waiting was for patients with a low-risk GC classification (41%) compared with those with an intermediate- (27%) or high-risk (11%) GC classification (P < .001). Among National Comprehensive Cancer Network patients with low and favorable-intermediate risk, higher GC risk class was associated with greater use of local therapy (OR = 4.79, 95% CI = 3.51 to 6.55, P < .001). Within this subset of patients who were subsequently treated with prostatectomy, high GC risk was associated with harboring adverse pathological findings (OR = 2.94, 95% CI = 1.38 to 6.27, P = .005). Use of radiation after prostatectomy was statistically significantly associated with higher GC risk groups (OR = 2.69, 95% CI = 1.89 to 3.84).
CONCLUSIONS
There is a strong association between use of the biopsy GC test and likelihood of conservative management. Higher genomic classifier scores are associated with higher rates of adverse pathology at time of surgery and greater use of postoperative radiotherapy.In this study the Decipher Prostate Genomic Classifier (GC) was used to analyze a US national database of men with prostate cancer. Use of the GC was associated with conservative management (ie, active surveillance). Among men who had high-risk GC scores and then had surgery, there was a 3-fold higher chance of having worrisome findings in surgical specimens.
Topics: Male; Humans; United States; Risk Assessment; Prostatic Neoplasms; Prostate-Specific Antigen; Prostate; Genomics
PubMed: 37525535
DOI: 10.1093/jncics/pkad052 -
Current Oncology (Toronto, Ont.) Sep 2023A recent approach to radiotherapy for prostate cancer is the administration of high doses of radiation to the prostate while minimizing the risk of side effects. Thus,... (Review)
Review
A recent approach to radiotherapy for prostate cancer is the administration of high doses of radiation to the prostate while minimizing the risk of side effects. Thus, image-guided radiotherapy utilizes advanced imaging techniques and is a feasible strategy for increasing the radiation dose. New radioactive particles are another approach to achieving high doses and safe procedures. Prostate brachytherapy is currently considered as a combination therapy. Spacers are useful to protect adjacent organs, specifically the rectum, from excessive radiation exposure.
Topics: Male; Humans; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Prostatic Neoplasms; Prostate; Rectum
PubMed: 37754502
DOI: 10.3390/curroncol30090587 -
JAMA Network Open May 2024Plant-based diets are associated with many health and environmental benefits, including primary prevention of fatal prostate cancer, but less is known about... (Observational Study)
Observational Study
IMPORTANCE
Plant-based diets are associated with many health and environmental benefits, including primary prevention of fatal prostate cancer, but less is known about postdiagnostic plant-based diet patterns in individuals with prostate cancer.
OBJECTIVE
To examine whether postdiagnostic plant-based dietary patterns are associated with risk of prostate cancer progression and prostate cancer-specific mortality.
DESIGN, SETTING, AND PARTICIPANTS
This longitudinal observational cohort study included men with biopsy-proven nonmetastatic prostate cancer (stage ≤T3a) from the diet and lifestyle substudy within the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) enrolled at 43 urology practices across the US from 1999 to 2018. Participants completed a comprehensive diet and lifestyle questionnaire (including a validated food frequency questionnaire [FFQ]) between 2004 and 2016. Data were analyzed from August 2022 to April 2023.
EXPOSURES
Overall plant-based diet index (PDI) and healthful plant-based diet index (hPDI) scores were calculated from the FFQ.
MAIN OUTCOMES AND MEASURES
The primary outcome was prostate cancer progression (recurrence, secondary treatment, bone metastases, or prostate cancer-specific mortality). The secondary outcome was prostate cancer-specific mortality.
RESULTS
Among 2062 participants (median [IQR] age, 65.0 [59.0-70.0] years), 61 (3%) identified as African American, 3 (<1%) identified as American Indian or Alaska Native, 9 (<1%) identified as Asian or Pacific Islander, 15 (1%) identified as Latino, and 1959 (95%) identified as White. Median (IQR) time from prostate cancer diagnosis to FFQ was 31.3 (15.9-62.0) months after diagnosis. During a median (IQR) follow-up of 6.5 (1.3-12.8) years after the FFQ, 190 progression events and 61 prostate cancer-specific mortality events were observed. Men scoring in the highest vs lowest quintile of PDI had a 47% lower risk of progression (HR, 0.53; 95% CI, 0.37-0.74; P for trend = .003). The hPDI was not associated with risk of progression overall. However, among 680 individuals with Gleason grade 7 or higher at diagnosis, the highest hPDI quintile was associated with a 55% lower risk of progression compared with the lowest hPDI quintile (HR 0.45; 95% CI, 0.25-0.81; P for trend = .01); no association was observed in individuals with Gleason grade less than 7.
CONCLUSIONS AND RELEVANCE
In this cohort study of 2062 men with prostate cancer, higher intake of plant foods after prostate cancer diagnosis was associated with lower risk of cancer progression. These findings suggest nutritional assessment and counseling may be recommended to patients with prostate cancer to help establish healthy dietary practices and support well-being and overall health.
Topics: Humans; Male; Prostatic Neoplasms; Disease Progression; Aged; Middle Aged; Longitudinal Studies; Diet, Vegetarian; United States; Cohort Studies; Diet, Plant-Based
PubMed: 38691361
DOI: 10.1001/jamanetworkopen.2024.9053