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Prostate cancer (PC) is one of the most commonly diagnosed tumours among men. Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone acetate (AbA) and enzalutamide (ENZ), are currently used in the management of metastatic castration-resistant PC (mCRPC). However, the treatment is challenging due to the lack of prognostic biomarkers. Meanwhile, single-nucleotide polymorphisms (SNPs) have emerged as potential prognostic indicators of mCRPC. Thus, this study evaluated the impact of relevant SNPs on the treatment outcomes of 123 mCRPC patients enrolled in a hospital-based cohort study. The CYP17A1 rs2486758 C allele was associated with a 50% reduction in the risk of developing castration resistance (hazard ratio (HR) = 0.55; p = 0.003). Among patients without metastasis at tumour diagnosis and under AbA, a marginal association between YBX1 rs10493112 and progression-free survival was detected (log-rank test, p = 0.056). In the same subgroup, significant associations of HSD3B1 rs1047303 (CC/CA vs. AA; HR = 3.41; p = 0.025), YBX1 rs12030724 (AT vs. AA; HR = 3.54; p = 0.039) and YBX1 rs10493112 (log-rank test, p = 0.041; CC vs. AA/AC; HR = 3.22; p = 0.053) with overall survival were also observed, which were confirmed by multivariate Cox analyses. Although validation with larger cohorts is required, these findings suggest that SNPs could enhance the prognosis assessment of mCRPC patients, leading to a more personalised treatment. [ABSTRACT FROM AUTHOR]

Monu Deswal,1 Durgavati Yadav,1 Vinay Kumar,2 Meenakshi Meenu,3 Pranay Tanwar,4 Shivani Srivastava,5 Prabhjot Singh,1 Kumar Sandeep6 1Department of Urology, All India Institute of Medical Sciences, New Delhi, India; 2Heart and Vascular Institute, Pennsylvania State University, Hershey Medical Center, Hershey, PA, USA; 3Department of Pharmacology, All India Institute of Medical Sciences, Bilaspur, Himachal Pradesh, India; 4Lab Oncology Unit, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India; 5Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; 6Preventive Oncology, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, IndiaCorrespondence: Prabhjot Singh, Department of Urology, All India Institute of Medical Sciences, New Delhi, India, Email drprabhjotsingh@aiims.edu Kumar Sandeep, Preventive Oncology, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India, Email drkumarsandeep@aiims.eduBackground: Prostate cancer (PCa) is not well understood because of its enormous biological heterogeneity and unreliable progression. We conducted this retrospective analysis to examine the variables predicting early and late progression to castration-resistant PCa (CRPC) for better management of this disease.Methods: This single institutional retrospective study was conducted from January 2018 to January 2022. A total of 98 consecutive men meeting with the diagnosis of CRPC as per the inclusion criteria were included in the study and were stratified in four quartiles on the basis of time to CRPC (time to castration resistance [TTCR]) development. Early CRPC (1st quartile, TTCR = 6– 12 months) and late CRPC (4th quartile, TTCR = 38– 120 months) were then compared on the basis of different clinical, pathological and AR-LBD sequence to find the correlation with response duration.Results: Median time to develop castration resistance was 25 ± 26.44 months. The mean age of the patients was 66.8 ± 9.20 years and median baseline PSA was calculated 100± 685.06 ng/mL respectively. Higher Gleason score (≥ 7– 10) was found to be significantly associated with early development of CRPC (p< 0.001) and lower nadir PSA was significantly indicating late CRPC progression (p< 0.005). No mutations were found in androgen receptor exon-5, 6, 7 except a homozygous mutation in the 7th intronic region, which is involved in splice variants formation playing noteworthy role in CRPC development.Conclusion: Time for metastatic PCa to CRPC ranges from 6– 120 months revealing its heterogeneous nature. Early age presentation in the clinic and high initial PSA and high grade (GS> 7) at diagnosis were positively associated with early CRPC while lower nadir PSA was correlated with late CRPC progression. No remarkable genomic mutations were discovered. Therefore, more data are needed and further research is required with large no. of patients to discover the predictive prognostic biomarkers for better patients’ management.Keywords: prostate cancer, castration resistance, early and late progression, PSA, androgen receptor, PCa

Opinion statement: The management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape and biology underpinning this form of prostate cancer. The implementation of various therapeutic agents has improved overall survival but despite the promising advances in therapeutic options, mCRPC remains incurable. The focus of treatment should be not only to improve survival but also to preserve the patient's quality of life (QoL) and ameliorate cancer-related symptoms such as pain. The choice and sequence of therapy for mCRPC patients are complex and influenced by various factors, such as side effects, disease burden, treatment history, comorbidities, patient preference and, more recently, the presence of actionable genomic alterations or biomarkers. Docetaxel is the first-line treatment for chemo-naïve patients with good performance status and those who have yet to progress on docetaxel in the castration-sensitive setting. Novel androgen agents (NHAs), such as abiraterone and enzalutamide, are effective treatment options that are utilized as second-line options. These medications can be considered upfront in frail patients or patients who are NHA naïve. Current guidelines recommend genetic testing in mCRPC for mutations in DNA repair deficiency genes to inform treatment decisions, as for example in breast cancer gene mutation testing. Other potential biomarkers being investigated include phosphatase and tensin homologues and homologous recombination repair genes. Despite a growing number of studies incorporating biomarkers in their trial designs, to date, only olaparib in the PROFOUND study and lutetium-177 in the VISION trial have improved survival. This is an unmet need, and future trials should focus on biomarker-guided treatment strategies. The advent of novel noncytotoxic agents has enhanced targeted drug delivery and improved treatment responses with favourable toxicity profiling. Trials should continue to incorporate and report health-related QoL scores and functional assessments into their trial designs. [ABSTRACT FROM AUTHOR]

Background and Objectives: Metastatic castration-sensitive prostate cancer (mCSPC) represents a critical juncture in the management of prostate cancer, where the accurate prediction of the onset of castration resistance is paramount for guiding treatment decisions. Methods: In this study, we underscore the power and efficiency of auto-ML models, specifically the Random Forest Classifier, for their low-code, user-friendly nature, making them a practical choice for complex tasks, to develop a predictive model for the occurrence of castration resistance events (CRE( . Utilizing a comprehensive dataset from MSK (Clin Cancer Res 2020), comprising clinical, genetic, and molecular features, we conducted a comprehensive analysis to discern patterns and correlations indicative of castration resistance. A random forest classifier was employed to harness the dataset's intrinsic interactions and construct a robust predictive model. Results: We used over 18 algorithms to find the best model, and our results showed a significant achievement, with the developed model demonstrating an impressive accuracy of 75% in predicting castration resistance events. Furthermore, the analysis highlights the importance of specific features such as 'Fraction Genome Altered ‘and the role of prostate specific antigen (PSA( in castration resistance prediction. Conclusion: Corroborating these findings, recent studies emphasize the correlation between high 'Fraction Genome Altered' and resistance and the predictive power of elevated PSA levels in castration resistance. This highlights the power of machine learning in improving outcome predictions vital for prostate cancer treatment. This study deepens our insights into metastatic castrationsensitive prostate cancer and provides a practical tool for clinicians to shape treatment strategies and potentially enhance patient results. [ABSTRACT FROM AUTHOR]

Abstract Background Therapies for metastatic castration-resistant prostate cancer (mCRPC) include targeting the androgen receptor (AR) with androgen receptor inhibitors (ARIs) and prostate-specific membrane antigen (PSMA). Having the ability to detect AR, AR splice variant 7 (AR-V7), or PSMA in circulating tumor cells (CTCs) or circulating exosomal cell-free RNA (cfRNA) could be helpful to guide selection of the appropriate therapy for each individual patient. The Vortex Biosciences VTX-1 system is a label-free CTC isolation system that enables the detection of the expression of multiple genes in both CTCs and exosomal cfRNA from the same blood sample in patients with mCRPC. Detection of both AR-V7 and PSMA gene expression in both CTCs and cfRNA simultaneously has not yet been reported. Methods To characterize the combined VTX-1-AdnaDetect workflow, 22Rv1 cancer cells were spiked into blood from healthy donors and processed with the VTX-1 to mimic patient samples and assess performances (capture efficiency, purity, AR and AR-V7 expression). Then, we collected 19 blood samples from 16 patients with mCRPC and therapeutic resistance to androgen receptor inhibitors (ARIs). Plasma was separated and the plasma-depleted blood was processed further with the VTX-1 to collect CTCs. Both plasma exosomal cfRNA and CTCs were subsequently analyzed for AR, AR-V7, PSMA, and prostate-specific antigen (PSA) mRNA expression using the AdnaTest ProstateCancerPanel AR-V7 assay. Results AR-V7 expression could be detected in 22Rv1 cells spiked into blood from healthy volunteers as well as in CTCs and plasma-derived exosomal cfRNA from patients with mCRPC by processing blood with the VTX-1 CTC isolation system followed by the AdnaTest ProstateCancerPanel AR-V7 assay. 94.7% of patient blood samples (18/19) had detectable AR expression in either CTCs or exosomal cfRNA (16 in CTCs, 12 in cfRNA). 15.8% of the 19 patient blood samples (3/19) were found to have AR-V7-positive (AR-V7+) CTCs, one of which was also AR-V7+ in the exosomal cfRNA analysis. 42.1% of patient blood samples (8/19) were found to be PSMA positive (PSMA+): 26.3% (5/19) were PSMA+ in the CTC analysis and 31.6% (6/19) were PSMA+ in the exosomal cfRNA analysis. Of those 8 PSMA+ samples, 2 had detectable PSMA only in CTCs, and 3 had detectable PSMA only in exosomal cfRNA. Conclusion VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood.

Background: Therapies for metastatic castration-resistant prostate cancer (mCRPC) include targeting the androgen receptor (AR) with androgen receptor inhibitors (ARIs) and prostate-specific membrane antigen (PSMA). Having the ability to detect AR, AR splice variant 7 (AR-V7), or PSMA in circulating tumor cells (CTCs) or circulating exosomal cell-free RNA (cfRNA) could be helpful to guide selection of the appropriate therapy for each individual patient. The Vortex Biosciences VTX-1 system is a label-free CTC isolation system that enables the detection of the expression of multiple genes in both CTCs and exosomal cfRNA from the same blood sample in patients with mCRPC. Detection of both AR-V7 and PSMA gene expression in both CTCs and cfRNA simultaneously has not yet been reported. Methods: To characterize the combined VTX-1-AdnaDetect workflow, 22Rv1 cancer cells were spiked into blood from healthy donors and processed with the VTX-1 to mimic patient samples and assess performances (capture efficiency, purity, AR and AR-V7 expression). Then, we collected 19 blood samples from 16 patients with mCRPC and therapeutic resistance to androgen receptor inhibitors (ARIs). Plasma was separated and the plasma-depleted blood was processed further with the VTX-1 to collect CTCs. Both plasma exosomal cfRNA and CTCs were subsequently analyzed for AR, AR-V7, PSMA, and prostate-specific antigen (PSA) mRNA expression using the AdnaTest ProstateCancerPanel AR-V7 assay. Results: AR-V7 expression could be detected in 22Rv1 cells spiked into blood from healthy volunteers as well as in CTCs and plasma-derived exosomal cfRNA from patients with mCRPC by processing blood with the VTX-1 CTC isolation system followed by the AdnaTest ProstateCancerPanel AR-V7 assay. 94.7% of patient blood samples (18/19) had detectable AR expression in either CTCs or exosomal cfRNA (16 in CTCs, 12 in cfRNA). 15.8% of the 19 patient blood samples (3/19) were found to have AR-V7-positive (AR-V7+) CTCs, one of which was also AR-V7+ in the exosomal cfRNA analysis. 42.1% of patient blood samples (8/19) were found to be PSMA positive (PSMA+): 26.3% (5/19) were PSMA+ in the CTC analysis and 31.6% (6/19) were PSMA+ in the exosomal cfRNA analysis. Of those 8 PSMA+ samples, 2 had detectable PSMA only in CTCs, and 3 had detectable PSMA only in exosomal cfRNA. Conclusion: VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood. [ABSTRACT FROM AUTHOR]

Purpose In men with metastatic castration-resistant prostate cancer (mCRPC), new bone lesions are sometimes not properly categorized through a confirmatory bone scan, and clinical significance of the test itself remains unclear. This study aimed to demonstrate the performance rate of confirmatory bone scans in a real-world setting and their prognostic impact in enzalutamide-treated mCRPC. Materials and Methods Patients who received oral enzalutamide for mCRPC during 2014-2017 at 14 tertiary centers in Korea were included. Patients lacking imaging assessment data or insufficient drug exposure were excluded. The primary outcome was overall survival (OS). Secondary outcomes included performance rate of confirmatory bone scans in a real-world setting. Kaplan-Meier analysis and multivariate Cox regression analysis were performed. Results Overall, 520 patients with mCRPC were enrolled (240 [26.2%] chemotherapy-naïve and 280 [53.2%] after chemotherapy). Among 352 responders, 92 patients (26.1%) showed new bone lesions in their early bone scan. Confirmatory bone scan was performed in 41 patients (44.6%), and it was associated with prolonged OS in the entire population (median, 30.9 vs. 19.7 months; p < 0.001), as well as in the chemotherapy-naïve (median, 47.2 vs. 20.5 months; p=0.011) and post-chemotherapy sub-groups (median, 25.5 vs. 18.0 months; p=0.006). Multivariate Cox regression showed that confirmatory bone scan performance was an independent prognostic factor for OS (hazard ratio 0.35, 95% confidence interval, 0.18 to 0.69; p=0.002). Conclusion Confirmatory bone scan performance was associated with prolonged OS. Thus, the premature discontinuation of enzalutamide without confirmatory bone scans should be discouraged. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common male cancer and is known to affect around one in eight males in the United States. However, it tends to progress slowly and is even curable in the early stages of the disease. Androgen receptor (AR) hyperactivity and overexpression are present in almost all cases of PCa. Targeting AR with androgen receptor signaling inhibitors (ARSIs) has proven effective at slowing tumor progression by chemically castrating the patient. However, this is not a permanent solution, as all tumors treated with ARSIs eventually become castration-resistant PCa (CRPC). This could be due to a myriad of reasons, such as mutated variants of AR, selective pressure from the use of ARSI drugs eliminating cells that express higher AR (AR+), or the activation of alternative pathways. Additionally, mutated variants of AR may bind to precursors or splice variants of androgens and be unaffected by ARSIs; the tumors themselves may produce more androgens, or the tumor cells may become androgen-independent through the alternate pathways. Further treatment is based on a case-to-case basis depending on various clinical or molecular features, such as the patient's performance status, cancer grade or stage, and dynamic changes in prostate-specific antigen. Options include chemotherapy, intensified androgen deprivation therapy, and targeted therapy for specific molecules. Research for more effective approaches to treating CRPC is currently underway. [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of drug resistance has become a global concern, impacting the effectiveness of various cancer treatments. One of the mechanisms of drug resistance involves cellular stress response, in which stress granules (SGs) form against pharmacological stress. Recent research pointed out that an SGs component, DEAD-box helicase 3 X-linked (DDX3X) protein, is upregulated in multiple cancers, but its role in cancer drug resistance has yet to be fully understood. This review aims to describe the relationship among DDX3X, SGs, and drug resistance in depth. The DEAD (Asp-Glu-Ala-Asp)-box helicase 3 X-linked (DDX3X) protein participates in many aspects of mRNA metabolism and stress granule (SG) formation. DDX3X has also been associated with signal transduction and cell cycle regulation that are important in maintaining cellular homeostasis. Malfunctions of DDX3X have been implicated in multiple cancers, including brain cancer, leukemia, prostate cancer, and head and neck cancer. Recently, literature has reported SG-associated cancer drug resistance, which correlates with a negative disease prognosis. Based on the connections between DDX3X, SG formation, and cancer pathology, targeting DDX3X may be a promising direction for cancer therapeutics development. In this review, we describe the biological functions of DDX3X in terms of mRNA metabolism, signal transduction, and cell cycle regulation. Furthermore, we summarize the contributions of DDX3X in SG formation and cellular stress adaptation. Finally, we discuss the relationships of DDX3X, SG, and cancer drug resistance, and discuss the current research progress of several DDX3X inhibitors for cancer treatment. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is one of the most commonly diagnosed tumours among men. Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone acetate (AbA) and enzalutamide (ENZ), are currently used in the management of metastatic castration-resistant PC (mCRPC). However, the treatment is challenging due to the lack of prognostic biomarkers. Meanwhile, single-nucleotide polymorphisms (SNPs) have emerged as potential prognostic indicators of mCRPC. Thus, this study evaluated the impact of relevant SNPs on the treatment outcomes of 123 mCRPC patients enrolled in a hospital-based cohort study. The CYP17A1 rs2486758 C allele was associated with a 50% reduction in the risk of developing castration resistance (hazard ratio (HR) = 0.55; p = 0.003). Among patients without metastasis at tumour diagnosis and under AbA, a marginal association between YBX1 rs10493112 and progression-free survival was detected (log-rank test, p = 0.056). In the same subgroup, significant associations of HSD3B1 rs1047303 (CC/CA vs. AA; HR = 3.41; p = 0.025), YBX1 rs12030724 (AT vs. AA; HR = 3.54; p = 0.039) and YBX1 rs10493112 (log-rank test, p = 0.041; CC vs. AA/AC; HR = 3.22; p = 0.053) with overall survival were also observed, which were confirmed by multivariate Cox analyses. Although validation with larger cohorts is required, these findings suggest that SNPs could enhance the prognosis assessment of mCRPC patients, leading to a more personalised treatment.

Purpose: In some patients with prostate cancer, bone marrow carcinomatosis develops later in the course of the disease, which has a poor prognosis. These are often heavily pretreated patients in the castration-resistant situation for whom there are no other therapeutic options, because either all available systemic therapies have already been used or the use of one is not possible due to the cytopenias associated with bone marrow carcinomatosis. In our literature search, there are no data on this treatment in the setting available, especially no clinical trial or even randomized data. This case series is to determine the clinical efficacy of metronomic cyclophosphamide in patients with metastatic castration-resistant prostate cancer and bone marrow carcinomatosis, particularly with regard to stabilization of the blood count (thrombocytopenias) and thus the possibility of further (more toxic) lines of therapy. Methods: Retrospective unicenter analysis was performed on eleven patients between 54 and 84 years of age on metronomic cyclophosphamide for bone marrow carcinomatosis in metastatic castration-resistant prostate cancer treated at a Swiss cancer center between 2014 and 2023. Results: Eleven patients received metronomic cyclophosphamide for varying periods of time; the majority had severe cytopenias (especially thrombocytopenias). Partially hematologic stabilization was achieved with administration of further systemic therapies. Conclusion: Our case series demonstrates that the use of metronomic cyclophosphamide allows hematologic stabilization for months, benefiting patients who had already received all available therapies for metastatic castration-resistant prostate cancer. Alternatively, it may act as bridging therapy to allow consecutive administration of more toxic therapies with proven survival benefit. [ABSTRACT FROM AUTHOR]

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Abstract Background Nowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients. Methods In this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed. Results The results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the “Homogeneous origin clonal model” was shorter than the “Heterogeneous origin clonal model”. The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance. Conclusion Our findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future.

Androgen-receptor-negative, androgen-independent (ARneg-AI) prostate cancer aggressively proliferates and metastasizes, which makes treatment difficult. Hence, it is necessary to continue exploring cancer-associated markers, such as oncofetal Receptor Tyrosine Kinase like Orphan Receptor 1 (ROR1), which may serve as a form of targeted prostate cancer therapy. In this study, we identify that Penta-O-galloyl-β-D-glucose (PGG), a plant-derived gallotannin small molecule inhibitor, modulates ROR1-mediated oncogenic signaling and mitigates prostate cancer phenotypes. Results indicate that ROR1 protein levels were elevated in the highly aggressive ARneg-AI PC3 cancer cell line. PGG was selectively cytotoxic to PC3 cells and induced apoptosis of PC3 (IC50 of 31.64 µM) in comparison to normal prostate epithelial RWPE-1 cells (IC50 of 74.55 µM). PGG was found to suppress ROR1 and downstream oncogenic pathways in PC3 cells. These molecular phenomena were corroborated by reduced migration, invasion, and cell cycle progression of PC3 cells. PGG minimally and moderately affected RWPE-1 and ARneg-AI DU145, respectively, which may be due to these cells having lower levels of ROR1 expression in comparison to PC3 cells. Additionally, PGG acted synergistically with the standard chemotherapeutic agent docetaxel to lower the IC50 of both compounds about five-fold (combination index = 0.402) in PC3 cells. These results suggest that ROR1 is a key oncogenic driver and a promising target in aggressive prostate cancers that lack a targetable androgen receptor. Furthermore, PGG may be a selective and potent anti-cancer agent capable of treating ROR1-expressing prostate cancers.

Background: Nowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients. Methods: In this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed. Results: The results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the "Homogeneous origin clonal model" was shorter than the "Heterogeneous origin clonal model". The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance. Conclusion: Our findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Accumulating evidence indicates importance of RNA regulation in cancer. This includes events such as splicing, translation, and regulation of noncoding RNAs, functions which are governed by RNA binding proteins (RBPs). Aims To find which RBPs could be relevant for prostate cancer, we performed systematic screening of RBP expression in clinical prostate cancer. Methods and Results We interrogated four proteome‐wide proteomics datasets including tumor samples of primary, castration resistant, and metastatic prostate cancer. We found that, while the majority of RBPs are expressed but not significantly altered during prostate cancer development and progression, expression of several RBPs increases in advanced disease. Interestingly, most of the differentially expressed RBPs are not targets of differential posttranscriptional phosphorylation during disease progression. The RBPs undergoing expression changes have functions in, especially, poly(A)‐RNA binding, nucleocytoplasmic transport, and cellular stress responses, suggesting that these may play a role in formation of castration resistance. Pathway analyzes indicate that increased ribosome production and chromatin‐related functions of RBPs are also linked to castration resistant and metastatic prostate cancers. We selected a group of differentially expressed RBPs and studied their role in cultured prostate cancer cells. With siRNA screens, several of these were indicated in survival (DDX6, EIF4A3, PABPN1), growth (e.g., EIF5A, HNRNPH2, LRRC47, and NVL), and migration (e.g., NOL3 and SLTM) of prostate cancer cells. Our analyzes further show that RRP9, a U3 small nucleolar protein essential for ribosome formation, undergoes changes at protein level during metastasis in prostate cancer. Conclusion In this work, we recognized significant molecular alterations in RBP profiles during development and evolution of prostate cancer. Our study further indicates several functionally significant RBPs warranting further investigation for their functions and possible targetability in prostate cancer.

Simple Summary: Despite the use of surgery and treatments that inhibit the androgen axis signaling, prostate cancer patients invariably become resistant to castration. In the case of metastatic disease, several alternatives have emerged in the past decade with the development of radionuclide therapies. These treatments may represent an interesting option as they could target either the microenvironment of sclerotic bone metastases or proteins that are specifically expressed at the surface of cancer cells, as it is the case with the prostate-specific membrane antigen. This review summarizes the clinical trials evaluating the efficacy of radionuclide therapies in patients with locally advanced or metastatic prostate tumors. Besides the theragnostic use of radionuclides, it also discusses the recent encouraging results that were obtained with 177Lu-PSMA-617 and the specific requirements for the use of this class of medication. Prostate cancer represents the second cause of death by cancer in males in western countries. While early-stage diseases are accessible to surgery and/or external radiotherapy, advanced metastatic prostate cancers are primarily treated with androgen deprivation therapy, to which new generation androgen receptor antagonists or taxane-based chemotherapies are added in the case of tumor relapse. Nevertheless, patients become invariably resistant to castration with a median survival that rarely exceeds 3 years. This fostered the search for alternative strategies, independent of the androgen receptor signaling pathway. In this line, radionuclide therapies may represent an interesting option as they could target either the microenvironment of sclerotic bone metastases with the use of radiopharmaceuticals containing samarium-153, strontium-89 or radium-223 or tumor cells expressing the prostate-specific membrane antigen (PSMA), a protein found at the surface of prostate cancer cells. This review gives highlights the chemical properties of radioligands targeting prostate cancer cells and recapitulates the clinical trials evaluating the efficacy of radionuclide therapies, alone or in combination with other approved treatments, in patients with castration-resistant prostate tumors. It discusses some of the encouraging results obtained, especially the benefit on overall survival that was reported with [177Lu]-PSMA-617. It also addresses the specific requirements for the use of this particular class of drugs, both in terms of medical staff coordination and adapted infrastructures for efficient radioprotection. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review paper, we explore the role of chronic inflammation in the pathogenesis of prostatic diseases, such as chronic prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer. Chronic inflammation is a significant risk factor for these diseases, but the molecular mechanisms behind it are not yet fully understood. Previous attempts to investigate, link, and target inflammatory signaling molecules in men with these conditions have been clinically ambiguous and inconclusive. As a result, we proposed a paradigm shift in which less-explored molecules in the inflammatory signaling cascade are investigated as possible therapeutic targets for prostate diseases. In addition, we comprehensively discuss how aberrant signaling of these molecules may cause prostate cancer stemness, neuroendocrine differentiation, castration resistance, metabolic reprogramming, and immunosuppression. In conclusion, we forecast that targeting the interleukin-1 receptor-associated kinases (IRAKs) signaling pathway may provide a far more effective therapeutic or prophylactic strategy for the management of chronic inflammation-driven prostatic diseases. Chronic inflammation is now recognized as one of the major risk factors and molecular hallmarks of chronic prostatitis, benign prostatic hyperplasia (BPH), and prostate tumorigenesis. However, the molecular mechanisms by which chronic inflammation signaling contributes to the pathogenesis of these prostate diseases are poorly understood. Previous efforts to therapeutically target the upstream (e.g., TLRs and IL1-Rs) and downstream (e.g., NF-κB subunits and cytokines) inflammatory signaling molecules in people with these conditions have been clinically ambiguous and unsatisfactory, hence fostering the recent paradigm shift towards unraveling and understanding the functional roles and clinical significance of the novel and relatively underexplored inflammatory molecules and pathways that could become potential therapeutic targets in managing prostatic diseases. In this review article, we exclusively discuss the causal and molecular drivers of prostatitis, BPH, and prostate tumorigenesis, as well as the potential impacts of microbiome dysbiosis and chronic inflammation in promoting prostate pathologies. We specifically focus on the importance of some of the underexplored druggable inflammatory molecules, by discussing how their aberrant signaling could promote prostate cancer (PCa) stemness, neuroendocrine differentiation, castration resistance, metabolic reprogramming, and immunosuppression. The potential contribution of the IL1R-TLR-IRAK-NF-κBs signaling molecules and NLR/inflammasomes in prostate pathologies, as well as the prospective benefits of selectively targeting the midstream molecules in the various inflammatory cascades, are also discussed. Though this review concentrates more on PCa, we envision that the information could be applied to other prostate diseases. In conclusion, we have underlined the molecular mechanisms and signaling pathways that may need to be targeted and/or further investigated to better understand the association between chronic inflammation and prostate diseases. [ABSTRACT FROM AUTHOR]

Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.

Background: After radical prostatectomy (RP), depending on stage, up to 40% of patients with prostate cancer (PCa) will experience biochemical failure (BF). Despite salvage therapy, approximately one-third of these patients will need permanent hormone therapy (pHT) and are at risk of progression to castration-resistant PCa (CRPC). Prognostic markers herald the need for neoadjuvant, adjuvant, or multimodal treatment. Objective: To evaluate the added value of blood LRG1 in predicting treatment failure in patients who have undergone radical prostatectomy (RP). Design, setting, and participants: We quantified LRG1 in serum or plasma sampled before radical prostatectomy from patients from the Martini-Klinik (Martini; n = 423), the Danish CuPCa cohort (CuPCa; n = 182), and Oslo University Hospital (OUH; n = 145). Outcome measurements and statistical analysis: The endpoints were BF, pHT, and CRPC. The association between LRG1 and survival outcomes was evaluated using Kaplan-Meier estimation and Cox proportional-hazards modeling. The added predictive value of LRG1 in nested models was estimated using the concordance index, time-dependent area under the receiver operating characteristic curve, and decision curve analysis. Results and limitations: In multivariable Cox models using preoperative characteristics, LRG1 was associated with an estimated lower risk of BF in the Martini cohort (adjusted hazard ratio [aHR] 0.68, 95% confidence interval [CI] 0.52–0.90) and in the CuPCa cohort (aHR 0.47, 95% CI 0.30–0.73). Using preoperative prognostic variables, our data showed that doubling of LRG1 was also associated with a lower risk of pHT receipt in the CuPCa cohort (aHR 0.43, 95% CI 0.20–0.93) and of CRPC development in the OUH cohort (aHR 0.32, 95% CI 0.15–0.69). Similar aHR values were observed using either preoperative or postoperative variables for all endpoints. Conclusions: PCa patients with high blood LRG1 are at lower risk of BF, pHT receipt, and progression to CRPC. Since LRG1 adds value to established prognostic models, new prognostic factor combinations including LRG1 should be considered in future studies. Patient summary: We measured concentrations of the blood-based protein LRG1 before surgery for prostate cancer. Patients with high LRG1 levels had better disease-free survival, suggesting that LRG1 can help in predicting prognosis.

The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan–Meier method, and Cox proportional hazards model. One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival. • Apalutamide + androgen deprivation therapy (ADT) resulted in a robust prostate-specific antigen (PSA) decline in TITAN. • Rapid, deep, and durable PSA decline with apalutamide + ADT was associated with improved long-term outcomes. • Results confirm the prognostic impact of PSA decline in patients with metastatic castration-sensitive prostate cancer. [ABSTRACT FROM AUTHOR]

Cholinergic receptor muscarinic 3 (CHRM3)‐mediated focal adhesion kinase/YES‐associated protein (YAP) signalling is essential for the growth of castration‐resistant prostate cancer (CRPC) cells. Here, we evaluated the molecular mechanisms through which CHRM3 overexpression facilitates castration‐resistant growth. Small RNA sequencing combined with in silico analyses revealed that CHRM3 was a putative target of miR‐15b‐5p. Notably, androgen deprivation suppressed miR‐15b‐5p expression and increased CHRM3 expression. Moreover, miR‐15b‐5p bound directly to CHRM3 and inhibited YAP activation induced by CHRM3 stimulation. Furthermore, miR‐15b‐5p abolished the growth of CRPC cells induced by CHRM3 stimulation. We conclude that the miR‐15b‐5p/CHRM3/YAP signalling axis promotes the castration‐resistant growth of prostate cancer. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) remains the principal treatment of advanced prostate cancer. However, most patients eventually experience treatment failure, resulting in castrate-resistant prostate cancer (CRPC). Loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) has been linked to poor survival in prostate cancer. We have recently shown that PTEN loss is evident in approximately 60% of prostate cancer cases in Jordan. However, the correlation between PTEN loss and response to ADT remains unclear. This study aimed to determine the relationship between PTEN loss and time to CRPC in Jordan. We conducted a retrospective analysis of confirmed CRPC cases at our institution from 2005 to 2019 (N=104). PTEN expression was assessed using immunohistochemistry. Time to CRPC was calculated from the initiation of ADT to the confirmed diagnosis of CRPC. Combination/sequential ADT was defined as the use of two or more classes of ADT concomitantly or switching from one class to another. We found that PTEN loss was evident in 60.6% of CRPC. Mean time to CRPC was not different between patients with PTEN loss (24.8 months) and those with intact PTEN (24.2 months; p=0.9). However, patients receiving combination/sequential ADT had a significantly delayed onset of CRPC compared to patients on monotherapy ADT (log-rank Mantel-Cox p=0.000). In conclusion, PTEN loss is not a major determinant of time to CRPC in Jordan. The use of combination/sequential ADT procures a significant therapeutic advantage over monotherapy regimens, delaying the onset of CRPC. [ABSTRACT FROM AUTHOR]

Objective: Androgen deprivation therapy (ADT) is still the principal treatment option for prostate cancer (PCa). In addition to reactivation of androgen receptor signaling, the resistance of PCa to apoptosis during ADT also contributes to castration resistant PCa (CRPC). A previous study reported that gene transfer of IL-13Rα2 into PCa cells sensitized the cells to the IL-13R-targeted cytotoxin IL13Rα1, leading to apoptosis. Compared with IL-13Rα2, IL13Rα1 is more constitutively expressed in PCa cells, but its function in PCa remains to be established. Methods: We determined the role and expression of IL13Rα1 in PCa cancer cells using western blotting, flow cytometry, and cell proliferation assays. Co-immunoprecipitation and mass spectrometry were used to identify the proteins that interacted with IL13Rα1, to elucidate its function. Results: In this study, we showed that IL13Rα1 was selectively suppressed in androgen-deprived PCa cells and that its suppression tended to be associated with poor prognoses of PCa patients. IL13Rα1 overexpression promoted apoptosis and inhibited tumor growth under androgen-deprived or castrated conditions (P < 0.01). Mechanistically, IL13Rα1 recruited and facilitated ubiquitin protein ligase E3C-mediated ubiquitination and degradation of hexokinase 2 (HK2), resulting in glycolytic inhibition and eventually leading to PCa cell apoptosis. Furthermore, our data revealed that mutated ataxia-telangiectasia kinase phosphorylated and facilitated the selective ubiquitin proteasome-mediated degradation of HK2. Notably, IL13Rα1-overexpressing PCa cells were more susceptible to apoptosis and exhibited reduced tumor growth after exposure to the HK2 inhibitor, 2-deoxy-D-glucose (P < 0.01). Conclusions: Our data identified a tumor suppressor role for IL13Rα1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis. IL13Rα1-mediated signaling involving HK2 may therefore provide a novel treatment target and strategy for CRPC.

IntroductionCancer-associated fibroblasts (CAFs) are one of the most abundant cell types in tumor microenvironment. However, the phenotypic and functional heterogeneities among CAFs have not been sufficiently investigated in prostate cancer.MethodsWe obtained and analyzed the single-cell RNA-sequencing data from 26 hormone-sensitive prostate cancer samples and 8 castration-resistant prostate cancer samples, along with the analysis of bulk-sequencing datasets. Furthermore, we performed multicolor immunofluorescence staining to verify the findings from the data analysis.ResultsWe identified two major CAFs subtypes with distinct molecular characteristics and biological functions in prostate cancer microenvironment, namely αSMA+ CAV1+ CAFs-C0 and FN1+ FAP+ CAFs-C1. Another single-cell RNA-sequencing dataset containing 7 bone metastatic prostate cancer samples demonstrated that osteoblasts in the bone metastatic lesions comprised two subtypes with molecular characteristics and biological functions similar to CAFs-C0 and CAFs-C1 in the primary tumor sites. In addition, we discovered a transcriptional factor regulatory network depending on CAFs-C1. CAFs-C1, but not CAFs-C0, was associated with castration resistance and poor prognosis. We also found that CAFs-C1 signature was involved in treatment resistance to immune checkpoint inhibitors.DiscussionIn summary, our results identified the presence of heterogeneous CAFs subtypes in prostate cancer microenvironment and the potential of specific CAFs subtype as therapeutic target for castration-resistant prostate cancer.

Prostate cancer (PCa) is the most common male malignancy and the fifth leading cause of cancer death in men worldwide. Prostate cancer cells are characterized by a hybrid glycolytic/oxidative phosphorylation phenotype determined by androgen receptor signaling. An increased lipogenesis and cholesterogenesis have been described in PCa cells. Many studies have shown that enzymes involved in these pathways are overexpressed in PCa. Glutamine becomes an essential amino acid for PCa cells, and its metabolism is thought to become an attractive therapeutic target. A crosstalk between cancer and stromal cells occurs in the tumor microenvironment because of the release of different cytokines and growth factors and due to changes in the extracellular matrix. A deeper insight into the metabolic changes may be obtained by a multi-omic approach integrating genomics, transcriptomics, metabolomics, lipidomics, and radiomics data. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a leading cause of cancer death in men, worldwide. Mortality is highly related to metastasis and hormone resistance, but the molecular underlying mechanisms are poorly understood. We have studied the presence and role of cancer stem cells (CSCs) and the Epithelial–Mesenchymal transition (EMT) in PCa, using both in vitro and in vivo models, thereby providing evidence that the stemness–mesenchymal axis seems to be a critical process related to relapse, metastasis and resistance. These are complex and related processes that involve a cooperative action of different cancer cell subpopulations, in which CSCs and mesenchymal cancer cells (MCCs) would be responsible for invading, colonizing pre-metastatic niches, initiating metastasis and an evading treatments response. Manipulating the stemness–EMT axis genes on the androgen receptor (AR) may shed some light on the effect of this axis on metastasis and castration resistance in PCa. It is suggested that the EMT gene SNAI2/Slug up regulates the stemness gene Sox2, and vice versa, inducing AR expression, promoting metastasis and castration resistance. This approach will provide new sight about the role of the stemness–mesenchymal axis in the metastasis and resistance mechanisms in PCa and their potential control, contributing to develop new therapeutic strategies for patients with metastatic and castration-resistant PCa. [ABSTRACT FROM AUTHOR]

Castration resistance is the leading cause of death in men with prostate cancer. Recent studies indicate long noncoding RNAs (lncRNAs) to be important drivers of therapy resistance. The aim of this study was to identify differentially expressed lncRNAs in castration-resistant prostate cancer (CRPC) and to functionally characterize them in vitro. Tumor-derived RNA-sequencing data were used to quantify and compare the expression of 11,469 lncRNAs in benign, primary prostate cancer, and CRPC samples. CRPC-associated lncRNAs were selected for semi-quantitative PCR validation on 68 surgical tumor specimens. In vitro functional studies were performed by antisense-oligonucleotide-mediated lncRNA knockdown in hormone-sensitive prostate cancer (HSPC) and CRPC cell line models. Subsequently, cell proliferation, apoptosis, cell cycle, transcriptome and pathway analyses were performed using the appropriate assays. Transcriptome analysis of a prostate cancer tumor specimens unveiled NAALADL2-AS2 as a novel CRPC-upregulated lncRNA. The expression of NAALADL2-AS2 was found to be particularly high in HSPC in vitro models and to increase under androgen deprived conditions. NAALADL2-AS2 knockdown decreased cell viability and increased caspase activity and apoptotic cells. Cellular fractionization and RNA fluorescent in situ hybridization identified NAALADL2-AS2 as a nuclear transcript. Transcriptome and pathway analyses revealed that NAALADL2-AS2 modulates the expression of genes involved with cell cycle control and glycogen metabolism. We hypothesize that the nuclear lncRNA, NAALADL2-AS2, functions as a pro-survival signal in prostate cancer cells under pressure of targeted hormone therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Accumulating evidence supports that prostate cancer stem-like cells (PCSCs) play significant roles in therapy resistance and metastasis of prostate cancer. Many studies also show that nitric oxide (NO) synthesized by NO synthases can function to promote tumor progression. However, the exact roles of NOSs and NO signaling in the growth regulation of PCSCs and castration-resistant prostate cancer (CRPC) are still not fully understood. Methods The regulatory functions of NOS-NO signaling were evaluated in prostate cancer cells, especially in PCSCs enriched by 3D spheroid culture and CD133/CD44 cell sorting. The molecular mechanisms of NOS-NO signaling in PCSCs growth regulation and tumor metastasis were investigated in PCSCs and mice orthotopic prostate tumor model. Results Endothelial NOS (eNOS) exhibited a significant upregulation in high-grade prostate cancer and metastatic CRPC. Xenograft models of CRPC exhibited notable increased eNOS expression and higher intracellular NO levels. PCSCs isolated from various models displayed significant enhanced eNOS-NO signaling. Functional analyses demonstrated that increased eNOS expression could promote in vivo tumorigenicity and metastatic potential of prostate cancer cells. Characterization of eNOS-NO involved downstream pathway which confirmed that enhanced eNOS signaling could promote the growth of PCSCs and antiandrogen-resistant prostate cancer cells via an activated downstream NO-sGC-cGMP-PKG effector signaling pathway. Interestingly, eNOS expression could be co-targeted by nuclear receptor ERRα and transcription factor ERG in prostate cancer cells and PCSCs. Conclusions Enhanced eNOS-NO signaling could function to promote the growth of PCSCs and also the development of metastatic CRPC. Besides eNOS-NO as potential targets, targeting its upstream regulators (ERRα and ERG) of eNOS-NO signaling could also be the therapeutic strategy for the management of advanced prostate cancer, particularly the aggressive cancer carrying with the TMPRSS2:ERG fusion gene.

Prostate cancer presents with soft tissue progression (STP) is highly aggressive. We analyzed the risk factor for STP in patients with metastatic castration-resistant prostate cancer (mCRPC) who developed abiraterone acetate (AA) resistance. This retrospective study included patients with mCRPC who received AA between February 2018 and July 2022. STP was defined as recurrent lesions in situ, multiple regional lymph node metastases (mLNM), or visceral metastases. Clinical features of patients with STP were analyzed, and risk factors for STP were further investigated. Sixty-three patients (mean age, 75.0 years; median follow-up time, 22.3 months) were included in this study. Twenty-three patients (36.5%) presented STP during follow up, the overall survival (OS) after STP was 4.6 months. The serum neuron-specific enolase (NSE) were significantly elevated in patients with STP. Biopsies for 8 patients with STP showed neuroendocrine prostate cancer (NEPC, n = 5) was the major pathological types. Further analysis showed that perineural invasion (PNI) in primary tumor were the independent risk factors (HR = 3.145, P = 0.020) for STP, and PNI was related to the aggressiveness of tumor. Patients with PNI showed shorter castration-resistant progression free survival (median, 23.73 months vs. 25.59 months) and STP progression free survival (median, 19.7 months vs. not reached) compared with patients without PNI. STP showed extremely poor prognoses in patients with mCRPC after AA resistance, NEPC is the main pathological type of STP, and PNI in primary tumor was an independent risk factor for STP and indicated poor prognosis of prostate cancer. The risk factors of soft tissue progression (STP) in patients with metastatic castration-resistant prostate cancer (mCRPC) is unknow. Our study showed that perineural invasion (PNI) in primary tumor was an independent risk factor for STP, and PNI indicated higher aggressive disease and poorer prognoses for patients with prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Several treatment strategies use upfront chemotherapy or androgen receptor axis‐targeting therapies for metastatic prostate cancer. However, there are no useful biomarkers for selecting appropriate patients who urgently require these treatments. Methods Novel patient‐derived xenograft (PDX) castration‐sensitive and ‐resistant models were established and gene expression patterns were comprehensively compared. The function of a gene highly expressed in the castration‐resistant models was evaluated by its overexpression in LNCaP prostate cancer cells. Protein expression in the tumors and serum of patients was examined by immunohistochemistry and ELISA, and correlations with castration resistance were analyzed. Results Expression of the α2 chain of interleukin‐13 receptor (IL13Rα2) was higher in castration‐resistant PDX tumors. LNCaP cells overexpressing IL13Rα2 acquired castration resistance in vitro and in vivo. In tissue samples, IL13Rα2 expression levels were significantly associated with castration‐resistant progression (p

Monoamine oxidase A (MAOA), a mitochondrial enzyme degrading biogenic and dietary amines, has been studied in the contexts of neuropsychiatry and neurological disorders for decades, but its importance in oncology, as best exemplified in prostate cancer (PC) to date, was only realized recently. PC is the most commonly diagnosed non-skin cancer and the second deadliest malignancy for men in the United States. In PC, the increased expression level of MAOA is correlated with dedifferentiated tissue microarchitecture and a worse prognosis. A wealth of literature has demonstrated that MAOA promotes growth, metastasis, stemness and therapy resistance in PC, mainly by increasing oxidative stress, augmenting hypoxia, inducing epithelial-to-mesenchymal transition, and activating the downstream principal transcription factor Twist1-dictated multiple context-dependent signaling cascades. Cancer-cell-derived MAOA also enables cancer-stromal cell interaction involving bone stromal cells and nerve cells by secretion of Hedgehog and class 3 semaphorin molecules respectively to modulate the tumor microenvironment in favor of invasion and metastasis. Further, MAOA in prostate stromal cells promotes PC tumorigenesis and stemness. Current studies suggest that MAOA functions in PC in both cell autonomous and non-autonomous manners. Importantly, clinically available monoamine oxidase inhibitors have shown promising results against PC in preclinical models and clinical trials, providing a great opportunity to repurpose them as a PC therapy. Here, we summarize recent advances in our understanding of MAOA roles and mechanisms in PC, present several MAOA-targeted strategies that have been nominated for treating PC, and discuss the unknowns of MAOA function and targeting in PC for future exploration.

Introduction: Advanced prostate cancer treatment has improved with androgen receptor signaling inhibitors (ARPI), yet many patients develop metastatic castration-resistant prostate cancer (mCRPC), characterized by sustained androgen receptor (AR) signaling. Bipolar androgen therapy (BAT) introduces supraphysiologic testosterone levels to inhibit tumor growth, offering novel treatment for mCRPC by exploiting AR-dependent mechanisms., Case Presentations: Case 1: A 53-year-old man with mCRPC, post multiple systemic therapies, initiated BAT and pembrolizumab, achieving PSA reduction and improved quality of life before progression. The patient exhibited AR amplification, which may have contributed to favorable response to BAT. Case 2: A 73-year-old man with recurrent prostate cancer, stable on ADT and abiraterone, experienced PSA decline with BAT to an undetectable level, maintaining stability post-therapy discontinuation. Case 3: A 73-year-old man with metastatic prostate cancer, initially resistant to enzalutamide, achieved clinical benefit and disease control with BAT, although he did not meet PSA response criteria, patient had remarkable response upon enzalutamide rechallenge. Case 4: A 90-year-old man with localized prostate cancer, refractory to multiple treatments, experienced symptom relief and PSA reduction with BAT before progression., Conclusion: BAT represents a promising treatment strategy for mCRPC. This case series underscores BAT's potential to induce significant clinical and biochemical responses, resensitize tumors to ARPIs, and improve patients' quality of life. Despite eventual progression in some cases, BAT offers a period of disease control. Further research is needed to optimize patient selection and understand the molecular determinants of BAT responsiveness., (© 2024 Wiley Periodicals LLC.)

Systemic treatments for metastatic castration-resistant prostate cancer (mCRPC) include androgen deprivation therapy, androgen receptor pathway inhibitors, chemotherapy, and radiopharmaceuticals, all of which have associated toxicity. Prostate-specific membrane antigen (PSMA) PET/CT allows for higher sensitivity in detecting metastatic disease than is possible with conventional imaging. We hypothesized that PSMA PET/CT-guided, metastasis-directed radiotherapy may offer durable disease control with low toxicity rates in patients with mCRPC who have a limited number of metastases. Methods: We retrospectively screened 5 prospective PSMA PET/CT studies for patients with mCRPC who had up to 5 sites of oligorecurrent or oligoprogressive disease on PSMA PET/CT and subsequently received definitive-intent, metastasis-directed radiotherapy to all new or progressing sites with concurrent androgen deprivation therapy. Progression-free survival, freedom from new lines of systemic therapy, and overall survival (OS) were calculated from the start of metastasis-directed radiotherapy using Kaplan-Meier analysis. Biochemical response was defined as at least a 50% decrease in prostate-specific antigen 6 mo after the start of treatment. Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 5. Results: Twenty-four patients met the inclusion criteria with a median follow-up of 33.8 mo (interquartile range, 27.6-45.1 mo). Between October 2017 and April 2023, 11 patients (45.8%) had 1 treated site, 10 patients (41.7%) had 2, and 3 patients (12.5%) had 3. Five sites were prostate or prostate bed, 15 were nodal, 19 were osseous, and 1 was visceral. Seventeen patients (70.8%) continued their preexisting systemic therapy, whereas 7 (29.2%) started a new systemic therapy. Median progression-free survival was 16.4 mo (95% CI, 9.8-23.0 mo). The biochemical response rate was 66.7%. Median freedom from a new line of systemic therapy was 29.0 mo (95% CI, 7.6-50.4 mo). Median OS was not reached. The 2- and 4-y OS rates were 91.1% (95% CI, 79.3%-100%) and 68.8% (95% CI, 45.1%-92.5%), respectively. Grade 2 and grade 3 or higher toxicity rates were 4.2% and 0%, respectively. Conclusion: PSMA PET/CT-guided, metastasis-directed radiotherapy appears to offer durable disease control with low toxicity rates for oligometastatic castration-resistant prostate cancer. Further prospective studies are needed to compare metastasis-directed radiotherapy with systemic therapy versus systemic therapy alone and PSMA PET/CT-guided versus conventional imaging-guided radiotherapy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Abstract Background Prostate cancer is most often diagnosed at the metastatic stage in many sub-Saharan African countries. The objective of our study is to analyze the management of metastatic prostatic adenocarcinoma based on epidemiological, clinical, therapeutic and evolutionary aspects in developing country context. Methods Retrospective study collecting 276 patients from January 1st, 2012 to December 31st, 2019 in Aristide Le Dantec University Hospital in Dakar, Senegal. Parameters studied: age, family history of prostate cancer, reasons for consultation, total Prostate Specific Antigen (PSA), anatomic pathology examination, extension assessment, treatment, nadir PSA, castration resistance, and overall survival. Results The average age was 71.4 years. A family history of prostate cancer was noted in 21 patients. Spinal pain was the most noted reason for consultation. The average total PSA level was 1967.1 ng/ml. The majority of patients had moderately differentiated prostate cancer. Bone metastases were the most common. All patients had androgen suppression. A tumor cytoreduction was performed in 89 patients. The average nadir PSA was 193 ng/ml as early as the sixth month. The time to onset of castration resistance ranged from 6 to 30 months. Abiraterone acetate was used in seven patients and docetaxel in 43 patients. The overall survival of the patients was 19.8 ± 1.2 months. Conclusion Metastatic prostate cancer was most often symptomatic at the time of diagnosis. Second-line treatments were rarely used during castration resistance. Overall survival was low.

Fionnuala Crowley,1 Michelle Sterpi,1 Conor Buckley,1 Lauren Margetich,1 Shivani Handa,1 Zach Dovey2 1Department of Internal Medicine, Icahn School of Medicine, Mount Sinai Morningside and West, New York, NY, USA; 2Department of Urology, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USACorrespondence: Shivani HandaDepartment of Internal Medicine, Mount Sinai Morningside and West, 1000 Tenth Avenue, New York, NY, 10019, USATel +1-917-520-3693Email Shivani.Handa@mountsinai.orgAbstract: Androgen deprivation therapy or ADT is one of the cornerstones of management of locally advanced or metastatic prostate cancer, alongside radiation therapy. However, despite early response, most advanced prostate cancers progress into an androgen unresponsive or castrate resistant state, which hitherto remains an incurable entity and the second leading cause of cancer-related mortality in men in the US. Recent advances have uncovered multiple complex and intermingled mechanisms underlying this transformation. While most of these mechanisms revolve around androgen receptor (AR) signaling, novel pathways which act independently of the androgen axis are also being discovered. The aim of this article is to review the pathophysiological mechanisms that help bypass the apoptotic effects of ADT to create castrate resistance. The article discusses castrate resistance mechanisms under two categories: 1. Direct AR dependent pathways such as amplification or gain of function mutations in AR, development of functional splice variants, posttranslational regulation, and pro-oncogenic modulation in the expression of coactivators vs corepressors of AR. 2. Ancillary pathways involving RAS/MAP kinase, TGF-beta/SMAD pathway, FGF signaling, JAK/STAT pathway, Wnt-Beta catenin and hedgehog signaling as well as the role of cell adhesion molecules and G-protein coupled receptors. miRNAs are also briefly discussed. Understanding the mechanisms involved in the development and progression of castration-resistant prostate cancer is paramount to the development of targeted agents to overcome these mechanisms. A number of targeted agents are currently in development. As we strive for more personalized treatment across oncology care, treatment regimens will need to be tailored based on the type of CRPC and the underlying mechanism of castration resistance.Keywords: castration resistance, prostate cancer, androgen-deprivation therapy, androgen insensitivity, androgen receptor

BackgroundWe hypothesized that pretreatment serum levels of insulin and other serum markers would predict Progression-free survival (PFS), defined as time to castration-resistant progression or death, in metastatic androgen-dependent prostate cancer (mADPC).MethodsSerum samples from treatment-naïve men participating in a randomized phase 3 trial of ADT +/- chemotherapy were retrospectively analyzed using multiplex assays for insulin and multiple other soluble factors. Cox proportional hazards regression models were used to identify associations between individual factor levels and PFS.ResultsSixty six patients were evaluable (median age = 72 years; median prostate surface antigen [PSA] = 31.5 ng/mL; Caucasian = 86 %; Gleason score ≥8 = 77 %). In the univariable analysis, higher insulin (HR = 0.81 [0.67, 0.98] p = 0.03) and C-peptide (HR = 0.62 [0.39, 1.00]; p = 0.05) levels were associated with a longer PFS, while higher Hepatocyte Growth Factor (HGF; HR = 1.63 [1.06, 2.51] p = 0.03) and Osteopontin (OPN; HR = 1.56 [1.13, 2.15]; p = 0.01) levels were associated with a shorter PFS. In multivariable analysis, insulin below 2.1 (ln scale; HR = 2.55 [1.24, 5.23]; p = 0.011) and HGF above 8.9 (ln scale; HR = 2.67 [1.08, 3.70]; p = 0.027) levels were associated with longer PFS, while adjusted by OPN, C-peptide, trial therapy and metastatic volume. Four distinct risk groups were identified by counting the number of risk factors (RF) including low insulin, high HGF, high OPN levels, and low C-peptide levels (0, 1, 2, and 3). Median PFS was 9.8, 2.0, 1.6, and 0.7 years for each, respectively (p

Objective To explore the predictive factors of metastatic prostate cancer progression to castration resistance and establish a risk prediction model. Methods Clinical data of 118 prostate cancer patients with bone metastasis who were diagnosed in our department from January 2010 to July 2020, initially received adjuvant endocrine therapy (AET) and then advanced to metastatic castration-resistant prostate cancer (mCRPC) were collected and retrospectively analyzed. The clinical information, including age, having diabetes or not, taking metformin or not, prostate specific antigen (PSA) level at diagnosis, nadir levels of PSA and testosterone, time to the nadirs, Gleason score, number of bone metastases, and serum levels of alkaline phosphatase, hemoglobin, albumin, lactate dehydrogenase, uric acid and cystatin C were collected and analyzed. Chi-square test was used to compare the differences of factors between groups with rapid and slow onset of CRPC. Kaplan-Meier survival analysis and Cox multivariate risk proportional regression model were used to compare the time difference of progression to CRPC in different groups. Cox risk proportional regression model was used to analyze and evaluate the effect of these factors on the time of CRPC progression, and a risk prediction model was established, and then the receiver operating characteristic (ROC) curve was used to detect the accuracy of the model. Results The median time for progression to CRPC was 17 (9.5~28.0) months. Univariate analysis indicated that the PSA nadir level, time to PSA nadir level, levels of alkaline phosphatase and lactate dehydrogenase, and number of bone metastases were significantly correlated with the time of progression to CRPC (P < 0.05). The results of multivariate analysis showed that the PSA nadir level (HR=2.549, 95%CI: 1.565~4.151, P < 0.001), time to PSA nadir level (HR=0.373, 95%CI: 0.227~0.612, P < 0.001), number of bone metastases (HR=2.393, 95%CI: 1.292~4.43, P=0.006), lactate dehydrogenase level (HR=1.681, 95%CI: 1.045~2.703, P=0.032) were independent risk factors for short-term progression to CRPC. Based on these 4 independent risk factors, a risk prediction model was established. The equation is pi=1.788×(the PSA nadir level)-1.275×(the time to PSA nadir level) +0.441×(lactate dehydrogenase level) +1.114×(number of bone metastases)-1.5. The area under ROC curve was 0.812 (95%CI: 0.731~0.893, P < 0.001, β=0.041). The sensitivity, specificity and Youden index were 0.803, 0.718 and 0.521, respectively. Conclusion The PSA nadir level, time to PSA nadir value, number of bone metastases, lactate dehydrogenase level are independent risk factors for progression to mCRPC after androgen deprivation therapy (ADT) in prostate cancer patients with bone metastasis. Based on these 4 factors, the establishment of CRPC prediction model can improve the accuracy of prediction

Background: The emergence of castration resistance is fatal for patients with prostate cancer (PCa); however, there is still a lack of effective means to detect the early progression. In this study, a novel combined nomogram was established to predict the risk of progression related to castration resistance. Methods: The castration-resistant prostate cancer (CRPC)-related differentially expressed genes (DEGs) were identified by R packages "limma" and "WGCNA" in GSE35988-GPL6480 and GSE70768-GPL10558, respectively. Relationships between DEGs and progression-free interval (PFI) were analyzed using the Kaplan–Meier method in TCGA PCa patients. A multigene signature was built by lasso-penalized Cox regression analysis, and assessed by the receiver operator characteristic (ROC) curve and Kaplan–Meier curve. Finally, the univariate and multivariate Cox regression analyses were used to establish a combined nomogram. The prognostic value of the nomogram was validated by concordance index (C-index), calibration plots, ROC curve, and decision curve analysis (DCA). Results: 15 CRPC-related DEGs were identified finally, of which 13 genes were significantly associated with PFI and used as the candidate genes for modeling. A two-gene (KIFC2 and BCAS1) signature was built to predict the risk of progression. The ROC curve indicated that 5-year area under curve (AUC) in the training, testing, and whole TCGA dataset was 0.722, 0.739, and 0.731, respectively. Patients with high-risk scores were significantly associated with poorer PFI (p < 0.0001). A novel combined nomogram was successfully established for individualized prediction integrating with T stage, Gleason score, and risk score. While the 1-year, 3-year, and 5-year AUC were 0.76, 0.761, and 0.762, respectively, the good prognostic value of the nomogram was also validated by the C-index (0.734), calibration plots, and DCA. Conclusion: The combined nomogram can be used to predict the individualized risk of progression related to castration resistance for PCa patients and has been preliminarily verified to have good predictive ability. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence supports that prostate cancer stem-like cells (PCSCs) play significant roles in therapy resistance and metastasis of prostate cancer. Many studies also show that nitric oxide (NO) synthesized by NO synthases can function to promote tumor progression. However, the exact roles of NOSs and NO signaling in the growth regulation of PCSCs and castration-resistant prostate cancer (CRPC) are still not fully understood. Methods: The regulatory functions of NOS-NO signaling were evaluated in prostate cancer cells, especially in PCSCs enriched by 3D spheroid culture and CD133/CD44 cell sorting. The molecular mechanisms of NOS-NO signaling in PCSCs growth regulation and tumor metastasis were investigated in PCSCs and mice orthotopic prostate tumor model. Results: Endothelial NOS (eNOS) exhibited a significant upregulation in high-grade prostate cancer and metastatic CRPC. Xenograft models of CRPC exhibited notable increased eNOS expression and higher intracellular NO levels. PCSCs isolated from various models displayed significant enhanced eNOS-NO signaling. Functional analyses demonstrated that increased eNOS expression could promote in vivo tumorigenicity and metastatic potential of prostate cancer cells. Characterization of eNOS-NO involved downstream pathway which confirmed that enhanced eNOS signaling could promote the growth of PCSCs and antiandrogen-resistant prostate cancer cells via an activated downstream NO-sGC-cGMP-PKG effector signaling pathway. Interestingly, eNOS expression could be co-targeted by nuclear receptor ERRα and transcription factor ERG in prostate cancer cells and PCSCs. Conclusions: Enhanced eNOS-NO signaling could function to promote the growth of PCSCs and also the development of metastatic CRPC. Besides eNOS-NO as potential targets, targeting its upstream regulators (ERRα and ERG) of eNOS-NO signaling could also be the therapeutic strategy for the management of advanced prostate cancer, particularly the aggressive cancer carrying with the TMPRSS2:ERG fusion gene. [ABSTRACT FROM AUTHOR]

Copyright of Der Urologe A is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Penile metastasis of prostate cancer is rare, with a poor prognosis, and only a limited number of relevant cases have been reported so far. With the application of 18F-PSMA-1007 PET/CT, the biochemical recurrence of prostate cancer can be detected at an early stage for providing important evidence, facilitating clinical decision-making. Here, we have reported a case of solitary penile metastatic recurrence in the context of mild PSA progression (PSA: 0.072 ng/ml). This case highlights the preferable sensitivity of 18F-PSMA-1007 PET/CT imaging in prostate cancer. [ABSTRACT FROM AUTHOR]

Treatment of advanced and metastatic prostate carcinoma (PCa) is still challenging and changing in the era of personalised medicine. Combination therapies with docetaxel and new anti-hormonal substances lead to improved OS (overall survival) in a broad group of patients with metastatic hormone sensitive prostate carcinoma (mHSPCa). Addition of docetaxel or an androgen receptor targeting agent (ARTA) with abiraterone plus prednisolone, with apalutamide or with enzalutamide leads to a significant improvement in OS and an increase in the time to transition to castration resistance. The choice of therapy sequence in advanced PCa should be based, among other things, on the side-effect profiles of the substances and patient's preferences. Within metastatic castration resistant prostate carcinoma (mCRPCa) setting, the therapy with abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223 is approved and indicated in Europe. Respectively, five substances are available, each of which has led to a significant increase in survival time in phase III studies. The optimal therapy sequence in the mCRPCa stage is still unclear. The current trend in personalised medicine in the next decade in therapy, regarding prostate carcinoma, are poly(ADP)-ribose polymerase (PARP) inhibitors, which are and will be available as an effective therapy option for patients with mutations in DNA repair genes. The most important question is when and how patients should be tested for mutations in DNA repair genes and to which line of therapy will PARP inhibitors belong. [ABSTRACT FROM AUTHOR]

Yiming Zhang,1,2,* Binshen Chen,1,2,* Naijin Xu,3 Peng Xu,1,2 Wenfeng Lin,1– 3 Chunxiao Liu,1,2 Peng Huang1– 3 1Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Guangzhou Key Laboratory of Inflammatory and Immune Diseases, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan*These authors contributed equally to this workCorrespondence: Peng Huang; Chunxiao LiuDepartment of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, People’s Republic of ChinaTel +86-20-62782726Fax +86-20-62782725Email huangpeng509@gmail.com; Liuchx888@hotmail.comBackground: Castration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined.Methods: Co-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression.Results: The results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation.Conclusions: Our findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.Keywords: prostate cancer, castration resistance, exosomes, heme oxygenase-1

The prevalence of prostate cancer continues to increase worldwide. The effectiveness of androgen deprivation therapy for advanced prostate cancer has a time limit, after which castration resistance and disease progression are formed. A part of patients with castrate-resistant prostate cancer has no metastases (according to standard imaging methods). The main goal of treatment of these patients is to prolong the time before metastasis formation. This article presents a review of the current understanding of the molecular mechanisms underlying the inhibition of androgen-receptor signaling with enzalutamide, a second-generation androgen receptor antagonist, and the results of clinical studies of its efficacy and safety in castrate-resistant prostate cancer without metastases. It was determined that enzalutamide stimulates the expression of a new class of genes that are not regulated by dihydrotestosterone. It was found that, in addition to inhibiting androgen receptors, enzalutamide can act as a partial transcriptional agonist. Enzalutamide therapy has been shown to reduce the risk of tumor progression and death in patients with non-metastatic castrate-resistant prostate cancer and is well tolerated. Treatment with this drug increases the time before metastases appear, before the first use of subsequent anti-tumor therapy is necessary, and the period before prostate-specific antigen levels have progressed. Study of mechanisms induced by enzalutamide – inhibition of prostate cancer cells growth and activation of genes contributing to cancer development by enzalutamide-related androgen receptor – can help to clarify possible ways of resistance formation to this drug and possibilities of its overcoming with combined therapy.

Background: The emergence of castration resistance is fatal for patients with prostate cancer (PCa); however, there is still a lack of effective means to detect the early progression. In this study, a novel combined nomogram was established to predict the risk of progression related to castration resistance.Methods: The castration-resistant prostate cancer (CRPC)-related differentially expressed genes (DEGs) were identified by R packages “limma” and “WGCNA” in GSE35988-GPL6480 and GSE70768-GPL10558, respectively. Relationships between DEGs and progression-free interval (PFI) were analyzed using the Kaplan–Meier method in TCGA PCa patients. A multigene signature was built by lasso-penalized Cox regression analysis, and assessed by the receiver operator characteristic (ROC) curve and Kaplan–Meier curve. Finally, the univariate and multivariate Cox regression analyses were used to establish a combined nomogram. The prognostic value of the nomogram was validated by concordance index (C-index), calibration plots, ROC curve, and decision curve analysis (DCA).Results: 15 CRPC-related DEGs were identified finally, of which 13 genes were significantly associated with PFI and used as the candidate genes for modeling. A two-gene (KIFC2 and BCAS1) signature was built to predict the risk of progression. The ROC curve indicated that 5-year area under curve (AUC) in the training, testing, and whole TCGA dataset was 0.722, 0.739, and 0.731, respectively. Patients with high-risk scores were significantly associated with poorer PFI (p < 0.0001). A novel combined nomogram was successfully established for individualized prediction integrating with T stage, Gleason score, and risk score. While the 1-year, 3-year, and 5-year AUC were 0.76, 0.761, and 0.762, respectively, the good prognostic value of the nomogram was also validated by the C-index (0.734), calibration plots, and DCA.Conclusion: The combined nomogram can be used to predict the individualized risk of progression related to castration resistance for PCa patients and has been preliminarily verified to have good predictive ability.

Penile metastasis of prostate cancer is rare, with a poor prognosis, and only a limited number of relevant cases have been reported so far. With the application of 18F-PSMA-1007 PET/CT, the biochemical recurrence of prostate cancer can be detected at an early stage for providing important evidence, facilitating clinical decision-making. Here, we have reported a case of solitary penile metastatic recurrence in the context of mild PSA progression (PSA: 0.072 ng/ml). This case highlights the preferable sensitivity of 18F-PSMA-1007 PET/CT imaging in prostate cancer.

The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of second-generation antiandrogen trials and FDA approvals and outline a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer. All published phase II-III randomized controlled trials reporting outcomes with the use of second-generation antiandrogens in prostate cancer are included as well as all published trials and retrospective studies of second-generation antiandrogen sequencing and/or combinations. Complete tabular and graphical representation of all available evidence is provided regarding the use and sequencing of second-generation antiandrogens in prostate cancer. In metastatic castration-resistant prostate cancer, evidence suggests prioritization of abiraterone before chemotherapy, chemotherapy after second-generation antiandrogen failure, and postchemotherapy enzalutamide in select patients to maximize agent efficacy and tolerability. We conclude that a rational, optimized sequencing of second-generation antiandrogens with other treatment options is feasible with present data. [ABSTRACT FROM AUTHOR]

Copyright of Der Urologe A is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)