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This article from BJU International presents a case study of a 74-year-old patient with castration-resistant prostate cancer who underwent stereotactic body radiotherapy (SBRT) for 20 metastatic lesions. The patient had a complex treatment history involving various therapies before receiving SBRT, which served as a bridge therapy while awaiting 177Lu-PSMA-617 therapy. The SBRT treatment was delivered without reported side effects, resulting in a decrease in PSA levels and a partial or complete response at treated sites. The article discusses the efficacy and challenges of SBRT in treating multiple metastatic sites, highlighting the evolving landscape of prostate cancer therapy. [Extracted from the article]

Background and purpose: Castration‐resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first‐line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC. Experimental approach: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC. Key results: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient‐derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells. Conclusion and implications: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer continues to be a major cause of morbidity and mortality for men worldwide. Enzalutamide, a second-generation non-steroidal antiandrogen that blocks androgen receptor (AR) transcriptional activity, is a treatment for biochemically recurrent, metastatic, castration-sensitive, and castration-resistant tumors. Unfortunately, most patients ultimately develop resistance to enzalutamide, making long-term treatment with this agent challenging. Areas covered: We performed a literature search of PubMed without date restrictions to investigate the literature surrounding enzalutamide and discuss the current uses of enzalutamide, proposed mechanisms driving resistance, and summarize current efforts to mitigate this resistance. Expert opinion: Enzalutamide is an effective prostate cancer therapy that is currently used in biochemically recurrent and metastatic disease and for both castration-sensitive and castration-resistant tumors. Unfortunately, resistance to enzalutamide occurs in each of these scenarios. In the clinical setting, enzalutamide-resistant tumors are either AR-driven or AR-indifferent. AR-dependent resistance mechanisms include genomic or epigenomic events that result in enhanced AR signaling. Tumors that do not require AR signaling instead may depend on alternative oncogenic pathways. There are numerous strategies to mitigate enzalutamide resistance, including concurrent use of PARP inhibitors or immune therapies. Additional work is required to uncover novel approaches to treat patients in the enzalutamide-resistant setting. [ABSTRACT FROM AUTHOR]

Background: Enzalutamide (Enz) resistance is a poor prognostic factor for patients with castration-resistant prostate cancer (CRPC), which often involves aberrant expression of the androgen receptor (AR). Myosin VI (MYO6), one member of the myosin family, plays an important role in regulating cell survival and is highly expressed in prostate cancer (PCa). However, whether MYO6 is involved in Enz resistance in CRPC and its mechanism remain unclear. Methods: Multiple open-access databases were utilized to examine the relationship between MYO6 expression and PCa progression, and to screen differentially expressed genes (DEGs) and potential signaling pathways associated with the MYO6-regulated Enz resistance. Both in vitro and in vivo tumorigenesis assays were employed to examine the impact of MYO6 on the growth and Enz resistance of PCa cells. Human PCa tissues and related clinical biochemical data were utilized to identify the role of MYO6 in promoting PCa progression and Enz resistance. The molecular mechanisms underlying the regulation of gene expression, PCa progression, and Enz resistance in CRPC by MYO6 were investigated. Results: MYO6 expression increases in patients with PCa and is positively correlated with AR expression in PCa cell lines and tissues. Overexpression of AR increases MYO6 expression to promote PCa cell proliferation, migration and invasion, and to inhibit PCa cell apoptosis; whereas knockdown of MYO6 expression reverses these outcomes and enhances Enz function in suppressing the proliferation of the Enz- sensitive and resistant PCa cells both in vitro and in vivo. Mechanistically, AR binds directly to the promoter region (residues − 503 to − 283 base pairs) of MYO6 gene and promotes its transcription. Furthermore, MYO6 activates focal adhesion kinase (FAK) phosphorylation at tyrosine-397 through integrin beta 8 (ITGB8) modulation to promote PCa progression and Enz resistance. Notably, inhibition of FAK activity by Y15, an inhibitor of FAK, can resensitize CRPC cells to Enz treatment in cell lines and mouse xenograft models. Conclusions: MYO6 has pro-tumor and Enz-resistant effects in CRPC, suggesting that targeting MYO6 may be beneficial for ENZ-resistant CRPC therapy through the AR/MYO6/FAK signaling pathway. [ABSTRACT FROM AUTHOR]

Objectives. The aim of this work is to evaluate energy deposition in the nucleus and cytoplasm in targeted alpha therapy of metastatic castration-resistant prostate cancer by modeling two cell lines, PC3 (osteolytic) and LNCaP C4-2 (osteoblastic), for actinium-225, astatine-211, and radium-223 and their progeny, using Monte Carlo simulations with the GATE/Geant4 code. Approach. We developed single cell and cell clusters models to Monte Carlo simulations, performed on the GATE platform version 9.3, with the GEANT4-DNA physics list emstandard_opt3_mixed_dna for At-211, Ac-225 and Ra-223 progenies. We considered three radionuclide distributions as a sources: the nucleus, the cytoplasm and the whole cell. Main results. When the nucleus was considered as a target, the S -values (N←N) calculated for At-211, Ac-225 and Ra-223 progenies were significantly higher, within 60%-90%, than S -values (N←Cy), demonstrating less influence of cytoplasm only internalization. When the cytoplasm was considering as a target, the S -values (Cy←Cy) calculated for At-211, Ac-225 and Ra-223 progeny were significantly higher, within 30%–90%, than the S -values (Cy←N). When no progeny migration occurs and for target nucleus, the cumulative S -values (N←N) calculated for At-211, Ac-225 and Ra-223 were significantly higher, within 50%–70%, than the S -values (N←N) computed for At-211, Ac-225, and Ra-223. Comparing the cumulative S -values, Ac-225 and Ra-223 therapies is more effective, in terms of deposited energy in a target, than that with At-211. Significance. The data presented in this research indicates that Ac-225 therapy may be the optimum choice due to the energy deposited in the nucleus, as long as the recoil effects and redistribution of progeny are understood. In contrast, At-211 is an alternative to avoid progeny migration. However, to completely analyze the efficacy of radionuclide therapy, other parameters must be considered, such as biological half-life, stability of the transport molecule, progeny migration, excretion pathways, and uptake in different organs. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is the most common malignancy of the male genitourinary system. Understanding the molecular mechanism of PCa and its prognostic markers will assist in the selection of better treatment. Aim: To explore the role of LINC01518 in the development of PCa and its prognostic value, and to understand its specific regulatory mechanism. Methods: The levels of LINC01518, hsa-miR-320a, and CNKSR2 mRNA were detected by RT-qPCR. ROC curve was constructed to evaluate the prognostic value of LINC01518 in PCa. The effects of LINC01518 on the functions of PCa cells were demonstrated by CCK-8, Transwell test, and the detection of apoptotic markers, after LINC01518 knockdown. The interaction between hsa-miR-320a and LINC01518 or CNKSR2 mRNA was examined by constructing luciferase vectors. Results: LINC01518 was abnormally expressed in PCa cells and tumor tissues, and knockdown of it inhibited the growth of PCa cells. LINC01518 predicted castration-resistant prostate cancer (CRPC) outcomes in PCa patients with AUC of 0.803, sensitivity and specificity of 75.4% and 74.6%, respectively. Hsa-miR-320a mimics reduced luciferase activity in PCa cells transfected with WT-LINC01518/CNKSR2 plasmids. Knocking down LINC01518 reduced CNKSR2 level, and this regulatory effect disappeared with the inhibition of hsa-miR-320a. Conclusion: High levels of LINC01518 predicted poor prognosis in PCa patients and promoted CNKSR2 expression by competitively binding hsa-miR-320a, contributing to the progression of PCa. [ABSTRACT FROM AUTHOR]

Radioligand therapies such as [177Lu] Lu-PSMA-617 have gained significant momentum in cancer treatment after clinical trials and multicenter studies demonstrated their safety and efficacy. As these innovative treatments become more widespread, rare and unique clinical manifestations are expected to be observed. In this report, we describe a case with metastatic castration-resistant prostate cancer (mCRPC) and peripancreatic lymph node metastases who developed acute pancreatitis following [177Lu] Lu-PSMA-617 therapy. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is among prevalent cancers in men. Numerous strategies have been proposed to intervene with the important prostate cancer-related signaling pathways. Among the most promising strategies is CRISPR/Cas9 strategy. This strategy has been used to modify expression of a number of genes in prostate cancer cells. Aims: This review summarizes the most recent progresses in the application of CRISPR/Cas9 strategy in modification of prostate cancer-related phenotypes with an especial focus on pathways related to androgen receptor signaling. Conclusion: CRISPR/Cas9 technology has successfully targeted several genes in the prostate cancer cells. Moreover, the efficiency of this technique in reducing tumor burden has been tested in animal models of prostate cancer. Most of targeted genes have been related with the androgen receptor signaling. Targeted modulation of these genes have affected growth of castration-resistant prostate cancer. PI3K/AKT/mTOR signaling and immune response-related genes have been other targets that have been successfully modulated by CRISPR/Cas9 technology in prostate cancer. Based on the rapid translation of this technology into the clinical application, it is anticipated that novel treatments based on this technique change the outcome of this malignancy in future. [ABSTRACT FROM AUTHOR]

Purpose: To determine new-onset or worsening T2DM risk in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone acetate (AA) vs. enzalutamide (ENZA) in England. Methods: Records of patients on AA and/or ENZA (2015−2021) were analysed retrospectively from UK- or England-wide databases and data sets. The primary endpoint was new-onset or worsening T2DM, analysed using a Cox model. Results: Of 1382 patients, 84 (6.1%) met the primary endpoint; 42 of 826 patients (5.1%) received ENZA and 42 of 556 patients (7.6%) received AA. Among patients without baseline T2DM (n = 1049), 50 developed new-onset T2DM: 24 (3.9%) on ENZA and 26 (5.9%) on AA. Among patients with baseline T2DM (n = 333), 34 (10.2%) had worsening T2DM: 18 (8.3%) on ENZA and 16 (13.8%) on AA. Patients on ENZA had longer median follow-up (445 vs. 408 days) and treatment duration (164 vs. 139 days) than those on AA, who were also more likely to have new-onset or worsening T2DM than those on ENZA (HR: 1.8; 95% CI: 1.4–2.7; P = 0.0101). The number needed to harm for an additional patient to experience new-onset or worsening T2DM when receiving AA instead of ENZA was 40 overall, 50 in patients without baseline T2DM, and 18 in patients with baseline T2DM. Conclusion: Patients with mCRPC receiving AA were more likely to experience new-onset or worsening T2DM than those on ENZA, despite having a shorter treatment duration. Further research is required to substantiate these findings in earlier disease settings with longer treatment duration. [ABSTRACT FROM AUTHOR]

Background: The optimal regimen for 177Lu-labeled prostate-specific membrane antigen-targeted radioligand therapy, including treatment intervals, remains under study, with evidence suggesting shorter intervals could benefit patients with high disease volume and rapid progression. This retrospective analysis evaluated treatment toxicity, PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) in matched cohorts of mCRPC patients receiving 177Lu-PSMA-RLT at 4-week versus 6-week intervals. Results: A PSA response (PSA decline ≥ 50%) was achieved in 47.8% and 21.7% of patients in the 4-week and 6-week treatment interval groups, respectively (p = 0.12). There was a trend towards longer PSA-PFS in the 4-week group compared to the 6-week group (median PSA-PFS, 26.0 weeks vs. 18.0 weeks; HR 0.6; p = 0.2). Although not statistically significant, there was a trend towards shorter OS in the 4-week group compared to the 6-week group (median OS, 15.1 months vs. 18.4 months; HR 1.3; p = 0.5). The 4-week group had a significantly greater decrease in leucocyte and platelet counts compared to the 6-week group (38.5% vs. 18.2% and 26.7% vs. 10.7%; p = 0.047 and p = 0.02). Severe adverse events were modest in both groups. Conclusions: Intensifying treatment intervals from 6 weeks to 4 weeks showed some improvements in PSA response and PSA-PFS for mCRPC patients, but did not significantly affect OS. Additionally, bone marrow reserve was significantly reduced with the intensified regimen. Therefore, the overall benefit remains uncertain, and further prospective studies are needed to compare 4-week and 6-week intervals regarding toxicity, treatment response, and outcome. [ABSTRACT FROM AUTHOR]

Although hypercoagulability is commonly associated with malignancies, whether coagulation factors directly affect tumor cell proliferation remains unclear. Herein, by performing single-cell RNA sequencing (scRNA-seq) of the prostate tumor microenvironment (TME) of mouse models of castration-resistant prostate cancer (CRPC), we report that immunosuppressive neutrophils (PMN-MDSCs) are a key extra-hepatic source of coagulation factor X (FX). FX activation within the TME enhances androgen-independent tumor growth by activating the protease-activated receptor 2 (PAR2) and the phosphorylation of ERK1/2 in tumor cells. Genetic and pharmacological inhibition of factor Xa (FXa) antagonizes the oncogenic activity of PMN-MDSCs, reduces tumor progression, and synergizes with enzalutamide therapy. Intriguingly, F10 high PMN-MDSCs express the surface marker CD84 and CD84 ligation enhances F10 expression. Elevated levels of FX, CD84, and PAR2 in prostate tumors associate with worse survival in CRPC patients. This study provides evidence that FXa directly promotes cancer and highlights additional targets for PMN-MDSCs for cancer therapies. [Display omitted] • PMNs are a key source of coagulation factor X (FX) in the tumor microenvironment • PMN-derived FX directly fuels tumor growth and CRPC • CD84 marks F10 high Cxcr2 low PMNs in CRPC • High FX, CD84, and PAR2 levels predict poorer survival in PCa patients Calì et al. demonstrate that CD84+ immunosuppressive PMNs release in the tumor microenvironment of castration-resistant prostate cancer the coagulation factor X (FX). FX promotes androgen-independent cell proliferation and therapy resistance, independently from the coagulation cascade, by binding PAR2 on prostate cancer cells. This research reveals a new interplay between coagulation factors, immune cells, and cancer. [ABSTRACT FROM AUTHOR]

Background: [177Lu]Lu–PSMA‐617 (177Lu‐PSMA‐617) plus protocol‐permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression‐free survival (rPFS) versus SOC in patients with prostate‐specific membrane antigen (PSMA)–positive metastatic castration‐resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health‐related quality of life (HRQOL). Methods: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu‐PSMA‐617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy–Prostate [FACT‐P] and 5‐level EQ‐5D [EQ‐5D‐5L]). Correlation analyses used an iterative multiple imputation copula‐based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong). Results: In the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT‐P total score and emotional and physical well‐being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time‐to‐worsening EQ‐5D‐5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms. Conclusions: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation. In patients with metastatic castration‐resistant prostate cancer participating in the VISION randomized phase 3 trial, radiographic progression‐free survival correlated strongly with overall survival but not with time to a first symptomatic skeletal event or worsening health‐related quality of life or pain. There were no clear or consistent differences in the strengths of correlation between the two treatment groups ([177Lu]Lu‐PSMA‐617 plus protocol‐permitted standard of care vs. standard of care alone). [ABSTRACT FROM AUTHOR]

PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study. [ABSTRACT FROM AUTHOR]

ABSTRACT Prostate cancer continues to be one of the most lethal cancers in men. While androgen deprivation therapy is initially effective in treating prostate cancer, most cases of advanced prostate cancer eventually progress to castration‐resistant prostate cancer (CRPC), which is incurable. Similarly, the most aggressive form of prostatic carcinoma occurs in dogs that have been castrated. To identify molecular similarities between canine prostate cancer and human CRPC, we performed a comparative analysis of gene expression profiles. Through this transcriptomic analysis, we found that prostatic carcinoma in castrated dogs demonstrates an androgen‐indifferent phenotype, characterised by low‐androgen receptor and neuroendocrine‐associated genes. Notably, we identified two genes, ISG15 and AZGP1, that were consistently up‐ and down‐regulated, respectively, in both canine prostatic carcinoma and human CRPC. Additionally, we identified several other genes, including GPX3, S100P and IFITM1, that exhibited similar expression patterns in both species. Protein–protein interaction network analysis demonstrated that these five genes were part of a larger network of interferon‐induced genes, suggesting that they may act together in signalling pathways that are disrupted in prostate cancer. Accordingly, our findings suggest that the interferon pathway may play a role in the development and progression of CRPC in both dogs and humans and chart a new therapeutic approach. [ABSTRACT FROM AUTHOR]

Hormone therapy, especially androgen deprivation therapy (ADT), is effective against prostate cancer (PC), whereas long-term ADT is a risk for metabolic/cardiovascular disorders including diabetes (DM), hypertension (HT) and dyslipidemia (DL), and might result in progression to castration-resistant prostate cancer (CRPC). We thus conducted a multicenter retrospective cohort study to ask whether CRPC progression would be associated positively with HT, DM or DL and negatively with statins prescribed for treatment of DL. In this study, 1,112 nonmetastatic PC patients undergoing ADT were enrolled. Univariate statistical analyses clearly showed significant association of HT or DM developing after ADT onset, though not preexisting HT or DM, with early CRPC progression. On the other hand, preexisting DL or statin use, but not newly developed DL or started statin prescriptions following ADT, was negatively associated with CRPC progression. Multivariate analysis revealed significant independent association of the newly developed DM or HT, or preexisting statin use with CRPC progression [adjusted hazard ratios (95% confidence intervals): 3.85 (1.65–8.98), p = 0.002; 2.75 (1.36–5.59), p = 0.005; 0.25 (0.09–0.72), p = 0.010, respectively]. Together, ADT-related development of HT or DM and preexisting statin use are considered to have positive and negative impact on CRPC progression, respectively. [ABSTRACT FROM AUTHOR]

This research investigates the intricate involvement of nuclear Transcription Factor Y Subunit Alpha (NFYA) in the advancement of castration-resistant prostate cancer (CRPC) and its consequential impact on early Growth Response 4 (EGR4) expression. NFYA demonstrates a significant elevation in CRPC tissues and cell lines, displaying robust upregulation in metastatic prostate cancer (mPCa) samples, closely associated with the Gleason score. Immunohistochemistry validates heightened nuclear staining of NFYA in CRPC patients, highlighting its crucial role in the progression of advanced prostate cancer. Silencing NFYA through siRNA in androgen-independent cell lines markedly impedes cell growth and migration, emphasizing NFYA's pivotal role in promoting CRPC behavior. RNA-seq analysis identifies EGR4 as a downstream target of NFYA, with both genes consistently upregulated in CRPC. Validating this finding, heightened expression of EGR4 is observed in CRPC samples. In vivo studies utilizing a mouse model demonstrate that NFYA silencing substantially inhibits LNCaP-AI/22RV1shNFYA xenograft tumor growth, accompanied by reduced expression of EGR4 and Ki67. This comprehensive study reveals the multifaceted role of NFYA in CRPC progression, elucidates its downstream impact on EGR4, and underscores the therapeutic potential of targeting NFYA to inhibit CRPC growth in vivo. These findings contribute valuable insights into potential therapeutic strategies for managing CRPC. [ABSTRACT FROM AUTHOR]

Most patients with metastatic prostate cancer eventually develop resistance to primary androgen deprivation therapy. To identify predictive biomarker for Abiraterone acetate/prednisone resistance, we screened alternative splice variants between responders and non-responders from the PROMOTE clinical study and pinned down the most significant variant, CENPK–delta8. Through preclinical patient-derived mouse xenograft (PDX) and 3D organoids obtained from responders and non-responders, as well as in vitro models, aberrant CENPK–delta8 expression was determined to link to drug resistance via enhanced migration and proliferation. The FLNA and FLOT1 were observed to specifically bind to CENK–delta8 rather than wild-type CENPK, underscoring the role of CENPK–delta8 in cytoskeleton organization and cell migration. Our study, leveraging data from the PROMOTE study, TCGA, and TCGA SpliceReq databases, highlights the important function of alternative splice variants in drug response and their potential to be prognostic biomarkers for improving individual therapeutic outcomes in precision medicine. [ABSTRACT FROM AUTHOR]

The preliminary role of [18F]fluoro-5α-dihydrotestosterone ([18F]FDHT) in identifying receptor status and managing cancer patients is promising. In this work, we compiled studies regarding the ability of [18F]FDHT to predict response to treatment in different stages of drug development. In the chemical development, the androgen receptor (AR) ligands of [18F]FDHT were the candidates evaluated and identified using preclinical methods. High uptake of [18F]FDHT levels was observed in cell lines and xenograft tumours in mice having glucuronidation-competent cells mimicking the sensitive type of castration-resistant prostate cancer (CRPC) treated with androgen deprivation therapy (ADT). In clinical trials, the detection of lesions with [18F]FDHT was in agreement with the standard radiotracer [18F]FDG in advanced prostate cancer (PC) and was even better in AR-positive without glycolytic activity (AR1Glyc0) subtypes, demonstrating the specific role of [18F]FDHT for the detection of tumour localisation. Moreover, the immunohistochemistry (IHC) correlation between [18F]FDHT and AR was stronger than the correlation between [68 Ga]Ga-PSMA-11 and prostate-specific membrane antigen (PSMA), suggesting that [18F]FDHT can be a standalone modality for the monitoring of AR-targeted therapy. [ABSTRACT FROM AUTHOR]

Background: The alpha-emitting radionuclide therapy [223Ra]RaCl2 (Radium-223) improves overall survival (OS) and time to symptomatic skeletal event (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC). Evidence suggests that the effect of Radium-223 is partly exerted through an impact on the surrounding bone matrix. We hypothesized that bone metabolism markers (BMM) could provide predictive information regarding response to Radium-223. Accordingly, the aim of this study was to investigate changes in BMM during Radium-223 therapy and evaluate association with clinical outcome. Methods: Prospective study of BMM in patients with mCRPC receiving Radium-223. Blood samples were collected before each administration of Radium-223 and the following BMM were quantified; bone-specific alkaline phosphatase (BALP), osteocalcin, procollagen type I N-propeptide (PINP), C-terminal telopeptide of type I collagen (CTX), C-terminal cross-linking telopeptide of type I collagen generated by matrix metalloproteinases (CTX-MMP), tartrate-resistant acid phosphatase isoform 5b (TRACP5b), receptor-activated nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. Clinical outcomes were scintigraphic progression during/after therapy, change in bone scan index (BSI), occurrence of SSE, and OS. Results: A total of 55 mCRPC patients were included. There was a significant linear association between skeletal extent of disease and CTX-MMP, PINP, BALP, and osteocalcin. No significant association between dynamics in BSI and BMM were detected. Median OS for the cohort was 14 months (95% CI: 10.7–16.8). Baseline levels of Log2-CTX-MMP (HR = 2.15 (95%CI: 1.1–4.1)) and Log2-BALP (HR = 1.59 (95%CI: 1.1–2.1)) were associated with OS. Patients with increasing CTX-MMP during therapy had significantly shorter OS (Median OS = 4 mo. (95%CI: 2.3–5.7)) than patients with stable or decreasing CTX-MMP (Median OS = 12 mo. (95%CI: 10.1–13.9), P < 0.001). Conclusion: BMM are significantly associated with scintigraphic extent of skeletal disease and OS in patients with mCRPC. Particularly, the bone resorption marker CTX-MMP is a promising surrogate marker for prediction of outcome in patients receiving Radium-223 therapy and could potentially improve selection of patients for therapy and assessment of response. Trial registration: Clinicaltrials.gov, NCT03247010. Registered 10th of August 2017, https://clinicaltrials.gov/study/NCT03247010?term=NCT03247010&rank=1. [ABSTRACT FROM AUTHOR]

BACKGROUND. Androgen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance. METHODS. To investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line. RESULTS. We confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation. CONCLUSION. Our findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes. FUNDING. National Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute. [ABSTRACT FROM AUTHOR]

Lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 improves survival and quality of life in patients with metastatic castration-resistant prostate cancer, but whether it confers a benefit in hormone-sensitive disease is unknown. We aimed to evaluate [177Lu]Lu-PSMA-617 before docetaxel treatment in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer. UpFrontPSMA was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 11 Australian hospitals. Eligible patients had prostate adenocarcinoma without clinically significant neuroendocrine differentiation or small-cell histology, were aged 18 years or older, had less than 4 weeks on androgen deprivation therapy, had an Eastern Cooperative Oncology Group performance status of 0–2, and had high-volume PSMA-avid disease on [68Ga]Ga-PSMA-11 PET-CT with no major discordance on 2-[18F] fluorodeoxyglucose-PET-CT. Patients were randomly assigned (1:1) to the experimental treatment ([177Lu]Lu-PSMA-617 followed 6 weeks later by docetaxel) or standard-of-care treatment (docetaxel alone) using computer-based block randomisation with random block sizes, stratified by disease volume by conventional imaging and duration of androgen deprivation therapy at the time of registration. Neither patients nor investigators were masked to treatment assignment. Patients in the experimental group received two cycles of [177Lu]Lu-PSMA-617 7·5 GBq every 6 weeks intravenously, followed 6 weeks later by six cycles of docetaxel 75 mg/m2 every 3 weeks intravenously, whereas patients in the standard-of-care treatment group received six cycles of docetaxel 75 mg/m2 every 3 weeks intravenously. All patients received continuous androgen deprivation therapy. The primary endpoint was undetectable prostate-specific antigen (≤0·2 ng/mL) at 48 weeks, assessed using a modified intention-to-treat analysis. The trial is registered with ClinicalTrials.gov , NCT04343885. Between May 5, 2020, and April 18, 2023, 130 patients were randomly assigned, 63 (48%) to [177Lu]Lu-PSMA-617 plus docetaxel and 67 (52%) to docetaxel alone. All patients were male and no race or ethnicity data were collected. Median follow-up was 2·5 years (IQR 1·8–3·0). Four patients in the docetaxel alone group withdrew consent after randomisation and no data beyond screening were collected. An additional four patients were not evaluable for the primary endpoint at 48 weeks (two in each group). 25 (41%) of 61 patients (95% CI 30–54) in the [177Lu]Lu-PSMA-617 plus docetaxel group had undetectable PSA at 48 weeks compared with ten (16%) of 61 patients (9–28) in the docetaxel alone group (OR 3·88, 95% CI 1·61–9·38; p=0·0020). The most common grade 3 or 4 treatment-related adverse events were febrile neutropenia (seven [11%] of 63 patients in the [177Lu]Lu-PSMA-617 plus docetaxel group vs six [10%] of 63 patients in the docetaxel alone group) and diarrhoea (four [6%] of 63 patients vs none). Serious adverse events occurred in 16 (25%) patients in the [177Lu]Lu-PSMA-617 plus docetaxel group (none were definitely related to [177Lu]Lu-PSMA-617) and 16 (25%) patients in the docetaxel alone group. No treatment-related deaths occurred. [177Lu]Lu-PSMA-617 followed by docetaxel improved antitumour activity in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer compared with docetaxel alone, without increased toxic effects. Our data potentially support a role for [177Lu]Lu-PSMA-617 in metastatic hormone-sensitive prostate cancer. Prostate Cancer Research Alliance (Movember Foundation and Australian Government Medical Research Future Fund), US Department of Defence Impact Award-Clinical Trials, Endocyte/Advanced Accelerator Applications (a Novartis company), Australian Nuclear Science and Technology Organization, Victorian Cancer Agency, University of Melbourne, and Peter MacCallum Cancer Foundation. [ABSTRACT FROM AUTHOR]

BACKGROUND: About one-quarter of patients with advanced prostate cancer have alterations in homologous recombination repair (HRR) genes. In a global phase 3 study, talazoparib plus enzalutamide significantly improved progression-free survival in patients with HRR-deficient metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVES: This article reviews the role of oncology nurses and advanced practice providers (APPs) in administering talazoparib plus enzalutamide in patients with mCRPC. METHODS: This review and hypothetical case study illustrate the role of oncology nurses and APPs in the administration of talazoparib plus enzalutamide and the management of adverse events to ensure safe and effective use in clinical practice. FINDINGS: Oncology nurses and APPs play an important role in the dosing and administration of talazoparib plus enzalutamide and can recognize and manage adverse events in patients with HRR-deficient mCRPC. [ABSTRACT FROM AUTHOR]

Objective [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 radioligand therapy (RLT) shows promise for metastatic castration-resistant prostate cancer (mCRPC) patients with positive PSMA positron emission tomography (PET) imaging. Identifying high-risk patients is crucial. We evaluated pretherapeutic PSMA PET-derived parameters to predict prostate-specific antigen (PSA) response in patients undergoing [ 177 Lu]Lu-PSMA-617 RLT. Materials and Methods We conducted a retrospective analysis among 27 patients (mean age: 71.0 ± 9.5 years; range: 52–85 years) who underwent PSMA PET/computed tomography (CT) and subsequent [ 177 Lu]Lu-PSMA-617 RLT between March 2019 and January 2023. After excluding patients with liver metastases, the number of patients left for analysis was 21 (14 responders and 7 nonresponders). Tumors were semiautomatically delineated with calculation of total tumor volume (PSMA-TV), lesion uptake (PSMA-TLU = PSMA-TV * standardized uptake value [SUV]mean), and lesion quotient (PSMA-TLQ = PSMA-TV/SUVmean) for each patient. Semiquantitative parameters were analyzed only in patients with mCRPC and no liver metastasis. Results In total, 17/27 patients (62.96%) had a decline in PSA levels; 15/27 patients (55.56%) experienced a decline of > 50%. Pretherapeutic PSMA PET/CT results revealed significant differences in PSMA-TV (p = 0.003), PSMA-TLU (p = 0.013), and PSMA-TLQ (p = 0.011) between responders and nonresponders. SUVmax was significantly correlated to the best percentage change in PSA response after 177 Lu-PSMA-617 treatment (r = −0.79, p = 0.006). No association was observed between PSMA-TV (p = 0.367), PSMA-TLU (p = 0.128), and PSMA-TLQ (p = 0.556), with the best percentage change in PSA response after 177 Lu-PSMA-617 therapy. Conclusion Pretherapeutic PSMA PET-derived PSMA-TV, PSMA-TLU, and PSMA-TLQ were significant negative predictors of PSA response in patients with mCRPC and no liver metastasis receiving [ 177 Lu]Lu-PSMA-617 RLT. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is the second most prevalent cancer in males, with a steadily increasing incidence in the Middle East (ME). The aim of this study was to capture real-world data on the characteristics, disease progression, and treatment patterns among PC patients in the ME. This was a retrospective, observational, multi-centre study conducted across ten hospitals/research centers in Lebanon, Kingdom of Saudi Arabia, Iraq and Kuwait. Data were abstracted from medical records of 615 male patients who were diagnosed with PC between January 2012 and the site initiation date (December 2018-May 2019) and received at least one PC treatment/intervention. The observation period ranged between 84 and 88 months. Data were collected on demographics, clinical characteristics, time to progression to the subsequent clinical state or therapy (progression from localised/ locally advanced PC to castration and to metastatic PC (metastatic castration-sensitive PC (mCSPC) or metastatic castration-resistant PC (mCRPC)), progression from mCSPC to mCRPC, and mCRPC patients' progression to first subsequent line of therapy), treatment patterns, and mortality. Most patients had localised/locally advanced PC (57.7%), followed by mCSPC (37.4%), and mCRPC (4.1%) at the time of inclusion in the study. Most patients were at tumours, nodes and metastases (TNM) stage IIIa (40.1%) or TNM stage IVb (27.8%) at study entry. Median time to metastatic disease, castration-resistance and next line therapy was 84 months (95% CI: 68--84), 41 months (95% CI: 30-56) and 7 months (95% CI: 0-41), respectively. The mortality rate was 3.6%. Disease progression was most common among patients with mCSPC (35.1%) or mCRPC (14.8%), and treatment discontinuation was most common among patients with mCRPC (36.6% treatments discontinued). The results show that most patients were at an advanced TNM stage at study entry, suggestive of a lack of awareness regarding PC. Disease progression was most common among patients with metastatic disease, reflecting the challenge of treating metastatic disease and highlighting the need for novel treatments. [ABSTRACT FROM AUTHOR]

Neuroendocrine transdifferentiation (NEtD), also commonly referred to as lineage plasticity, emerges as an acquired resistance mechanism to molecular targeted therapies in multiple cancer types, predominately occurs in metastatic epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer treated with EGFR tyrosine kinase inhibitors and metastatic castration‐resistant prostate cancer treated with androgen receptor targeting therapies. NEtD tumors are the lethal cancer histologic subtype with unfavorable prognosis and limited treatment. A comprehensive understanding of molecular mechanism underlying targeted‐induced plasticity could greatly facilitate the development of novel therapies. In the past few years, increasingly elegant studies indicated that NEtD tumors share key the convergent genomic and phenotypic characteristics irrespective of their site of origin, but also embrace distinct change and function of molecular mechanisms. In this review, we provide a comprehensive overview of the current understanding of molecular mechanism in regulating the NEtD, including genetic alterations, DNA methylation, histone modifications, dysregulated noncoding RNA, lineage‐specific transcription factors regulation, and other proteomic alterations. We also provide the current management of targeted therapies in clinical and preclinical practice. [ABSTRACT FROM AUTHOR]

Introduction Anti-osteoclast treatment with denosumab or zoledronate is known to effectively reduce the need for radiotherapy to bone and other skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we analyze primary versus secondary initiation of bone-targeting agents (BTAs) relative to first palliative bone radiotherapy in patients dying of mCRPC. Methods Provincial administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n  = 98 646) who received continuous androgen deprivation therapy (n  = 29 453), died of prostate cancer (2013-2018, n  = 3864), and received life-prolonging therapy for mCRPC (n  = 1850). Variables were collected looking back 3 years from death. Multivariable analysis explored the relationship between clinical variables and BTAs. Results Of the 58% (1066/1850) patients with mCRPC who received BTA, only 289 (25.4%) started BTA prior to first palliative bone radiotherapy as primary prevention. Eight hundred and forty-eight (74.6%) patients either never received BTA before death (n  = 447) or started BTA only after first bone radiotherapy (n  = 401). More patients received denosumab (n  = 825, 77%) than zoledronic acid (n  = 241, 23%). 51.2% (582/1137) of palliative bone radiotherapy was initiated in the last 12 months of life. Factors associated with the use of BTA included elevated alkaline phosphatase (OR = 1.0, P  = .023), de novo metastases (OR = 1.4, P  = .005), medical oncologist involvement (OR = 2.0, P  = .007), diagnosis 2012-2017 versus 2007-2011 (OR = 0.75, P  = .034), and academic center (OR = 0.061, P  = .007). Conclusion A majority of patients with mCRPC never receive BTAs prior to first SRE, despite universal access and availability of these agents in Ontario. These results highlight an opportunity to improve outcomes by emphasizing early introduction of BTA in patients with mCRPC being started on systemic therapy. [ABSTRACT FROM AUTHOR]

The incidence rate of prostate cancer (PCa) has risen by 3% per year from 2014 through 2019 in the United States. An estimated 34,700 people will die from PCa in 2023, corresponding to 95 deaths per day. Castration resistant prostate cancer (CRPC) is the leading cause of deaths among men with PCa. Androgen receptor (AR) plays a critical role in the development of CRPC. N-terminal domain (NTD) is the essential functional domain for AR transcriptional activation, in which modular activation function-1 (AF-1) is important for gene regulation and protein interactions. Over last 2 decades drug discovery against NTD has attracted interest for CRPC treatment. However, NTD is an intrinsically disordered domain without stable threedimensional structure, which has so far hampered the development of drugs targeting this highly dynamic structure. Employing high throughput cell-based assays, small-molecule NTD inhibitors exhibit a variety of unexpected properties, ranging from specific binding to NTD, blocking AR transactivation, and suppressing oncogenic proliferation, which prompts its evaluation in clinical trials. Furthermore, molecular dynamics simulations reveal that compounds can induce the formation of collapsed helical states. Nevertheless, our knowledge of NTD structure has been limited to the primary sequence of amino acid chain and a few secondary structure motif, acting as a barrier for computational and pharmaceutical analysis to decipher dynamic conformation and drug-target interaction. In this review, we provide an overview on the sequence-structure-function relationships of NTD, including the polymorphism of mono-amino acid repeats, functional elements for transcription regulation, and modeled tertiary structure of NTD. Moreover, we summarize the activities and therapeutic potential of current NTD-targeting inhibitors and outline different experimental methods contributing to screening novel compounds. Finally, we discuss current directions for structure-based drug design and potential breakthroughs for exploring pharmacological motifs and pockets in NTD, which could contribute to the discovery of new NTD inhibitors. [ABSTRACT FROM AUTHOR]

For metastatic prostate cancer, androgen deprivation therapy (ADT) is the key strategy to control the disease. However, after 18–24 months of treatment, most patients will progress from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) even with ADT. Once patients enter into mCRPC, they face with significant declines in quality of life and a dramatically reduced survival period. Thus, doublet therapy, which combines ADT with new hormone therapy (NHT) or ADT with docetaxel chemotherapy, substitutes ADT alone and has become the "gold standard" for the treatment of mHSPC. In recent years, triplet therapy, which combines ADT with NHT and docetaxel chemotherapy, has also achieved impressive effects in mHSPC. This article provides a comprehensive review of the recent applications of the triplet therapy in the field of mHSPC. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most common cancers affecting the health of men worldwide. Castration-resistant prostate cancer (CRPC), the advanced and refractory phase of prostate cancer, has multiple mechanisms of resistance to androgen deprivation therapy (ADT) such as AR mutations, aberrant androgen synthase, and abnormal expression of AR-related genes. Based on the research of the AR pathway, new drugs for the treatment of CRPC have been developed in clinical practice, such as Abiraterone and enzalutamide. However, many areas in this pathway are still worth exploring. In this study, single-cell sequencing analysis was utilized to scrutinize significant genes in the androgen receptor (AR) pathway related to CRPC. Our analysis of single-cell sequencing combined with bulk-cell sequencing revealed a substantial downregulation of AR-regulated AFF3 in CRPC. Overexpression of AFF3 restricted the proliferation and migration of prostate cancer cells whilst also increasing their sensitivity towards enzalutamide, while knockdown of AFF3 had the opposite effect. To elucidate the mechanism of tumor inhibition by AFF3, we applied GSVA and GSEA to investigate the metabolic pathways related to AFF3 and revealed that AFF3 had an impact on fatty acids metabolism and ferroptosis through the regulation of ACSL4 protein expression. Based on correlation analysis and flow cytometry, we can speculate that AFF3 can impact the sensitivity of the CRPC cell lines to the ferroptosis inducer (RSL3) by regulating ACSL4. Therefore, our findings may provide new insights into the mechanisms of drug resistance in CRPC, and AFF3 may serve as a novel prognostic biomarker in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Abiraterone acetate (AA) is used in treatment of patients with metastatic prostate cancer. Despite the survival advantage, AA is associated with hypertension due to mineralocorticoid excess syndrome. Objective: We conducted a single-center retrospective analysis to evaluate the real-world incidence and severity of AA-induced hypertension. Methods: Electronic health records were used to collect baseline characteristics and prostate cancer history. Patient data, including blood pressure at each 4 (±2)-week interval, were collected for 24 weeks after the initiation of AA therapy. The primary endpoint was the incidence and severity of AA-induced hypertension. The secondary endpoints include effect of different prednisone dosing regimens and prostate cancer types on hypertensive incidence and the impact of clinical pharmacists' involvement in managing AA-induced hypertension. Results: A total of 142 patients who met our inclusion criteria received AA for metastatic prostate cancer, 73 (51.4%) with metastatic castration-resistant prostate cancer (mCRPC), and 69 (48.6%) with metastatic castration-sensitive prostate cancer (mCSPC). Of all, 43.7% experienced all-grade hypertension, and 28.2% experienced grade 3-4 hypertension. There was no difference in incidence of hypertension between patients receiving 5 mg of prednisone daily and those receiving 5 mg of prednisone twice daily. All-grade hypertension occurred in 39.7% of mCRPC and 47.8% of mCSPC patients (P = 0.33). Thirty-two percent of patients were actively managed by a clinical pharmacist and had an overall trend of reduced hypertension severity after 12 weeks. Conclusion and relevance: This single-center, retrospective cohort study found that real-world metastatic prostate cancer patients who received AA had substantially higher incidence and severity of hypertension compared with clinical trials regardless of prednisone dose. In patients with mCRPC and mCSPC, the role of prednisone dose in hypertension incidence and severity warrants further investigation. Overall, results indicate the need for closely monitoring hypertension and optimization of anti-hypertensive therapy by multidisciplinary teams in metastatic prostate cancer patients receiving AA. [ABSTRACT FROM AUTHOR]

[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of 177Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer. In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous 177Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff. Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive 177Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177Lu-PSMA-617 cycles was 6·0 (IQR 4·0–6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38–10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77–not estimable) in the 177Lu-PSMA-617 group versus 5·55 months (4·04–5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29–0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24–27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30–14·19) in the 177Lu-PSMA-617 group versus 5·59 months (4·21–5·95) in the ARPI change group (HR 0·49 [95% CI 0·39–0·61]). The incidence of grade 3–5 adverse events was lower in the 177Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related]). 177Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, 177Lu-PSMA-617 may be an effective treatment alternative. Novartis. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), as a novel endocrine therapy, has been investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) in recent years. Multiple large-scale clinical trials have consistently demonstrated that various PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, confer longer radiographic progression-free survival (rPFS) compared to new hormonal agents (NHA) in mCRPC patients with homologous recombination deficiency (HRD). Moreover, the incidence of grade 3 and above adverse events did not significantly increase. Additionally, when combined with androgen receptor signaling inhibitors (ARSI), olaparib, niraparib, and talazoparib have shown significant extension of rPFS but also an increased occurrence of serious adverse events in HRD-positive patients. Only PROpel yielded positive results among the homologous recombination repair (HRR) mutation negative population. Therefore, it remains uncertain whether ARSI-PARPi combination therapy should be considered as first-line treatment for mCRPC patients without HRR mutations. In this review article, we aim to elucidate the necessity and feasibility of combination therapy versus monotherapy specifically within the HRR mutant population while exploring its potential applicability to other non-HRR mutant subtypes. Furthermore, we conducted a comprehensive search on registered clinical trials at present to summarize the research progress of PARP inhibitors in prostate cancer patients at different disease stages. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer is the second leading cause of male cancer-related deaths in Western countries, which is predominantly attributed to the metastatic castration-resistant stage of the disease (CRPC). There is an urgent need for better prognostic and predictive biomarkers, particularly for androgen receptor targeted agents and taxanes. Methods: We have searched the PubMed database for original articles and metaanalyses providing information on blood-based markers for castration-resistant prostate cancer monitoring, risk group stratification and prediction of therapy response. Results: The molecular markers are discussed along with the standard clinical parameters, such as prostate specific antigen, lactate dehydrogenase or Creactive protein. Androgen receptor (AR) alterations are commonly associated with progression to CRPC. These include amplification of AR and its enhancer, point mutations and splice variants. Among DNA methylations, a novel 5-hydroxymethylcytosine activation marker of TOP2A and EZH2 has been identified for the aggressive disease. miR-375 is currently the most promising candidate among non-coding RNAs and sphingolipid analysis has recently emerged as a novel approach. Conclusions: The promising biomarkers have the potential to improve the care of metastatic prostate cancer patients, however, they need further validation for routine implementation. [ABSTRACT FROM AUTHOR]

Background: Inhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first‐ and second‐generation, non‐covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. Purpose: In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR‐R1PCa cell lines to second‐generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi). Methods: 2D and 3D mono‐ and co‐cultures of cancer cells, and cancer‐associated fibroblasts (CAFs) were used to mimic tumor‐stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real‐time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced. Results: The FGFRis were more effective in mono‐cultures of the cancer cells compared with co‐cultures with CAFs. The FRS2αi was specifically effective in co‐cultures with CAFs but was not cytotoxic to CAF mono‐cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p‐FRS2α, p‐ERK1/2, and activated apoptosis as monitored by cleaved caspase‐3 activity in a concentration‐dependent manner in the co‐cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co‐cultures as indicated by their reduced size and Ki67 expression. Conclusions: CAFs exert a protective effect on cancer cells and should be included in the in vitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co‐cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next‐generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Upfront novel androgen receptor signaling inhibitors (ARSIs) are the first-line treatment for metastatic castration-sensitive prostate cancer (mCSPC). However, there are a certain number of cases in which androgen deprivation therapy (ADT) is more effective in patients of Asian descent. If we can identify patients who show a marked response to ADT within 12 weeks after ADT, which is the inclusion criterion for upfront ARSI clinical trials, it would be valuable from an economic standpoint. A total of 218 patients who received ADT treatment at Kanazawa University Hospital between 2000 and 2020 were included in this study. Multivariate analysis revealed that a decrease in PSA levels of <95% at 12 weeks after ADT initiation was a predictor of short time to castration resistance (TTCR) in low-risk patients. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs, based on the rate of PSA reduction at 12 weeks. Background: The treatment strategy for metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly in recent years. Based on various guidelines, an upfront androgen receptor signaling inhibitor (ARSI) is the first choice, but in patients of Asian descent, including Japanese patients, there are a certain number of cases in which androgen deprivation therapy (ADT) and CAB are more effective. If patients can be identified who show a marked response to ADT within 12 weeks after the initiation of ADT, which is the inclusion criterion for ARSI clinical trials targeting mCSPC, it would be valuable from an economic standpoint. Methods: A total of 218 patients with pure prostate adenocarcinoma and treated with ADT at the Kanazawa University Hospital between January 2000 and December 2020 were included in this study. As a risk classification for mCSPC, in addition to the LATITUDE and CHAARTED criteria, we used the castration-sensitive prostate cancer classification proposed by Kanazawa University (Canazawa), developed by the Department of Urology of Kanazawa University. The Canazawa classification was based on three factors: Gleason pattern 5, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) ≥ 300 IU/L. It defined patients with one factor or less as low-risk and patients with two or three factors as high-risk. The overall survival (OS) and time to castration resistance (TTCR) were estimated retrospectively using the Kaplan–Meier method, and factors associated with TTCR were identified using univariate and multivariate analyses. Results: The median follow-up period was 40.4 months, the median OS period was 85.2 months, and the median TTCR period was 16.4 months. The Canazawa risk classification provided the clearest distinction between the OS and TTCR in mCSPC patients. Multivariate analysis revealed a decrease in PSA levels of <95% at 12 weeks after ADT initiation and was a predictor of short TTCR in low-risk, low-volume patients across all risk classifications. Conclusion: The Canazawa classification differentiated the prognosis of mCSPC patients more clearly. A PSA reduction rate of <95% at 12 w after starting ADT in low-risk, low-volume patients of all risk classifications was significantly shorter than the TTCR. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs based on the rate of PSA reduction at 12 w. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the evolution of treatment strategies for metastatic castration-sensitive prostate cancer, emphasizing the benefits of early treatment intensification with androgen deprivation therapy, androgen receptor pathway inhibitors, and chemotherapy. Despite robust evidence and guideline recommendations, their real-world adoption remains low. The review discusses clinical trial findings, real-world data, and ongoing challenges, advocating for a personalized treatment approach based on disease characteristics and patient fitness to optimize outcomes and narrow the gap between clinical evidence and practice. The contemporary treatment for metastatic castration-sensitive prostate cancer (mCSPC) has evolved significantly, building on successes in managing metastatic castration-resistant prostate cancer (mCRPC). Although androgen deprivation therapy (ADT) alone has long been the cornerstone of mCSPC treatment, combination therapies have emerged as the new standard of care based on recent advances, offering improved survival outcomes. Landmark phase 3 trials demonstrated that adding chemotherapy (docetaxel) and androgen receptor pathway inhibitors to ADT significantly enhances overall survival, particularly for patients with high-volume, high-risk, or de novo metastatic disease. Despite these advancements, a concerning gap between evidence-based guidelines and real-world practice remains, with many patients not receiving recommended combination therapies. The challenge in optimizing therapy sequences, considering both disease control and treatment burdens, and identifying clinical and biological subgroups that could benefit from personalized treatment strategies persists. The advent of triplet therapy has shown promise in extending survival, but the uro-oncology community must narrow the gap between evidence and practice to deliver the most effective care. Current research is focused on refining treatment approaches and utilizing biomarkers to guide therapy selection, aiming to offer more personalized and adaptive strategies for mCSPC management. Thus, aligning clinical practices with the evolving evidence is urgently needed to improve outcomes for patients facing this incurable disease. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the influence of various pharmacokinetic parameters on 177Lu-PSMA therapies via physical, biological, and statistical measures. Employing a clinically validated physiologically based pharmacokinetic (PBPK) model, realistic time–activity curves (TACs) in tumors, salivary glands, and kidneys are generated, allowing for the calculation of metrics such as AUC, dose, BED, and fBED. The results demonstrate the significant impact of multiple parameters on the measured outcomes. In addition to the great impact of administered ligand amount, tumor volume, and receptor density, other pharmacokinetic parameters such as rates of radiopharmaceutical association, internalization, and release were identified as key influencers. Notably, alterations in the parameters induced distinct modifications in TAC features, affecting radiobiological, pharmacokinetic, and statistical aspects. These insights contribute to advancing personalized treatment regimens by understanding the key contributions of various parameters towards improving therapeutic efficacy while minimizing radiation-related toxicities. Purpose: To investigate the impact of physiologically based pharmacokinetic (PBPK) parameters on physical, biological, and statistical measures in lutetium-177-labeled radiopharmaceutical therapies (RPTs) targeting the prostate-specific membrane antigen (PSMA). Methods: Using a clinically validated PBPK model, realistic time–activity curves (TACs) for tumors, salivary glands, and kidneys were generated based on various model parameters. These TACs were used to calculate the area-under-the-TAC (AUC), dose, biologically effective dose (BED), and figure-of-merit BED (fBED). The effects of these parameters on radiobiological, pharmacokinetic, time, and statistical features were assessed. Results: Manipulating PBPK parameters significantly influenced AUC, dose, BED, and fBED outcomes across four different BED models. Higher association rates increased AUC, dose, and BED values for tumors, with minimal impact on non-target organs. Increased internalization rates reduced AUC and dose for tumors and kidneys. Higher serum protein-binding rates decreased AUC and dose for all tissues. Elevated tumor receptor density and ligand amounts enhanced uptake and effectiveness in tumors. Larger tumor volumes required dosimetry adjustments to maintain efficacy. Setting the tumor release rate to zero intensified the impact of association and internalization rates, enhancing tumor targeting while minimizing the effects on salivary glands and kidneys. Conclusions: Optimizing PBPK parameters can enhance the efficacy of lutetium-177-labeled RPTs targeting PSMA, providing insights for personalized and effective treatment regimens to minimize toxicity and improve therapeutic outcomes. [ABSTRACT FROM AUTHOR]

The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of ARindependent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/ or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response. [ABSTRACT FROM AUTHOR]

Introduction: Neuroendocrine/small‐cell prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer, which typically develops after prolonged treatment for metastatic castration‐resistant disease, but can, less commonly, occur de novo. Case Presentation: We describe a case of de novo NEPC in a tumor with mixed pathology including acinar adenocarcinoma and neuroendocrine/small‐cell carcinoma with rapid progression of metastatic disease. Despite initiation of treatment with androgen deprivation therapy (ADT) and chemotherapy, the patient continued to exhibit progression leading to multiple complications including a large bowel obstruction and ultimately progressive hepatic metastases resulting in liver failure. Conclusion: This case illustrates the clinical presentation and highly aggressive nature of de novo NEPC. Recognizing atypical clinical progression in prostate cancer is critical for the detection of NEPC; however, despite early identification and initiation of treatment, the prognosis remains poor, thus highlighting the need for further study into NEPC biology and novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Intermediate cells are present in the early stages of human prostate development and adenocarcinoma. While primary cells isolated from benign human prostate tissues or tumors exhibit an intermediate phenotype in vitro, they cannot form tumors in vivo unless genetically modified. It is unclear about the stem cell properties and tumorigenicity of intermediate cells. Methods: We developed a customized medium to culture primary human intermediate prostate cells, which were transplanted into male immunodeficient NCG mice to examine tumorigenicity in vivo. We treated the cells with different concentrations of dihydrotestosterone (DHT) and enzalutamide in vitro and surgically castrated the mice after cell transplantation in vivo. Immunostaining, qRT-PCR, RNA sequencing, and western blotting were performed to characterize the cells in tissues and 2D and 3D cultures. Results: We found intermediate cells expressing AR+PSA+CK8+CK5+ in the luminal compartment of human prostate adenocarcinoma by immunostaining. We cultured the primary intermediate cells in vitro, which expressed luminal (AR+PSA+CK8+CK18+), basal (CK5+P63+), intermediate (IVL+), and stem cell (CK4+CK13+PSCA+SOX2+) markers. These cells resisted castration in vitro by upregulating the expression of AR, PSA, and proliferation markers KI67 and PCNA. The intermediate cells had high tumorigenicity in vivo, forming tumors in immunodeficient NCG mice in a month without any genetic modification or co-transplantation with embryonic urogenital sinus mesenchyme (UGSM) cells. We named these cells human castration-resistant intermediate prostate cancer stem cells or CriPCSCs and defined the xenograft model as patient primary cell-derived xenograft (PrDX). Human CriPCSCs resisted castration in vitro and in vivo by upregulating AR expression. Furthermore, human CriPCSCs differentiated into amplifying adenocarcinoma cells of luminal phenotype in PrDX tumors in vivo, which can dedifferentiate into CriPCSCs in vitro. Conclusions: Our study identified and established methods for culturing human CriPCSCs, which had high tumorigenicity in vivo without any genetic modification or UGSM co-transplantation. Human CriPCSCs differentiated into amplifying adenocarcinoma cells of luminal phenotype in the fast-growing tumors in vivo, which hold the potential to dedifferentiate into intermediate stem cells. These cells resisted castration by upregulating AR expression. The human CriPCSC and PrDX methods hold significant potential for advancing prostate cancer research and precision medicine. [ABSTRACT FROM AUTHOR]

Conventional androgen deprivation therapy (ADT) targets the androgen receptor (AR) inhibiting prostate cancer (PCa) progression; however, it can eventually lead to recurrence as castration‐resistant PCa (CRPC), which has high mortality rates and lacks effective treatment modalities. The study confirms the presence of high glutathione peroxidase 4 (GPX4) expression, a key regulator of ferroptosis (i.e., iron‐dependent program cell death) in CRPC cells. Therefore, inducing ferroptosis in CRPC cells might be an effective therapeutic modality for CRPC. However, nonspecific uptake of ferroptosis inducers can result in undesirable cytotoxicity in major organs. Thus, to precisely induce ferroptosis in CRPC cells, a genetic engineering strategy is proposed to embed a prostate‐specific membrane antigen (PSMA)‐targeting antibody fragment (gy1) in the macrophage membrane, which is then coated onto mesoporous polydopamine (MPDA) nanoparticles to produce a biomimetic nanoplatform. The results indicate that the membrane‐coated nanoparticles (MNPs) exhibit high specificity and affinity toward CRPC cells. On further encapsulation with the ferroptosis inducers RSL3 and iron ions, MPDA/Fe/RSL3@M‐gy1 demonstrates superior synergistic effects in highly targeted ferroptosis therapy eliciting significant therapeutic efficacy against CRPC tumor growth and bone metastasis without increased cytotoxicity. In conclusion, a new therapeutic strategy is reported for the PSMA‐specific, CRPC‐targeting platform for ferroptosis induction with increased efficacy and safety. [ABSTRACT FROM AUTHOR]

Prostate cancer is a common and serious disease among American men, but it has a high survival rate when detected early. This editorial discusses the factors that contribute to the progression of prostate cancer and its lethality, including abnormalities in the androgen receptor pathway, microRNA, and the bony microenvironment. The authors suggest potential targets for therapy to improve survival in men with advanced prostate cancer. The document also includes information about funding and conflicts of interest, as well as a disclaimer that the views expressed are solely those of the authors. References to other articles and studies on prostate cancer treatment are provided. [Extracted from the article]

Introduction: Prostate cancer (PCa), one of the most prevalent malignant tumors in the genitourinary system, is characterized by distant metastasis and the development of castration-resistant prostate cancer (CRPC), which are major determinants of poor prognosis. Current treatment approaches for PCa primarily involve surgery and endocrine therapy, but effective strategies for managing distant metastasis and CRPC remain limited. Methods: We utilized qPCR, WB, and other methods to measure the expression levels of respective proteins, concurrently assessing lipid metabolism to validate the role of FATP5 in lipid metabolism. Additionally, we employed bioinformatics analysis and WB techniques to explore the corresponding mechanisms. Results: In this study, we conducted an analysis of clinical samples and public databases to identify differential expression of FATP5 and further investigated its association with clinical outcomes. Through biochemical and functional experiments, we elucidated the potential underlying mechanisms by which FATP5 facilitates the progression of PCa. Our findings demonstrate that specific upregulation of FATP5 significantly enhances proliferation, migration, and invasion of PCa cell lines, while also modulating lipid metabolism in PCa. Mechanistically, the expression of FATP5 is closely associated with the Hippo signaling pathway, as it promotes the nuclear accumulation of YAP1 by inhibiting AMPK and facilitating the activation of β-catenin and RHOA. Furthermore, the transcription of FATP5 is mediated by TEAD4, and this transcriptional activation requires the involvement of YAP1. Discussion: FATP5 is highly expressed in prostate cancer and can enhance the biological activity and lipid metabolism of prostate cancer. We have also elucidated that FATP5 is regulated by the Hippo signaling pathway. This provides a new potential target for the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The management of advanced prostate cancer continues to evolve rapidly, particularly with the earlier use of survival-prolonging therapies in metastatic castration-sensitive prostate cancer (mCSPC). Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is little evidence determining the outcomes of taxane chemotherapies as the first subsequent taxane (FST) in mCRPC pts who received docetaxel intensification (DI) in mCSPC. The purpose of this study is to compare outcomes between the survival-prolonging taxanes, docetaxel and cabazitaxel as FST after DI. Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 December 2020 were retrospectively reviewed. Pts were considered eligible if they received DI for mCSPC and then received either docetaxel or cabazitaxel in mCRPC. Variables of interest were collected from electronic medical records. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from the FST start date. PSA responses were compared using the chi-squared test, and time-based endpoints were compared using the Kaplan–Meier method. Results: In total, 34 pts were identified: docetaxel = 22 and cabazitaxel = 12 as FST. 91.2% of pts (docetaxel 95.5% vs. cabazitaxel 83.3%) received FST in 2nd line mCRPC. The median age at diagnosis (63.1 vs. 67.1 yrs, p = 0.236) and the median time to CRPC (18.6 vs. 14.2 mos, p = 0.079) were similar for docetaxel and cabazitaxel, respectively. The median time to FST (24.1 vs. 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs. 52.7 mos, p = 0.002) were significantly shorter for pts receiving cabazitaxel vs. docetaxel. PSA responses occurred in 40.9% of pts treated with docetaxel compared to 25.0% treated with cabazitaxel (p = 0.645). There was no significant difference in median PFS (2.7 vs. 3.5 mos, p = 0.727) or median OS (11.4 vs. 8.1 mos, p = 0.132) from the time of FST for pts treated with docetaxel vs. cabazitaxel, respectively. Conclusions: Both docetaxel and cabazitaxel demonstrated activity as FST after DI in mCSPC. Pts who received cabazitaxel had a shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for cabazitaxel in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with docetaxel compared to cabazitaxel. While limited by its retrospective nature and small sample size, this study suggests that docetaxel is active as FST despite treatment with DI in mCSPC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Few studies have evaluated health-related quality of life (HRQoL) with abiraterone acetate plus prednisone (abiraterone) compared to enzalutamide in metastatic castration resistant prostate cancer (mCRPC). So, this study aimed to assess impact of abiraterone and enzalutamide on patients´ functioning in mCRPC real-world setting. METHODS: In this 12-month, prospective, observational study, 36 mCRPC patients from Slovakia were included. Patients were treated with abiraterone or enzalutamide according to routine practice. HRQoL was assessed at baseline and 3-/6-/9-/12-month visits using the Functional Assessment of Cancer Therapy-- Prostate (FACT-P) and European Quality of Life 5 Dimensions (EQ-5D) questionnaires. Changes from baseline and occurrence of deteriorations/improvements were compared using two-sample t-test/Mann- Whitney test and Pearson's chi-square/Fisher's exact test, respectively. Mixed-effects model for repeated measures was used to evaluate the difference between the two arms in mean changes of quality of life after 12 months. RESULTS: Frequency of clinically meaningful deterioration of quality of life assessed by FACT-P was similar for abiraterone and enzalutamide: 0%, 14.3%, 23.1%, 16.7% vs. 10%, 26.3%, 22.2%, 40% at 3-, 6-, 9- and 12 months of therapy (p=0.496, 0.670, 1.000 and 0.236, respectively). After 12 months of treatment, no statistically significant difference between the treatment arms was observed in estimated mean changes in FACT-P total scores (p=0.620) and its components, EQ-5D index (p=0.108), and EQ-5D visual analogue scale (p=0.324). CONCLUSION: According to the results of this study, abiraterone and enzalutamide had a comparable impact on quality of life in chemo-naive mCRPC in routine practice [ABSTRACT FROM AUTHOR]

Despite recent advances in the treatment of metastatic prostate cancer, progression to a castration-resistant state remains inevitable for most and prognosis is limited. Genetic testing for homologous recombination repair pathway alterations is recommended for all patients with advanced prostate cancer given that a mutation is present in up to 25% of cases. Poly(ADP-ribose) polymerase (PARPis) are now approved for use in patients with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor pathway inhibitor (ARPI) and harbour a germline or somatic homologous recombination repair mutation. Preclinical data support a synergistic effect with an ARPI and PARPi, and various ARPI-PARPi combinations have therefore been explored in phase III clinical trials. Despite heterogeneous findings, a clear hierarchy of benefit is evident, with patients harbouring a BRCA mutation deriving the greatest magnitude of benefit, followed by any homologous recombination repair mutation. The benefit in homologous recombination repair-proficient cohort is less clear, and questions remain about whether ARPI-PARPi combination therapy should be offered to patients without a homologous recombination repair mutation. With ARPIs now considered standard-of-care for metastatic hormone-sensitive prostate cancer, ARPI-PARPi combination therapy is currently being explored earlier in the treatment paradigm. The purpose of this review is to discuss the rationale behind ARPI-PARPi combination therapy, summarise the results of key clinical trials, and discuss clinical considerations and future perspectives. [ABSTRACT FROM AUTHOR]

The 2024 ACVIM Forum Research Report Program, published in the Journal of Veterinary Internal Medicine, features abstracts on various topics in veterinary medicine. The abstracts cover areas such as cardiology, equine health, neurology, nutrition, and small animal internal medicine. One study in cardiology examines the impact of right-sided heart disease on gastrointestinal health in dogs, finding that gastrointestinal dysfunction increases with the severity of the disease. Another study in cardiology compares different echocardiographic estimates of stroke volume in healthy dogs, finding that these estimates are not interchangeable. A study in serology evaluates different tests for detecting Trypanosoma cruzi infection in dogs, finding that the indirect fluorescent antibody test had the highest positivity rate. This study aimed to investigate the changes in nerve conduction associated with age and osteoarthritis (OA) in cats. The researchers conducted a prospective, randomized comparison of nerve conduction in healthy cats and cats with OA. They found that cats with OA had alterations in sensory and motor nerve conduction compared to healthy cats. These changes were correlated with age and quantitative sensory testing results. The study suggests that nerve conduction changes may contribute to the mobility and sensory function alterations observed in cats with OA. This study aimed to determine the biological variation of serum phosphorus and fibroblast growth factor-23 (FGF-23) in healthy cats and cats with chronic kidney disease (CKD). The results showed that both phosphorus and FGF-23 exhibited significant [Extracted from the article]

Cancer-associated fibroblast (CAF)s in the tumour microenvironment (TME) modulate the extracellular matrix, interact with cancer cells, and facilitate communication with infiltrating leukocytes, significantly contributing to cancer progression and therapeutic response. In prostate cancer (PCa), CAFs promote malignancy through metabolic rewiring, cancer stem cell regulation, and therapy resistance. Pre-clinical studies indicate that targeting amino acid metabolism, particularly glutamine (Gln) metabolism, reduces cancer proliferation and stemness. However, most studies lack the context of CAF–cancer interaction, focusing on monocultures. This study assesses the influence of CAFs on PCa growth by manipulating Gln metabolism using colour-labelled PCa cell lines (red) and fibroblast (green) in a co-culture system to evaluate CAFs' effects on PCa cell proliferation and clonogenic potential. CAFs increased the proliferation of hormone-sensitive LNCaP cells, whereas the castration-resistant C4-2 cells were unaffected. However, clonogenic growth increased in both cell lines. Gln deprivation and GLS1 inhibition experiments revealed that the increased growth rate of LNCAP cells was associated with increased dependence on Gln, which was confirmed by proteomic analyses. Tissue analysis of PCa patients revealed elevated GLS1 levels in both the PCa epithelium and stroma, suggesting that GLS1 is a therapeutic target. Moreover, the median overall survival analysis of GLS1 expression in the PCa epithelium and stroma identified a "high-risk" patient group that may benefit from GLS1-targeted therapies. Therefore, GLS1 targeting appears promising in castration-resistant PCa patients with high GLS1 epithelium and low GLS1 stromal expression. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most common and prevalent cancers in men worldwide. The majority of PCa-related deaths result from metastasis rather than primary tumors. Several studies have focused on the relationship between male-specific genes encoded on the Y chromosome and PCa metastasis; however, the relationship between the male specific protein encoded on the Y chromosome and tumor suppression has not been fully clarified. Here, we report a male specific protein of this type, the histone H3 lysine 4 (H3K4) demethylase JARID1D, which has the ability to inhibit the gene expression program related to cell invasion, and can thus form a phenotype that inhibits the invasion of PCa cells. However, JARID1D exhibits low expression level in advanced PCa, and which is related to rapid invasion and metastasis in patients with PCa. Curcumin, as a multi-target drug, can enhance the expression and demethylation activity of JARID1D, affect the androgen receptor (AR) and epithelial-mesenchymal transition (EMT) signaling cascade, and inhibit the metastatic potential of castration resistant cancer (CRPC). These findings suggest that using curcumin to increase the expression and demethylation activity of JARID1D may be a feasible strategy to inhibit PCa metastasis by regulating EMT and AR. Highlights: Knockdown of JARID1D can enhance the invasion and metastasis ability of prostate cancer cells. Curcumin improves the expression and demethylation activity of JARID1D. Curcumin can stimulate the JARID1D/AR/EMT signaling cascade through demethylation to inhibit the metastatic potential of castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Background and objective: Treatment planning through the diagnostic dimension of theranostics provides insights into predicting the absorbed dose of RPT, with the potential to individualize radiation doses for enhancing treatment efficacy. However, existing studies focusing on dose prediction from diagnostic data often rely on organ-level estimations, overlooking intra-organ variations. This study aims to characterize the intra-organ theranostic heterogeneity and utilize artificial intelligence techniques to localize them, i.e. to predict voxel-wise absorbed dose map based on pre-therapy PET. Methods: 23 patients with metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA I&T RPT were retrospectively included. 48 treatment cycles with pre-treatment PET imaging and at least 3 post-therapeutic SPECT/CT imaging were selected. The distribution of PET tracer and RPT dose was compared for kidney, liver and spleen, characterizing intra-organ heterogeneity differences. Pharmacokinetic simulations were performed to enhance the understanding of the correlation. Two strategies were explored for pre-therapy voxel-wise dosimetry prediction: (1) organ-dose guided direct projection; (2) deep learning (DL)-based distribution prediction. Physical metrics, dose volume histogram (DVH) analysis, and identity plots were applied to investigate the predicted absorbed dose map. Results: Inconsistent intra-organ patterns emerged between PET imaging and dose map, with moderate correlations existing in the kidney (r = 0.77), liver (r = 0.5), and spleen (r = 0.58) (P < 0.025). Simulation results indicated the intra-organ pharmacokinetic heterogeneity might explain this inconsistency. The DL-based method achieved a lower average voxel-wise normalized root mean squared error of 0.79 ± 0.27%, regarding to ground-truth dose map, outperforming the organ-dose guided projection (1.11 ± 0.57%) (P < 0.05). DVH analysis demonstrated good prediction accuracy (R2 = 0.92 for kidney). The DL model improved the mean slope of fitting lines in identity plots (199% for liver), when compared to the theoretical optimal results of the organ-dose approach. Conclusion: Our results demonstrated the intra-organ heterogeneity of pharmacokinetics may complicate pre-therapy dosimetry prediction. DL has the potential to bridge this gap for pre-therapy prediction of voxel-wise heterogeneous dose map. [ABSTRACT FROM AUTHOR]