The currently available clinical anticancer approaches pertaining to the treatment of prostate cancer are summarized here. After providing an overview of the main features of this highly impactful global disease, the currently available clinical treatments are briefly reviewed. Then, alternative and innovative nano-based therapeutic options that have been proposed or are currently being explored to significantly improve prostate cancer management (i.e. anti-prostate cancer polymeric nanoparticles loaded with drugs to promote their release and biological activity, including non-targeted and functionalized PLGA-PEG NPs and AuNPs), are introduced. Furthermore, the problem of gathering insights into the mechanistic aspects related to the fate of the nanoformulation in complex matrices, such as blood plasma, is addressed.

The incidence of prostate cancer (PC) has recently increased in Japan. Androgen deprivation therapy (ADT) has been a key treatment in patients with castration-sensitive PC (CSPC); however, resistance typically emerges through multiple mechanisms, leading to metastatic castration-resistant PC (mCRPC). Taxane-based therapy (i.e., docetaxel, cabazitaxel) has been standard care in patients with mCRPC. New evidence supporting the addition of androgen receptor signaling inhibitors (ARSIs, e.g., enzalutamide, abiraterone) to docetaxel and ADT for patients with metastatic CSPC (mCSPC) raises questions about the role of taxane-based therapies and their optimal sequencing, as well as how to identify patients who may benefit from taxane-based therapy. Here we review the evidence on taxane-based therapy, including cabazitaxel, in the treatment of PC, with a focus on clinical and real-world evidence from Japan. Cabazitaxel has proven effective for patients with mCRPC who have a history of ARSI and docetaxel use, and it is preferable to a second alternative ARSI, as indicated in the CARD study. The safety profile of cabazitaxel (particularly, the incidence of neutropenia) can be managed through prophylactic use of granulocyte colony-stimulating factor, as well as a lower dosage and possibly variation of the dosage interval. However, a certain dose intensity is required because neutropenia has been identified as a potential prognostic indicator for treatment effectiveness. In the ARSI era for mCSPC, evidence on mCRPC treatment sequencing is limited. A better understanding of PC biology and the collection of real-world data is essential for effective treatment and improved safety-benefit outcomes.

Puerto Rican (PR) Hispanic/Latino (H/L) men are an understudied population that has the highest prostate cancer (PCa) specific mortality among other Hispanic populations. Little information is known about the higher mortality in PR H/L men. It is thought that epigenetic changes in key genes may play a critical role in aggressive tumors.

We aimed to identify key 5-hydroxymethylcytosine (5hmC) changes in PR H/L men with aggressive PCa. We performed sequencing analysis using the 5hmC-enriched DNA from 22 prostate tumors and 24 adjacent normal FFPE samples.

We identified 808 differentially methylated genes (DMGs) in tumors compared to adjacent normal tissues. These genes suggest key mechanisms, including upregulated signatures of negative Androgen Receptor (AR) regulation, Wnt/β-catenin pathway activation, and downregulation of tumor suppressor genes. Pathway analysis of DMGs demonstrated that DNA repair pathway was most upregulated in tumors. Since 5hmC abundance positively correlates with gene expression levels, we further investigated 808 DMGs in TCGA PCa gene expression data. Further, we identified 59 DMGs with significant gene expression changes in the same direction. Additionally, we identified 111 aggressiveness-related DMGs, of which, two hypomethylated genes (CCDC122, NUDT15) and four hypermethylated genes (PVT1, RPL30, TRMT12, UBR5) were found to be altered at transcriptomic level in a concordant manner in PR H/L PCa patients. Aberrant 5hmC and GE changes in these six genes were also associated with progression-free survival in the mixed PCa population.

The 5hmC modifications and associated gene expression changes in these six genes could be linked to the highest prostate cancer (PCa)-specific mortality in PR H/L men. In conclusion, our study identified 59 DMGs showing concordant epigenetic and transcriptomic changes in tumor tissues and 111 DMGs showing association with aggressive PCa among PR H/L men. Our findings have significant implications for understanding these key genes' molecular mechanisms, which may drive PCa progression and mortality in this population. This will help in developing potential biomarkers or therapeutic targets for personalized treatment strategies in this high-risk subgroup. Future research will explore how these genes contribute to PCa-specific mortality through molecular analyses, with plans to validate them in a larger validation cohort.

The cell cycle mechanism is an integration point where information is sent through an upstream signaling network, making it a potential target for cancer diagnosis and treatment. The LAP1 protein, encoded by the Tor1aip1 gene, is required to maintain the shape of the nuclear envelope and the progression of the cell cycle. The aim of this study was to determine the role of Tor1aip1 gene in PRAD development and its mechanism. We analyzed the expression and survival data of TOR1 AIP1 in PRAD patients in the TCGA database and verified the low expression of TOR1 AIP1 in prostate cancer by qPCR, western blot and immunohistology, which was correlated with the tumor stage and survival prognosis of PRAD. In addition, lentiviral vectors were used to mediate the up-regulation or down-regulation of TOR1 AIP1 expression in prostate cancer cells, and the effects of TOR1 AIP1 on tumor proliferation and related signaling pathways were investigated by cell counting kit- 8, colony formation assay, transwell assay, western blot, and flow cytometry. As a result, we found that TOR1 AIP1 enhances protein stability of p53 by directly interacting with p53, consequently inhibited tumor proliferation and invasion by inducing the cell cycle to be arrested in the S phase. Therefore, TOR1 AIP1 represents a promising therapeutic target in PRAD due to its ability to stabilize p53 and enhance its tumor-suppressive functions. Future studies should focus on elucidating its mechanisms, developing targeted therapies, and exploring its clinical potential in combination with existing treatments. By advancing our understanding of TOR1 AIP1, we may unlock new strategies for improving outcomes in PRAD patients.

Prostate cancer (PC) contributes to male mortality worldwide. The objective of this study is to comprehensively depict the scientific accomplishments and research trends in nanotechnology for PC applications.

Utilizing the Web of Science Core Collection database, publications were gathered on the basis of inclusion and selection criteria. The publications were analyzed and visualized using VOSviewer, R-studio and CiteSpace software tools.

A total of 1949 studies were incorporated. Farokhzad was the most productive author. The United States and China released 58.13% of the total publications. The Chinese Academy of Sciences was the most influential institution, and the International Journal of Nanomedicine stood out as a prominent journal in this field. The most frequently referenced publication and research subject category were identified. The most extensively investigated area was nanoparticle-based drug delivery, while recent research has focused on anticancer with novel nanocarriers.

A bibliometric analysis in the PC and nanotechnology was conducted between 2004 and 2023. The overview and characteristics of the publications were identified. We discussed the application and restrictions faced by nanotechnology in PC management. The study of nanotechnology in PC treatment needs to be further studied.

This study aims to screen and identify microRNA (miRNA) expression profiles across different stages of prostate cancer (PCa) and benign prostatic hyperplasia (BPH) using high-throughput sequencing. The study seeks to determine whether specific miRNAs show consistent differential expression across various stages of PCa, with the goal of identifying potential biomarkers relevant to disease progression. In this study, a total of 12 specimens of PCa and BPH were collected from September 2021 to June 2022 in the Second Affiliated Hospital of Nanchang University, 330,006, P.R. China (including 3 specimens of early localized tumor, local invasion, and distant metastasis tumor and 3 specimens of BPH). The expression profile of miRNA was screened by high-throughput sequencing technology, and the differentially expressed miRNA between each group was screened by relevant bioinformatics analysis. Further targeted miRNA site analysis GO enrichment analysis and KEGG enrichment analysis of miRNA-derived genes were performed on the above differentially expressed miRNAs. Finally, the expression of hsa-miR-6715b-3p in PCa tissues was verified using qRT-PCR assay. A total of 1526 miRNAs were identified through high-throughput sequencing. By comparing groups, 228 differentially expressed miRNAs were identified, with 100 upregulated and 128 downregulated. Additionally, 69 novel miRNAs were predicted. qRT-PCR results showed that hsa-miR-6715b-3p was highly expressed in PCa tissues compared to BPH tissues. This study presents a preliminary investigation of the miRNA expression profiles in PCa and identifies hsa-miR-6715b-3p as a promising biomarker for disease progression. Our findings validate the high expression of hsa-miR-6715b-3p in PCa tissues and highlight its potential role in critical oncogenic pathways. These results provide a theoretical foundation for further functional studies to explore its clinical utility and its role in therapy resistance and disease progression, contributing to the growing knowledge of miRNA-based biomarkers in PCa.

As a diuretic, ethacrynic acid (EA) has been shown to play a suppressive role in cancers, including prostate cancer (PC). However, its molecular regulatory mechanism is still unclear. Therefore, our study is centered on investigating the effect of EA on PC development and its mechanism.

To verify the binding relationship between EA and GSTP1, molecular docking and cellular thermal shift assay (CETSA) were conducted. To examine how EA affects PC cell proliferation, cell cycle, and apoptosis, cell function assays were performed. qRT-PCR was used to detect GSTP1 mRNA expression. The expression of GSTP1 protein and PI3K-AKT signaling pathway-related proteins in cells was detected by western blot (WB). To verify how EA and GSTP1 influence cell growth in PC, in vivo experiments were conducted.

The binding relationship between GSTP1 and EA was confirmed by molecular docking and CETSA results. Cell experiments showed that EA could hinder PI3K/AKT pathway and PC cell proliferation, arrest the cell cycle in G0/G1 phase, and facilitate apoptosis by binding to GSTP1. In vivo experiments in nude mice verified that the interaction between EA and GSTP1 reduced PI3K and AKT phosphorylation and inhibited the growth of PC cells.

EA inhibits PC progression by binding to GSTP1 to downregulate the activity of PI3K/AKT pathway, and this result suggests the potential of EA to be an anticancer agent for PC therapy.

Cancer stem cells (CSCs) contribute to the resistance of intractable prostate cancer, and dopamine receptor (DR)D2 antagonists exhibit anticancer activity against prostate cancer and CSCs. Human prostate cancer PC-3 cells were used to generate CSC-like cells, serving as a surrogate system to identify the specific DR subtype the inhibition of which significantly affects prostate-derived CSCs. Additionally, the present study aimed to determine the downstream signaling molecules of this DR subtype that exert more profound effects compared with other DR subtypes. The inhibitory effects of specific antagonists or small interfering (si)RNAs on DR subtypes were compared by analyzing morphological changes of cells, expression patterns of pluripotency markers, cell growth inhibitory activities and in vitro cell invasion. L-741,626, a specific DRD2 antagonist, induced morphological changes in PC-3-derived CSC-like cells, suppressed the expression of Oct4 (a pluripotency marker), and inhibited the growth of cells and tumors. The proliferation of heterozygous null PC-3 cells, generated using the CRISPR/Cas9 method, was slow, and their sphere-forming ability was substantially reduced, indicating a diminished capacity to produce CSCs. In addition, the phosphorylation of AMPK was suppressed by DRD2 siRNA and the heterozygous knockout of DRD2 in PC-3 cells, indicating that AMPK may be a putative downstream signaling molecule involved in the production and maintenance of PC-3-derived CSC-like cells. Specific inhibition or suppression of DRD2 caused PC-3-derived CSC-like cells to lose their properties and inhibited the formation of PC-3-derived CSC-like cells, followed by inhibition of the phosphorylation of AMPK, which is considered a putative downstream signaling molecule of DRD2. Further understanding of the mechanisms by which DRD2 regulates AMPK and the effects of AMPK inhibition on the properties of PC-3-derived CSC-like cells may provide valuable insights into the identification of molecular targets for treating intractable prostate cancer wherein AMPK is constitutively activated.

Prostate cancer is a prevalent malignancy that is frequently managed with radiotherapy. However, resistance to radiotherapy remains a significant challenge in controlling this disease. Early radiotherapy is employed for locally confined prostate cancer (PCa), while recurrent disease post-surgery and metastatic castration-resistant prostate cancer (mCRPC) are treated with late-stage radiotherapy, including radium-223. Combination therapies to integrate radiotherapy and chemotherapy have demonstrated enhanced treatment efficacy. Nonetheless, both modalities can induce severe local and systemic toxicities. Consequently, selectively sensitizing prostate tumors to radiotherapy could improve therapeutic outcomes while minimizing systemic side effects. The mechanisms underlying radioresistance in prostate cancer are multifaceted, including DNA damage repair (DDR) pathways, hypoxia, angiogenesis, androgen receptor (AR) signaling, and immune evasion. The advent of 177Lu-PSMA-617, which was approved in 2022, has shown promise in targeting prostate-specific membrane antigen (PSMA) in advanced prostate cancer. Experimental and clinical studies have yielded promising results in suppressing prostate tumors by targeting these pathways. This paper reviews potential targets for sensitizing prostate tumors to radiotherapy. We discuss cellular and molecular mechanisms contributing to therapy resistance and examine findings from experimental and clinical trials on promising targets and drugs that can be used in combination with radiotherapy.

Androgen-receptor signaling inhibitors (ARSIs) become the new standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). It is unknown whether time to castration resistance (TTCR), when using the first-line ARSIs, offers predictive value in mHSPC. We sought to assess the clinical outcomes for mHSPC patients treated with first-line ARSIs focusing on the TTCR.

Data from the ULTRA-Japan study cohort from five academic institutes (496 mHSPC patients) were retrospectively analyzed.

The median overall survival (OS) in the total cohort was 80 months with a median follow-up of 18 months. Of 496 patients, 332 (67%), 82 (16.5%), and 82 (16.5%) were treated with first-line abiraterone acetate + prednisone, enzalutamide, and apalutamide, respectively. During the follow-up, a total of 155 (31%) were diagnosed with mCRPC with a median TTCR of 10 months. In those 155 patients, TTCR > 12 months is an independent predictor of longer OS from the first-line ARSIs. Cox regression analysis of the TTCR from initiating first-line ARSI in 496 mHSPC patients revealed three variables as independent predictors of shorter TTCR, including Gleason's score (GS) ≥ 9, the extent of disease (EOD) ≥ 2, and the presence of liver metastasis.

Our results indicate that mHSPC patients with those three features are likely to have primary resistance to first-line ARSIs (doublet therapy), thus requiring consideration of other options, such as the recent triplet approach.

Estrogen receptor β (ERβ) is aberrantly expressed in castration-resistant prostate cancer (CRPC). Therefore, a diagnostic and therapeutic ERβ probe not only helps to reveal the complex role of ERβ in prostate cancer (PCa), but also promotes ERβ-targeted PCa therapy. Herein, we reported a novel ERβ-targeted near-infrared fluorescent probe D3 with both imaging and therapeutic functions, which had the advantages of high ERβ selectivity, good optical performance, and strong anti-interference ability. In addition, it displayed excellent antiproliferative activity in CRPC cells. Finally, D3 was also successfully applied to the in vivo imaging of ERβ in the prostate cancer mouse model. Thus, this ERβ-targeted near-infrared fluorescent probe can be used as a potential tool for the study of ERβ-targeted diagnostic and therapeutic PCa.

We aimed to examine trends in novel antiandrogen receptor signal inhibitor (ARSI) usage and medical costs by collecting real-world big data included in The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data, covering most of the clinical practices throughout Japan.

Usage data for outpatient prescriptions from 2016 to 2021 were extracted from the NDB Open Data. Among the 459,610 million tablets/capsules prescribed, prostate cancer-specific agents (bicalutamide, estramustine phosphate, flutamide, abiraterone, enzalutamide, apalutamide, and darolutamide) were selected to investigate the trends of usage and medical costs.

In total, 764.8 billion medications were recorded. Among these, standard dose-adjusted prescriptions for bicalutamide, abiraterone, enzalutamide, apalutamide, darolutamide, and other vintages (estramustine phosphate, flutamide) was 276, 14.2, 18.1, 2.19, 0.34, and 20.3 million, respectively. The usage of ARSI increased significantly from 6.1% in 2016 to 16% in 2021. The medical costs for prostate cancer-specific agents increased significantly (1.8-fold) from 2016 to 2021. Despite the limited usage of ARSIs, a majority of the medical costs had been spent on ARSIs. Medical costs associated with ARSIs increased significantly from 59% to 89% (p < 0.001).

ARSI usage and medical costs associated with prostate cancer increased significantly from 2016 to 2021. Despite the limited use of ARSIs, a considerable proportion of the medical costs for prostate cancer-specific agents had been spent on ARSIs.

The objective of this study is to assess the trends in treatment selection for patients with de novo metastatic castration-sensitive prostate cancer in the era of upfront combination therapy.

This multicenter retrospective study included 595 patients treated with either upfront combination therapy (upfront novel hormonal therapies and taxane-based chemotherapy) or vintage therapy (androgen deprivation therapy with or without bicalutamide) between 2016 and 2021. High tumor burden metastatic disease was defined when a patient met the CHAARTED or LATITUDE criteria. We evaluated trends in treatment selection and reasons for selecting vintage therapy.

Of the 595, 123 and 472 patients were classified as having low and high tumor-burden disease, respectively. The Use of upfront combination therapy was found to be rapidly increasing with utilization rates of 72% and 54% in 2021 for high and low tumor-burden disease, respectively. Multivariable logistic regression analysis found older age, poor performance status, and nonacademic center were significantly associated with the selection of vintage therapy. Of the 163 patients who received vintage hormone therapy after approval of upfront therapy, 74.2% had a specific reason for avoiding upfront therapy. The reasons for selecting vintage therapy included refusal (39.8%), older age (67.6%), frailty (56.3%), and comorbidity (40.8%). Furthermore, 16.9% of patients declined upfront combination therapy due to cost concerns.

Upfront combination therapy use has 72% and 54% prevalence among patients with high and low tumor burden diseases, respectively, in this current practice. Older age, poor performance status, and facility bias were negatively associated with the use of upfront combination therapy.

Prostate cancer is the second most common cancer in men. The different stages of prostate cancer which include localised (low, intermediate, and high risk) disease, locally advanced, non-metastatic castration-resistant prostate cancer (M0 CRPCa), and metastatic disease. The main treatment of locally advanced disease is external beam radiotherapy with hormonal therapy which are associated with good prognosis.

Current treatments for M0 CRPCa include androgen deprivation therapy in combination with apalutamide, darolutamide or enzalutamide, all of which are associated with good metastatic-free survival rates in clinical trials. Hormone-naive metastatic prostate cancer comprises the same treatments as M0 CRPCa, whereas further treatment includes docetaxel and abiraterone. Metastatic castration-resistant prostate cancer treatments include sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, which aim to slow down the progression of the disease and to prolong life. This article also provides insight into the development of new drugs recently approved for metastatic castration prostate cancer, which include PARP inhibitors and Lutetium-177 which have shown to have significantly good overall survival and to improve radiographic progression-free survival. In addition, new clinical trials are ongoing to test new medications such as cabozantinb and chimeric-antigen receptor T-cell therapy for the treatment of advanced prostate cancer. With the aim to slow down the progression of the disease and to prolong life, new drug developments are underway to hopefully provide a positive impact on overall survival and improve progression-free survival, especially in advanced prostate cancer.

This study aimed to identify the clinical predictors for the response of patients with mCRPC to ARATs.

We retrospectively collected data on consecutive patients who were diagnosed with mCRPC and underwent ARAT treatment during this stage of the disease. Clinical parameters were obtained through medical chart reviews. ARAT failure was defined as a continuous increase in the serum prostate-specific antigen (PSA) level above nadir to > 2 ng/mL, accompanied by radiographic progression. ARAT failure-free survival and overall survival were assessed through Kaplan-Meier survival analysis and Cox regression survival analysis. Nomogram analysis based on significant predictors of ARAT failure-free survival was performed.

In total, 319 patients with mCRPC who underwent ARAT were included. Multivariate analysis revealed that age, International Society of Urological Pathology (ISUP) grading, and chemotherapy-naïve status were significant predictors of ARAT failure-free survival. For overall survival, age, ISUP grading, and nadir PSA level during androgen deprivation therapy (ADT) were significant predictors. Through nomogram analysis based on age, ISUP grading, and chemotherapy-naïve status, the likelihood of ARAT duration being more or less than 1 year could be predicted.

For mCRPC patients, being older, having ISUP Grade 5 cancer, and having a history of chemotherapy were associated with a shorter duration of response to next-line ARATs. Therefore, other therapeutic agents should be prioritized for such patients. Notably, among the included patients, those who were older, had a higher ISUP grade and a higher nadir PSA level during ADT exhibited worse overall survival.

Puerto Rican (PR) Hispanic/Latino (H/L) men are an understudied population that has the highest prostate cancer (PCa) specific mortality among other Hispanic populations. Little information is known about the higher mortality in PR H/L men. It is thought that epigenetic changes in key genes may play a critical role in aggressive tumors. We aimed to identify key 5-hydroxymethylcytosine (5hmC) changes in PR H/L men with aggressive PCa. We performed sequencing analysis using the 5hmC-enriched DNA from 22 prostate tumors and 24 adjacent normal FFPE samples. We identified 808 differentially methylated genes (DMGs) in tumors compared to adjacent normal tissues (FDR<0.05, log2FC>|0.4|). Pathway analysis of DMGs demonstrated that DNA repair pathway was most upregulated in tumors. Since 5hmC abundance positively correlates with gene expression levels, we further investigated 808 DMGs in TCGA PCa gene expression data. Further, we identified 59 DMGs (80.1%, FDR<0.05, ΔGE (gene expression) >|1|) with significant gene expression changes in the same direction. Additionally, we identified 111 aggressiveness-related DMGs, of which, two hypomethylated genes ( CCDC122 , NUDT15 ) and four hypermethylated genes ( PVT1 , RPL30 , TRMT12 , UBR5 ) were found to be altered at transcriptomic level in a concordant manner in PR H/L PCa patients (N=86). The aberrant 5hmC (N=55) and GE (N=497) changes in these six genes were also associated with progression-free survival in the mixed PCa population. In conclusion, our study identified 59 DMGs showing concordant epigenetic and transcriptomic changes in tumor tissues and 111 DMGs showing association with aggressive PCa among PR H/L men.

Introduction: Radium-223 dichloride (radium-223) is a bone-targeting radioisotope therapy that aids in the survival of patients with metastatic castration-resistant prostate cancer (mCRPC) to bones. This study aimed to describe the clinical characteristics and outcomes of patients with mCRPC treated with radium-223 in a real-world setting. Methods: This was a retrospective study of patients with mCRPC treated with radium-223 between 2016 and 2020 at the London Health Sciences Centre in London, Canada. The baseline characteristics between the patients receiving 1-3 and 4-6 treatment cycles were compared using a two-sample t-test and Chi-square test. ANOVA was used to determine if there was a difference in each diagnostic variable per treatment cycle. Kaplan-Meier curves were generated to estimate progression-free survival (PFS) and overall survival in the patients treated with different numbers of cycles. Results: Fifty eligible patients were identified. The median age was 71 years (IQR: 66-76). Most patients (62%) received radium-223 beyond the third-line treatment. The mean number of radium-223 treatments was four. While 60% of the patients received 4-6 injections, 40% received 1-3 injections. Fifty-eight percent (58%) of the patients demonstrated a clinical benefit, with the remainder expressing either disease progression (28%) or stable disease (10%). The patients treated with 4-6 cycles had a delay to disease progression compared to those given 1-3 cycles of radium-223 (F5,35 = 10.52, p < 0.001). A higher alkaline phosphatase level prior to treatment was associated with a longer PFS (z33 = 2.362, p = 0.018). Treatment-related hospitalization for skeletal-related events was noted in 8% of the patients, and 14% required treatment discontinuation due to hematologic toxicity. Conclusions: This study confirms the safety of radium-223 in patients with mCRPC in a real-world setting. The radium-223 treatment was associated with a clinical benefit in the majority of the patients, particularly in those with higher pre-treatment serum alkaline phosphatase levels. Further studies to identify the predictive biomarkers are warranted to better guide the contemporary use of radium-223.

MicroRNAs are a conserved class of small, tissue-specific, non-coding RNAs that regulate gene expression to preserve cellular homeostasis. Proper miRNA expression is crucial for physiological balance because it affects numerous genetic pathways, including cell cycle control, proliferation, and apoptosis, through gene expression targeting. Deregulated miRNA expression has been implicated in several cancer types, including prostate cancer (PC), acting as tumor suppressors or oncogenes. Despite the availability of promising therapies to control tumor growth and progression, effective diagnostic and therapeutic strategies for different types of cancer are still lacking. PC continues to be a significant health challenge, particularly its castration-resistant (CRPC) form, which presents major therapeutic obstacles because of its resistance to conventional androgen deprivation treatments. This review explores miRNAs' critical roles in gene regulation and cancer biology, as well as various miRNA delivery systems, highlighting their potential and the challenges in effectively targeting cancer cells. It aims to provide a comprehensive overview of the status of miRNA research in the fight against CRPC, summarizing miRNA-based therapies' successes and limitations. It also highlights the promise of miRNAs as therapeutic agents for CRPC, underlining the need for further research to overcome existing challenges and move these therapies toward clinical applications.

Tumors have long posed a significant threat to human life and health, and the messenger ribonucleic acid (mRNA) vaccine is seen as an attractive approach for cancer immunotherapy due to its developmental simplicity, rapid manufacture, and increased immune safety and efficiency. In this review, we have summarized details of the developmental history of mRNA vaccines, discussed the basic molecular structure and the effect on the stable and translation level of mRNA, analyzed the underlying immune efficiency and mechanisms on tumors, and assessed the current status of clinical research. We explored the treatment and application prospects of mRNA vaccines, aiming to provide perspectives on the future of mRNA tumor vaccines for ongoing clinical research.

Data are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy.

This retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or nonmetastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis.

This study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive (38.47 (95% CI = 32.84-NA) vs. 34.19 (95% CI = 33.33-38.83; P = .03)), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses.

Outcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

Abiraterone and enzalutamide are two androgen receptor pathway inhibitors approved, among others, for the treatment of metastatic castration-resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based regimen. Although hematological effects, especially neutropenia, are one of the main complications of other oral antineoplastic drugs, these adverse effects are infrequent in the case of androgen receptor pathway inhibitors.

We report the case of a patient diagnosed with metastatic castration-resistant prostate cancer who discontinued an androgen receptor pathway inhibitor due to drug-related grade 4 neutropenia. His control blood counts before enzalutamide starting were normal. After one month of treatment, he developed a grade 4 neutropenia, with complete neutrophil count recovery four weeks later. He underwent a bone marrow aspiration, which revealed normocelullar results, and enzalutamide was restarted. Three weeks later, the treatment was eventually discontinued due to neutropenia reappearance. Neutrophil count recovery was achieved one month later. Then, he started treatment with abiraterone, but two weeks later neutropenia reappeared. Abiraterone was withdrawn, and the patient recovered from neutropenia 2 weeks later.

This case exposes not only the occurrence of rare toxicity of two individual drugs but also the description of a probable drug-class adverse event not reported before. The patient recovered from neutropenia after the androgen receptor pathway inhibitor was withdrawn, thereby supporting the diagnosis of probable drug-induced neutropenia.

There is scarce evidence in the literature concerning androgen receptor pathway inhibitor-related neutropenia. However, its life-threatening potential cannot be ignored, so healthcare professionals should be warned of the possibility of the occurrence of such adverse reactions.

Androgen-regulated DNA damage response (DDR) is one of the essential mechanisms in prostate cancer (PCa), a hormone-sensitive disease. The heterogeneous nuclear ribonucleoprotein K (hnRNPK)-homology splicing regulatory protein known as far upstream element-binding protein 2 (KHSRP) is an RNA-binding protein that can attach to AU-rich elements in the 3' untranslated region (3'-UTR) of messenger RNAs (mRNAs) to mediate mRNA decay and emerges as a critical regulator in the DDR to preserve genome integrity. Nevertheless, how KHSRP responds to androgen-regulated DDR in PCa development remains unclear. This study found that androgen can significantly induce acetylation of KHSRP, which intrinsically drives tumor growth in xenografted mice. Moreover, enhanced KHSRP acetylation upon androgen stimuli impedes KHSRP-regulated DDR gene expression, as seen by analyzing RNA sequencing (RNA-seq) and Gene Set Enrichment Analysis (GSEA) datasets. Additionally, NAD-dependent protein deacetylase sirtuin-7 (SIRT7) is a promising deacetylase of KHSRP, and androgen stimuli impairs its interaction with KHSRP to sustain the increased KHSRP acetylation level in PCa. We first report the acetylation of KHSRP induced by androgen, which interrupts the KHSRP-regulated mRNA decay of the DDR-related genes to promote the tumorigenesis of PCa. This study provides insight into KHSRP biology and potential therapeutic strategies for PCa treatment, particularly that of castration-resistant PCa.

Cancer cells exhibit altered metabolic pathways, prominently featuring enhanced glycolytic activity to sustain their rapid growth and proliferation. Dysregulation of glycolysis is a well-established hallmark of cancer and contributes to tumor progression and resistance to therapy. Increased glycolysis supplies the energy necessary for increased proliferation and creates an acidic milieu, which in turn encourages tumor cells' infiltration, metastasis, and chemoresistance. Circular RNAs (circRNAs) have emerged as pivotal players in diverse biological processes, including cancer development and metabolic reprogramming. The interplay between circRNAs and glycolysis is explored, illuminating how circRNAs regulate key glycolysis-associated genes and enzymes, thereby influencing tumor metabolic profiles. In this overview, we highlight the mechanisms by which circRNAs regulate glycolytic enzymes and modulate glycolysis. In addition, we discuss the clinical implications of dysregulated circRNAs in cancer glycolysis, including their potential use as diagnostic and prognostic biomarkers. All in all, in this overview, we provide the most recent findings on how circRNAs operate at the molecular level to control glycolysis in various types of cancer, including hepatocellular carcinoma (HCC), prostate cancer (PCa), colorectal cancer (CRC), cervical cancer (CC), glioma, non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer (GC). In conclusion, this review provides a comprehensive overview of the significance of circRNAs in cancer glycolysis, shedding light on their intricate roles in tumor development and presenting innovative therapeutic avenues.

The objective of this study was to compare the prognostic outcomes between metastatic castration-sensitive prostate cancer (mCSPC) patients receiving conventional androgen deprivation therapy (ADT) and those receiving ADT plus a novel androgen-receptor signaling inhibitor (ARSI) in routine clinical practice in Japan.

This was conducted as a retrospective multicenter study including 581 mCSPC patients, consisting of 305 receiving ADT alone or in combination with bicalutamide (group 1) and 276 receiving ADT plus one of the following ARSIs: abiraterone acetate, apalutamide, or enzalutamide (group 2). Prognostic outcomes between these 2 groups were comprehensively compared.

In the entire cohort, prostate-specific antigen-progression-free survival (PSA-PFS) in group 2 was significantly longer than that in group 1, while no significant difference was noted in overall survival (OS) between the two groups. In patients corresponding to the LATITUDE high-risk group, however, both PSA-PFS and OS in group 2 were significantly longer than those in group 1. Of several factors examined, the following were identified as independent predictors of poor PSA-PFS in the entire cohort as well as the LATITUDE high-risk group: high C-reactive protein, high lactate dehydrogenase, high alkaline phosphatase, high Gleason score, and group 1. Furthermore, it was possible to precisely classify both the entire cohort and LATITUDE high-risk group into 3 risk groups regarding PSA-PFS according to the positive numbers of independent factors: positive for ≤1 factor, favorable; 2 factors, intermediate; and ≥3 factors, poor.

Combined use of ARSIs with ADT could improve the prognostic outcomes of mCSPC patients, particularly those in the LATITUDE high-risk group, in real-world clinical practice in Japan.

Prostate cancer (PC) is a significant cause of mortality in men worldwide, hence the need for a comprehensive understanding of the molecular mechanisms underlying its progression and resistance to treatment. Heme oxygenase-1 (HO-1), an inducible enzyme involved in heme catabolism, has emerged as a critical player in cancer biology, including PC. This review explores the multifaceted role of HO-1 in PC, encompassing its function, regulation, and implications in cancer therapy. HO-1 influences cell proliferation, anti-apoptotic pathways, angiogenesis, and the tumor microenvironment, thereby influencing tumor growth and metastasis. HO-1 has also been associated with therapy resistance, affecting response to standard treatments. Moreover, HO-1 plays a significant role in immune modulation, affecting the tumor immune microenvironment and potentially influencing therapy outcomes. Understanding the intricate balance of HO-1 in PC is vital for developing effective therapeutic strategies. This review further explores the potential of targeting HO-1 as a therapeutic approach, highlighting challenges and opportunities. Additionally, clinical implications are discussed, focusing on the prognostic value of HO-1 expression and the development of novel combined therapies to augment PC sensitivity to standard treatment strategies. Ultimately, unraveling the complexities of HO-1 in PC biology will provide critical insights into personalized treatment approaches for PC patients.

Background: Circular RNAs (circRNA) have a vital role in the progression of cancers. For instance, circTP63 is upregulated in prostate cancer (PCa) tissues compared with adjacent normal tissues. However, the role of circTP63 in prostate cancer is still unclear. Methods: qRT-PCR assays were applied to detected the expression of circTP63 and miR-421 in PCa samples. Functionally, CCK-8, apoptosis assay, and transwell migration and invasion assays were used to explore the role of circTP63 in PCa progression. Mechanistically, the interaction between circTP63 and miR-421 were verified using qRT-PCR and dual-luciferase report assay. Western blot, qRT-PCR, and dual-luciferase report assay were applied to detect the interaction between miR-421 and VAMP associated protein A (VAPA). And xenograft animal model was used to detect the role of circTP63 in vivo. Results: circTP63 was upregulated and miR-421 was downregulated in PCa tissues. Functional assays revealed that circTP63 promoted the proliferation and metastasis of PCa cells in vitro. In addition, the inhibition effect of circTP63 knockdown could be rescued by miR-421 inhibition or VAPA overexpression. Mechanistically, circTP63-mediated PCa progression through directly binding to miR-421, and subsequently releasing the VAPA. In vivo, silencing of circTP63 significantly impaired PCa progression. Conclusion: In summary, our study identified circTP63 as an oncogenic circRNA, which could be a promising diagnostic and therapeutic target for PCa treatment.

Men with African ancestry have the highest incidence and mortality rates of prostate cancer (PCa) worldwide.

This study aimed to identify differentially methylated genes between tumor vs. adjacent normal and aggressive vs. indolent PCa in 121 African American patients. Epigenome-wide DNA methylation patterns in tumor DNA were assessed using the human Illumina Methylation EPIC V1 array.

Around 5,139 differentially methylated CpG-sites (q < 0.01, lΔβl > 0.2) were identified when comparing normal vs. tumor, with an overall trend of hypermethylation in prostate tumors.  Multiple representative differentially methylated regions (DMRs), including immune-related genes, such as CD40, Galectin3, OX40L, and STING, were detected in prostate tumors when compared to adjacent normal tissues. Based on an epigenetic clock model, we observed that tumors' total number of stem cell divisions and the stem cell division rate were significantly higher than adjacent normal tissues. Regarding PCa aggressiveness, 2,061 differentially methylated CpG-sites (q < 0.05, lΔβl > .05) were identified when the grade group (GG)1 was compared with GG4/5. Among these 2,061 CpG sites, 155 probes were consistently significant in more than one comparison. Among these genes, several immune system genes, such as COL18A1, S100A2, ITGA4, HLA-C, and ADCYAP1, have previously been linked to tumor progression in PCa.

Several differentially methylated genes involved in immune-oncologic pathways associated with disease risk or aggressiveness were identified. In addition, 261 African American-specific differentially methylated genes related to the risk of PCa were identified. These results can shedlight on potential mechanisms contributing to PCa disparities in the African American Population.

Second-generation androgen receptor (AR) signaling inhibitors (ARSIs), such as abiraterone and enzalutamide, prolong the life of patients with castration-resistant prostate cancer (CRPC). However, patients receiving ARSIs ultimately develop resistance through various complex mechanisms, including AR mutations, constitutively active AR-splice variants (AR-Vs), and AR overexpression. Here, we characterized a novel AR pure antagonist, TAS3681, which inhibits AR transcriptional activity and downregulates AR-full length (AR-FL) and AR-Vs. TAS3681 reduced the protein levels of AR-FL and AR-Vs including AR-V7 in enzalutamide-resistant cells (SAS MDV No. 3-14), in vitro and in vivo, showing strong antitumor efficacy in an AR-V7-positive xenograft model. In AR-overexpressing VCaP (prostate cancer) cells, conversely to enzalutamide, TAS3681 effectively suppressed cell proliferation and downregulated AR expression. Importantly, TAS3681 blocked the transcriptional activity of various mutant ARs, including mutations F877L/T878A and H875Y/T878A, which confer resistance to enzalutamide, and V716M and H875Y mutations, which confer resistance to darolutamide. Our results demonstrate that TAS3681 suppresses the reactivation of AR signaling, which causes resistance to ARSIs, via a newly identified mechanism of action. Therefore, TAS3681 could be a new therapeutic option for CRPC treatment.

Wearable technology is used to monitor and motivate physical activity (PA) and provides continuous, objective PA and sleep data outside the clinical setting. We reviewed the literature to understand how wearables are integrated into prostate cancer (PC) investigations in order to identify current practices, gaps, and research opportunities.

We conducted a literature search for articles using wearables, among PC survivors published between 2012 and 2022. We extracted study details, interventions and outcomes, participant baseline characteristics, and device characteristics and grouped them by study type: randomized control trials (RCTs) and non-randomized studies.

Of 354 articles screened, 44 met eligibility criteria (23 RCTs, and 21 non-randomized). 89% used wearables to monitor PA metrics, 11%, sleep metrics, and 6.8%, both. Most studies involved exercise (70% RCTs, 9% non-randomized studies) or lifestyle interventions (30% RCTs, 9% non-randomized studies). Intervention delivery methods included personalized computer-based (48%), in-person (e.g., trainer) (20%), and education web or print-based (20%). Interventions occurred at the participant's home (48%) or at a gym (20%). 57% of the studies evaluated the feasibility and acceptability of the wearable as an activity-measuring device or as part of a remotely delivered computer-based intervention. Studies used wearables to monitor adherence to PA interventions, motivate behavior change, to assess patient outcomes (e.g., patient function, quality of life, mood), or as data collection tools.

Wearables are primarily being used to assess daily activity and monitor adherence to exercise interventions in clinical studies involving PC survivors. Findings suggest that they are feasible for use in this population. More research is needed to understand how to integrate wearables into routine clinical care, expand their use to predict clinical outcomes, or to deliver tailored interventions for PC survivors.

Prostate cancer (PCa) is one of the most common malignant epithelial tumors in men worldwide. PCa patients are initially sensitive to chemotherapy, but patients in the advanced stages of PCa eventually develop resistance, leaving them with limited therapeutic options. Therefore, it is very important to screen new drugs for treating PCa. Salvia miltiorrhiza is a common Chinese herbal medicine used in some Asian countries. It has many functions and is widely used to treat a variety of diseases, including heart diseases and cancers. For the past few years, research has shown that liposoluble constituents of tanshinones (TANs), including cryptotanshinone, TAN IIA, dihydrotanshinone I, and TAN I, exhibit good anticancer activity in PCa. In this study, we review the progress of TAN compounds (cryptotanshinone, TAN IIA, dihydrotanshinone I, and TAN I) in treating PCa over the past decade. These compounds can act on the same molecular mechanisms, as they have a very similar structure; they are also found to work slightly differently in PCa. According to current studies, compared with other TAN compounds, TAN IIA appears to hold more potential for treating PCa. The toxicity, side effects or biodistribution of Salvia miltiorrhiza and these four TANs need to be confirmed with further research. Findings obtained in this study may provide important information for the potential clinical application of cryptotanshinone, TAN IIA, dihydrotanshinone I, and TAN I in the treatment of PCa.

To explore the mechanism of tumor-associated fibroblasts (CAFs) for regulating proliferation and migration of prostate cancer (PCa) cells.

We conducted a bioinformatics analysis to identify miRNAs with high expression in PCa. The proliferation, migration and hsa-miR-18b-5p expression levels were observed in PCa cells co-cultured with CAFs. We further examined hsa-miR-18b-5p expression level in 20 pairs of PCa and adjacent tissue samples and in different PCa cell lines and normal epithelial cells using RT-qPCR. In PCa cell lines C4-2 and LNCAPNC, the effects of transfection with a hsa-miR-18b-5p inhibitor on cell proliferation, migration, invasion, drug resistance, apoptosis and cell cycle were evaluated, and the effects of has-miR-18b-5p knockdown on C4-2 cell xenograft growth and mouse survival were observed in nude mice. Dual luciferase reporter gene assay was used to validate the targeting relationship between hsa-miR-18b-5p and its target genes, whose expressions were detected in PCa cells using RT-qPCR and Western blotting.

The expression of hsa-miR-18b-5p was significantly increased in the co-culture of CAFs and PCa cell lines, which exhibited significantly enhanced proliferation and migration abilities. Transfection with has-miR-18b-5p inhibitor strongly attenuated the effect of CAFs for promoting proliferation and migration of PCa cells, and in C4-2 and LNCAP cells cultured alone, inhibition of hsa-miR-18b-5p obviously suppressed cell proliferation, migration, invasion, and drug resistance. In the tumor-bearing mice, hsa-miR-18b-5p knockdown in the transplanted cells significantly inhibited xenograft growth and increased the survival time of the mice. Target gene prediction suggested that FBXL3 was a potential target of hsa-miR-18b-5p, and dual luciferase reporter gene confirmed a binding site between them. In C4-2 and LNCAP cells, hsa-miR-18b-5p knockdown resulted in significantly increased expression levels of FBXL3.

CAFs promotes proliferation and migration of PCa cells by up-regulating hsa-miR-18b-5p to suppress FBXL3 expression.

This study analyzed the risk factors associated with positive surgical margins (PSM) and five-year survival after prostate cancer resection to construct a positive margin prediction model.

We retrospectively analyzed the clinical data of 148 patients treated with prostatectomy. The patients were divided into PSM group and Negative surgical margins (NSM) group. Several parameters were compared between the groups. All patients were followed up for 60 months. The risk factors for PSM and five-year survival were evaluated by univariate analysis, followed by multifactorial dichotomous logistic regression analysis. Finally, ROC curves were plotted for the risk factors to establish a predictive model for PSM after prostate cancer resection.

(1) Serum PSA, percentage of positive puncture stitches, clinical stage, surgical approach, Gleason score on puncture biopsy, and perineural invasion were significantly associated with the risk of PSM (P < 0.05). Serum PSA, perineural invasion, Gleason score on puncture biopsy, and percentage of positive puncture stitches were independent risk factors for PSM. (2) Total prostate-specific antigen (tPSA) by puncture, nutritional status, lymph node metastasis, bone metastasis, and seminal vesicle invasion may be risk factors for five-year survival. Lymph node metastasis and nutritional status were the main risk factors for the five-year survival of patients with prostate cancer. (3) After plotting the ROC curve, the area under the curve (AUC) [AUC: 0.776, 95%, confidence interval (CI): 0.725 to 0.854] was found to be a valid predictor of PSM; the AUC [AUC: 0.664, 95%, confidence interval (CI): 0.576 to 0.753] was also a valid predictor of five-year survival (P < 0.05). (4) The scoring system had a standard error of 0.02 and a cut-off value of 6. It predicted PSM after prostate cancer resection with moderate efficacy.

Serum PSA, perineural invasion, puncture biopsy Gleason score, and percentage of positive puncture stitches were independent risk factors for positive surgical margins (PSM). Also, lymph node metastasis and nutritional status were the main risk factors for the five-year survival of patients with prostate cancer. Overall, the prediction efficacy of this scoring system concerning the risk of PSM after prostate cancer resection was moderate.

The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer (PCa) as well as to elucidate biological mechanisms underlying the associations. We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify risk-associated circRNAs by using the MiOncoCirc database. We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls, and identified circHIBADH rs11973492 T>C as a significant risk-associated variant (odds ratio = 1.20, 95% confidence interval: 1.08-1.34, P = 7.06 × 10 -4) in a dominant genetic model, which altered the secondary structure of the corresponding RNA chain. In the in silico analysis, we found that circHIBADH sponged and silenced 21 RNA-binding proteins (RBPs) enriched in the RNA splicing pathway, among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house (four tissue samples) and publicly available single-cell transcriptomes. Additionally, we demonstrated that HNRNPA1 influenced hallmarks including MYC target, DNA repair, and E2F target signaling pathways, thereby promoting carcinogenesis. In conclusion, genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1, playing an oncogenic role in PCa.

Advanced prostate cancer (PCa) is usually treated initially with androgen deprivation therapy (ADT). Although they experience a period of disease regression, most patients progress to metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC now have an unprecedented number of approved treatment options, including chemotherapies, hormone therapies, targeted therapies, etc. However, the improvement of overall survival (OS) in patients with mCRPC and its special subtype neuroendocrine prostate cancer (NEPC) is limited. In recent years, with the use of immune checkpoint inhibitors (ICIs), such as PD1/PDL1 and CTLA4 inhibitors, immunotherapy has once again become a promising treatment choice to stimulate antitumor immunity. However, the efficacy of NEPC receiving ICI has not been reported. Here, we describe a patient with mCRPC who developed primary resistance to current endocrine and chemotherapy regimens and progressed to mCRPC with NEPC as the main component, showing a significant and lasting response to PD1 monoclonal antibody combined with radiotherapy.