Prognostic Marker In Prostate Cancer Research Articles

Identification of KLHL17 as a prognostic marker for prostate cancer based on single-cell sequencing and in vitro/in vivo experiments

BackgroundProstate cancer (PCa) is a leading cause of cancer-related mortality among men, characterized by significant heterogeneity that complicates diagnosis and treatment.Methods and resultsTo enhance our understanding of PCa, we utilized single-cell RNA sequencing (scRNA-seq) data to identify distinct malignant epithelial cell subpopulations and their molecular characteristics. By integrating scRNA-seq data with bulk RNA-seq data, we constructed a prognostic risk score model. The influence of key genes identified in the risk score on PCa was validated through both in vitro and in vivo experiments. Our study revealed eight unique malignant epithelial cell clusters, each exhibiting distinct molecular characteristics and biological functions. KEGG and GO enrichment analyses highlighted their involvement in various pathways. The prognostic risk score model demonstrated strong predictive power for patient outcomes, particularly in predicting progression-free survival (PFS). Notably, KLHL17, identified as a high-risk gene, was found to significantly impact PCa cell proliferation, migration, invasion, and apoptosis upon knockdown. This finding was further validated in vivo using a subcutaneous xenograft tumor model, where reduced KLHL17 expression led to decreased tumor growth.ConclusionOur research provides a comprehensive analysis of PCa heterogeneity and highlights KLHL17 as a potential therapeutic target.

Unveiling four axes ADAMTS9-AS2|MEG3/hsa-miR-150/PRKCA|MMP14 within prostate cancer through establishment of the ceRNA network

Prostate cancer is among the most common cancers in males. Recent application of system biology methods has resulted in identification of key genes in the process of carcinogenesis. In the current study, we selected two datasets related to prostate cancer (PCa) and performed bulk RNA-seq analysis by selecting samples with Gleason scores greater than 7 and combining them. Subsequently, using several systems biology approaches, we constructed the ceRNA network and ultimately identified key axes related to PCa. Our analyses revealed importance of ADAMTS9-AS2/miR-150/PRKCA, ADAMTS9-AS2/miR-150/MMP14, MEG3/miR-150/PRKCA and MEG3/miR-150/MMP14 with miR-150 being a central component. Remarkably, miR-150 exhibited strong statistical significance in survival analyses. Further, analyzing expression levels from TCGA datasets, the expression of the identified genes associates significantly with prostate cancer compared to normal tissue confirming the bioinformatic analyses. Therefore, these genes can be regarded as prognostic markers in prostate cancer and the pathways are potential targets for therapeutic interventions.

Identification of prostate cancer bone metastasis related genes and potential therapy targets by bioinformatics and invitro experiments.

The aetiology of bone metastasis in prostate cancer (PCa) remains unclear. This study aims to identify hub genes involved in this process. We utilized machine learning, GO, KEGG, GSEA, Single-cell analysis, ROC methods to identify hub genes for bone metastasis in PCa using the TCGA and GEO databases. Potential drugs targeting these genes were identified. We validated these results using 16 specimens from patients with PCa and analysed the relationship between the hub genes and clinical features. The impact of APOC1 on PCa was assessed through invitro experiments. Seven hub genes with AUC values of 0.727-0.926 were identified. APOC1, CFH, NUSAP1 and LGALS1 were highly expressed in bone metastasis tissues, while NR4A2, ADRB2 and ZNF331 exhibited an opposite trend. Immunohistochemistry further confirmed these results. The oxidative phosphorylation pathway was significantly enriched by the identified genes. Aflatoxin B1, benzo(a)pyrene, cyclosporine were identified as potential drugs. APOC1 expression was correlated with clinical features of PCa metastasis. Silencing APOC1 significantly inhibited PCa cell proliferation, clonality, and migration invitro. This study identified 7 hub genes that potentially facilitate bone metastasis in PCa through mitochondrial metabolic reprogramming. APOC1 emerged as a promising therapeutic target and prognostic marker for PCa with bone metastasis.

Disulfidptosis-related genes serve as potential prognostic biomarkers and indicate tumor microenvironment characteristics and immunotherapy response in prostate cancer

Disulfidptosis, a newly identified programmed cell death pathway in prostate cancer (PCa), is closely associated with intracellular disulfide stress and glycolysis. This study aims to elucidate the roles of disulfidptosis-related genes (DRGs) in the pathogenesis and progression of PCa, with the goal of improving diagnostic and therapeutic approaches. We analyzed PCa datasets and normal tissue transcriptome data from TCGA, GEO, and MSKCC. Using consensus clustering analysis and LASSO regression, we developed a risk scoring model, which was validated in an independent cohort. The model's predictive accuracy was confirmed through Kaplan–Meier curves, receiver operating characteristic (ROC) curves, and nomograms. Additionally, we explored the relationship between the risk score and immune cell infiltration, and examined the tumor microenvironment and somatic mutations across different risk groups. We also investigated responses to immunotherapy and drug sensitivity. Our analysis identified two disulfidosis subtypes with significant differences in survival, immune environments, and treatment responses. According to our risk score, the high-risk group exhibited poorer progression-free survival (PFS) and higher tumor mutational burden (TMB), associated with increased immune suppression. Functional enrichment analysis linked high-risk features to key cancer pathways, including the IL-17 signaling pathway. Moreover, drug sensitivity analysis revealed varied responses to chemotherapy, suggesting the potential for disulfidosis-based personalized treatment strategies. Notably, we identified PROK1 as a crucial prognostic marker in PCa, with its reduced expression correlating with disease progression. In summary, our study comprehensively assessed the clinical implications of DRGs in PCa progression and prognosis, offering vital insights for tailored precision medicine approaches.

Deposition of collagen III and alterations in basement membrane integrity as candidate prognostic markers in prostate cancer

The extracellular matrix surrounding the tumor undergoes changes in its organization during the metastasis process. The present study aims to quantify total collagen, collagen I (Col I) and collagen III (Col III), analyze the alignment of collagen fibers and assess the basement membrane integrity in samples from patients with metastatic and non-metastatic prostate cancer. Tissue samples from 60 patients were classified into groups based on prognostic parameters: better prognosis (n = 20), worse prognosis without metastasis (n = 23) and metastatic (n = 17). Picrosirius red with further analysis under polarizing microscope was used to quantify (with validation using immunohistochemistry) and analyze collagen alignment, and Periodic Acid Schiff staining was used to analyze the basement membrane integrity. The Col I/Col III ratio was found to be higher in the metastatic group than in the groups with better prognosis (p = 0.012) and worse prognosis without metastasis (p = 0.018). Basement membrane integrity constitution in malignant tumor tissue differed from that of adjacent non-tumor tissue (p < 0.001). Moreover, the worsening in the tumor tissue integrity was positively correlated with worse prognostic parameters. All in all, absence of Col III and basement membrane integrity might be indicators of poor prognosis in prostate cancer.

AAT resistance-related AC007405.2 and AL354989.1 as novel diagnostic and prognostic markers in prostate cancer.

Prostate cancer (PCa) is the second disease threatening men's health, and anti-androgen therapy (AAT) is a primary approach for treating this condition. Increasing evidence suggests that long non-coding RNAs (lncRNAs) play crucial roles in the development of PCa and the process of AAT resistance. The objective of this study is to utilize bioinformatics methods to excavate lncRNAs association with AAT resistance and investigate their biological functions. AAT resistance-related risk score model (ARR-RSM) was established by multivariate Cox analysis. Paired clinical tissue samples of 36 PCa patients and 42 blood samples from patients with PSA over 4 ng/ml were collected to verify the ARR-RSM. In vitro, RT-qPCR, CCK-8 and clone formation assays were displayed to verify the expression and function of AL354989.1 and AC007405.2. Pearson correlation analysis identified 996 lncRNAs were associated with AAT resistance (ARR-LncRs). ARR-RSM was established using multivariate Cox regression analysis, and PCa patients were divided into high-risk and low-risk groups. High-risk patients showed increased expression of AL354989.1 and AC007405.2 had poorer prognoses. The high-risk score correlated with advanced T-stage and N-stage. The AUC of ARR-RSM outperformed tPSA in diagnosing PCa. Silencing of AC007405.2 and AL354989.1 inhibited PCa cells proliferation and AAT resistance. In this study, we have discovered the clinical significance of AC007405.2 and AL354989.1 in predicting the prognosis and diagnosing PCa patients. Furthermore, we have confirmed their correlation with various clinical features. These findings provide potential targets for PCa treatment and a novel diagnostic and predictive indicator for precise PCa diagnosis.

Impact of Circulating Tumor Cell-Expressed Prostate-Specific Membrane Antigen and Prostate-Specific Antigen Transcripts in Different Stages of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer micrometastases. This study evaluated whether a circulating tumor cell (CTC)-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in prostate cancer. We prospectively enrolled 21 healthy individuals and 247 patients with prostate cancer [localized prostate cancer (LPCa), n = 94; metastatic hormone-sensitive prostate cancer (mHSPC), n = 44; and metastatic castration-resistant prostate cancer (mCRPC), n = 109]. The mRNA expression of six transcripts [PSMA, prostate-specific antigen (PSA), AR, AR-V7, EpCAM, and KRT 19] from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. CTC detection rates were 75.5%, 95.3%, and 98.0% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA [hazard ratio (HR), 3.35; P = 0.028) and PSA mRNA (HR, 1.42; P = 0.047] expressions were associated with BCR. Patients with mHSPC with high PSMA (HR, 4.26; P = 0.020) and PSA mRNA (HR, 3.52; P = 0.042) expressions showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expressions were significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. PSMA and PSA mRNA expressions are associated with BCR in LPCa. In advanced prostate cancer, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.

Abstract LB110: Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate cancer

Abstract PurposeProstate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer (PCa) micrometastases. This study evaluated whether a circulating tumor cell (CTCs-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in PCa. Experimental design We prospectively enrolled 21 healthy individuals and 247 patients with PCa (localized PCa [LPCa]: 94; metastatic hormone-sensitive PCa [mHSPC]: 44; and metastatic castration-resistant PCa [mCRPC]: 109). The mRNA expression of six transcripts (PSMA, prostate-specific antigen [PSA], AR, AR-V7, EpCAM, and KRT 19) from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. Results CTC detection rates were 75.5%, 95.3%, and 98% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA (hazard ratio [HR]: 3.35; P=0.028) and PSA mRNA (HR: 1.42; P=0.047) expression was associated with BCR. mHSPC patients with high PSMA (HR: 4.26; P=0.020) and PSA mRNA (HR: 3.52; P=0.042) expression showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expression was significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. Conclusion PSMA and PSA mRNA expression is associated with BCR in LPCa. In advanced PCa, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance. Citation Format: Hyungseok Cho, Seok-Soo Byun, Nak-Hoon Son, Jae Il Chung, Won Ik Seo, Chan Ho Lee, Todd M Morgan, Ki-Ho Han, Jae-Seung Chung. Impact of circulating tumor cell-expressed prostate-specific membrane antigen and prostate-specific antigen transcripts in various stages of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB110.

Abstract 2993: TmiS: A prognostic indicator for prostate cancer survival based on total tumor cell miRNA levels

Abstract Background: MicroRNAs (miRNAs) are small noncoding RNAs that bind mRNA and inhibit translation or encourage degradation. MiRNAs play a significant regulatory role, with approximately 60% of protein-coding genes harboring miRNA binding sites. MiRNA dysregulation is associated with tumor onset, growth, and metastasis. These important regulatory RNAs have been studied as potential cancer biomarkers, yet the widespread adoption of any miRNA signature has been hindered by the variable nature of miRNA targeting, which is highly context specific. Total tumor cell mRNA content, or TmS, has been shown to have potential as a pan-cancer prognostic indicator. Here we expand the TmS framework using deconvolved miRNA expression to calculate TmiS, an estimate of total tumor-cell miRNA content and investigate the utility of TmiS as a prognostic marker in prostate cancer. Methods: Whole exome sequencing and miRNA sequencing, along with clinical annotations were downloaded for prostate cancer patient samples from The Cancer Genome Atlas (TCGA). Sample purity and ploidy were estimated from exomes using ASACT and ABSOLUTE. Tumor miRNA proportion was estimated using our previously developed miRNA deconvolution method DeMixMir, and TmiS, the total miRNA content per haploid genome per tumor cell, was calculated for each sample. Patients were separated by Gleason category and were binarized into High-TmiS and Low-TmiS within samples with Gleason 7 and Gleason 8+ scores separately. Results: We find Low-TmiS patients to have significantly better prognosis in both Gleason 7 (P = 0.04) and Gleason 8+ (P = 0.01) prostate cancer. We confirm that TmiS is indeed an aggregate measure of total miRNA levels, with no strong correlations observed with any one miRNA. We identify differentially expressed miRNAs and mRNAs between high and low TmiS, and find distinct enriched pathways between Gleason 7 and Gleason 8+ samples, and that several of the differentially expressed miRNAs are well-characterized cancer-related transcripts. Conclusions: In spite of their important regulatory function, the variable and context specific nature of miRNA targeting has been a barrier to their implementation as a robust biomarker. We find TmiS to be a measure of total miRNA dysregulation, and that patients with high total miRNA content show poorer survival within prostate samples graded at Gleason 7 (as well as Gleason 8+), which has been a challenging group for further risk classification. In summary, while the consequences of miRNA dysregulation are subtype specific, we find that by measuring total tumor cell miRNA, TmiS has potential as a robust prognostic indicator independent cellular context. Citation Format: Matthew Montierth, Kinga Németh, George A. Calin, Wenyi Wang. TmiS: A prognostic indicator for prostate cancer survival based on total tumor cell miRNA levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2993.

A Phase II Study of Rucaparib Monotherapy in Nonmetastatic, Hormone-Sensitive Prostate Cancer Demonstrating "BRCAness" Genotype (ROAR).

Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms. This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle. The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen. Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946).

Ubiquitin B, Ubiquitin C, and β-Catenin as Promising Diagnostic and Prognostic Tools in Prostate Cancer.

Prostate cancer (PC) is a major global public health concern, imposing a significant burden on men and ranking as the second most prevalent malignancy. This study delves into the intricate world of ubiquitination processes and expression regulation, with a specific focus on understanding the roles of ubiquitin B (UBB), ubiquitin C (UBC), and β-Catenin in PC development. We thoroughly analyze the expression profiles of UBB, UBC, and β-Catenin, investigating their interactions and associations with clinical and histopathological data. These findings offer valuable insights into their potential as robust prognostic markers and their significance for patient survival. Our research uncovers the upregulation of UBB and UBC expression in PC tissues, and an even more pronounced expression in lymph node metastases, highlighting their pivotal roles in PC progression. Moreover, we identify a compelling correlation between high UBB and UBC levels and diminished overall survival in PC patients, emphasizing their clinical relevance. Additionally, we observe a significant reduction in membranous β-Catenin expression in PC tissues. Importantly, abnormal β-Catenin expression is strongly associated with shorter survival in PC patients and serves as a significant, independent prognostic factor for patient outcomes. Kaplan-Meier survival analysis indicates that patients with tumors characterized by simultaneous UBB and aberrant β-Catenin expression exhibit the poorest overall survival. These collective insights underline the clinical importance of evaluating UBB, UBC, and β-Catenin as combined prognostic markers in PC.

A Study of Ki-67 Immunostaining in Prostate Carcinomas and Its Correlation with Gleason's Score and Prognosis: An Experience at a Tertiary Centre in the Himalayan Foothills.

Prostate cancer is a significant cause of cancer-related mortality among men worldwide, necessitating the exploration of prognostic biomarkers to aid in accurate risk assessment and treatment decision-making. This cross-sectional study aimed to comprehensively evaluate the role of Ki-67 as a prognostic marker in prostate cancer by examining its association with clinicopathological parameters. A total of 102 archived cases of prostate core biopsy specimens, histopathologically reported as prostate carcinoma, were included in this study. Histopathological grading was conducted using Gleason's scoring and grading system based on morphology. The statistical software "R" was utilized for data analysis. Kruskal-Wallis test and Fisher's exact test were employed to analyze the association between Ki-67 expression and clinicopathological parameters. The study revealed significant correlations between Ki-67 expression and various clinicopathological parameters in prostate cancer cases. High Ki-67 expression levels were associated with higher Gleason scores, increased incidence of perineural invasion, advanced T stages, lymph node metastasis, presence of distant metastasis, and higher prognostic stage groups. The findings of this cross-sectional study support the potential of Ki-67 as a prognostic marker in prostate cancer. The significant associations observed between Ki-67 expression and clinicopathological parameters indicate its usefulness in risk stratification and treatment decision-making. The incorporation of histopathological grading, including Gleason scoring, and analysis of perineural invasion strengthens the validity of the study. Ki-67, in combination with morphological assessments, provides valuable prognostic information for prostate cancer patients.

MicroRNAs as biomarkers in prostate cancer: A mini review

Among men one of the most common cancers identified globally is prostate cancer. Although the serum prostate specific antigen remains important for prognosis and diagnosis, the PSA assay is not highly accurate. In the search for improved minimally invasive methods as a biomarker, the expression patterns of circulating miRNAs have a potential importance and are emerging as a promising candidate as prognostic markers for prostate cancer.

Pretreatment level of serum sialic acid predicts both qualitative and quantitative bone metastases of prostate cancer.

Recently, serum sialic acid (SA) has emerged as a distinct prognostic marker for prostate cancer (PCa) and bone metastases, warranting differential treatment and prognosis for low-volume (LVD) and high-volume disease (HVD). In clinical settings, evaluating bone metastases can prove advantageous. We aimed to establish the correlation between SA and both bone metastasis and HVD in newly diagnosed PCa patients. We conducted a retrospective analysis of 1202 patients who received a new diagnosis of PCa between November 2014 and February 2021. We compared pretreatment SA levels across multiple groups and investigated the associations between SA levels and the clinical parameters of patients. Additionally, we compared the differences between HVD and LVD. We utilized several statistical methods, including the non-parametric Mann-Whitney U test, Spearman correlation, receiver operating characteristic (ROC) curve analysis, and logistic regression. The results indicate that SA may serve as a predictor of bone metastasis in patients with HVD. ROC curve analysis revealed a cut-off value of 56.15 mg/dL with an area under the curve of 0.767 (95% CI: 0.703-0.832, P < 0.001) for bone metastasis versus without bone metastasis and a cut-off value of 65.80 mg/dL with an area under the curve of 0.766 (95% CI: 0.644-0.888, P = 0.003) for HVD versus LVD. Notably, PCa patients with bone metastases exhibited significantly higher SA levels than those without bone metastases, and HVD patients had higher SA levels than LVD patients. In comparison to the non-metastatic and LVD cohorts, the cohort with HVD exhibited higher levels of alkaline phosphatase (AKP) (median, 122.00 U/L), fibrinogen (FIB) (median, 3.63 g/L), and prostate-specific antigen (PSA) (median, 215.70 ng/mL), as well as higher Gleason scores (> 7). Multivariate logistic regression analysis demonstrated that an SA level of > 56.15 mg/dL was independently associated with the presence of bone metastases in PCa patients (OR = 2.966, P = 0.018), while an SA level of > 65.80 mg/dL was independently associated with HVD (OR = 1.194, P = 0.048). The pretreatment serum SA level is positively correlated with the presence of bone metastases.

Expression of the microtubule-associated protein 2 (MAP2) as a potential independent prognostic marker in prostate cancer

PurposeInvestigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer.Material and MethodsMAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay.ResultsMAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001).ConclusionThe present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities.

Immunohistochemical Expression Status of HER2/neu and E-cadherin in Prostate Adenocarcinoma: A Cross-sectional Study

Introduction: Prostate cancer is a common tumour, accounting for 92% of malignancies in the male genital tract. Due to the high recurrence rate, it is important to identify prognostic markers in prostate cancer. Human Epidermal Growth Factor Receptor 2 (HER2) and Epithelial cadherin (E-cadherin) are speculated to be associated with carcinogenesis, but the literature has provided controversial results. Aim: To investigate the expression of HER2/neu and E-cadherin in prostatic adenocarcinoma and its correlation with clinicopathological parameters. Materials and Methods: A retrospective cross-sectional study was conducted at the Department of Pathology, SDM University, Dharwad, Karnataka, India. The study duration was one year and five months, from October 2020 to March 2022. A total of 45 cases diagnosed as prostatic adenocarcinoma between October 2016 and September 2019 were included. Clinicopathological parameters such as age, Prostate- Specific Antigen (PSA) levels, metastasis, perineural invasion, Gleason score, Gleason grade, and two-year survival were retrieved from hospital records and through telephone interviews. Immunohistochemistry (IHC) staining for HER2 and E-cadherin was performed and assessed by pathologists. Statistical analysis was conducted using Statistical Package for Social Sciences (SPSS) version 20.0, and the Chi-square test was applied. Results: The mean age of the study participants was 69.6 years, ranging from 52 to 95 years. The rates of HER2/neu overexpression/positivity and reduced E-cadherin expression were 25 (55.5%) and 14 (31.1%), respectively. No statistically significant associations were found between HER2 and E-cadherin expression and age, PSA levels, perineural invasion, Gleason score, Gleason grade, and two-year survival (p&gt;0.05). However, a statistically significant association was observed between HER2 expression and distant metastasis (p-value=0.006), whereas no significant association was found with E-cadherin (p-value=0.81). Conclusion: The study demonstrated a significant association between HER2/neu overexpression and tumour metastasis, suggesting that HER2/neu could serve as a prognostic parameter to assist surgeons. In contrast, E-cadherin showed no association with clinicopathological parameters, raising questions about its involvement in the progression of prostatic adenocarcinoma.

Prognostic significance of soluble PD-L1 in prostate cancer.

The aim of this study was to assess the role of sPD-L1 and sPD-1 as potential biomarkers in prostate cancer (PCa). The association of the values of these soluble proteins were correlated to the clinical data: stage of disease, Gleason score, biochemical recurrence etc. For a comprehensive study, the relationship between sPD-L1 and sPD-1 and circulating immune cells was further investigated. A total of 88 patients with pT2 and pT3 PCa diagnosis and 41 heathy men were enrolled. Soluble sPD-L1 and sPD-1 levels were measured in plasma by ELISA method. Immunophenotyping was performed by flow cytometry analysis. Our study's findings demonstrate that PCa patients had higher levels of circulating sPD-L1 and sPD-1 comparing to healthy controls (p < 0.001). We found a statistically significant (p < 0.05) relationship between improved progression free survival and lower initial sPD-L1 values. Furthermore, patients with a lower sPD-1/sPD-L1 ratio were associated with a higher probability of disease progression (p < 0.05). Additionally, a significant (p < 0.05) association was discovered between higher Gleason scores and elevated preoperative sPD-L1 levels and between sPD-1 and advanced stage of disease (p < 0.05). A strong correlation (p < 0.05), between immunosuppressive CD4+CD25+FoxP3+ regulatory T cells and baseline sPD-L1 was observed in patients with unfavorable postoperative course of the disease, supporting the idea that these elements influence each other in cancer progression. In addition to the postoperative drop in circulating PD-L1, the inverse relationship (p < 0.05), between the percentage of M-MDSC and sPD-L1 in patients with BCR suggests that M-MDSC is not a source of sPD-L1 in PCa patients. Our findings suggest the potential of sPD-L1 as a promising prognostic marker in prostate cancer.

Abstract B119: First-in-class orally active pharmacological inhibitors of TRPV6 for the treatment of advanced prostate cancer

Abstract The highly calcium selective ion channel TRPV6, has pronouced overexpression in many prostate cancers, is a promotor of prostate cancer growth and has been proposed as a prognostic marker in prostate cancer. A novel series of first-in-class TRPV6 inhibitors has been developed by the Queensland Emory Drug Discovery Initiative (QEDDI), a drug discovery and development group aiming to collaborativey translate academic biomedical research into new medicines. The preclinical lead drug candidate QED-203, is orally active and potently inhibits (low nM) calcium influx mediated by TRPV6 as assessed by both Ca2+ probe and electrophysiology assays, and TRPV6-driven NFAT activation as assessed by a luciferase reporter assay. Using RNAseq and qPCR analysis TRPV6 pharmacological inhibition and/or siRNA-mediated silencing was shown to remodel the expression of genes related to both NFAT and WNT signalling, as well as ER stress and the cell cycle. In prostate cancer cell lines that had increased levels of TRPV6, TRPV6 inhibition promoted cell cycle arrest, decreased proliferation and promoted apoptosis. Proliferation of enzalutamide resistant prostate cancer cell lines was also inhibited by QED-203. QED-203 exhibited greater potency over enzalutamide, darolutamide and apalutamide [androgen receptor targeting agents (ARTA)] in prostate cancer cell lines with clinically relevant AR mutations or those with the ARV7 splice variant. QED-203 appeared well suited to once-a-day oral dosing with a high bioavailability and an advantageous pharmacokinetic profile. In preclinical models, QED-203 was well tolerated in rodents and had similar in vivo efficacy to enzalutamide in a castrated LNCaP mouse model of prostate cancer as assessed by tumour growth and PSA levels. Increases in urine calcium levels and gene expression changes consistent with TRPV6 inhibition in isolated xenograft tumours, confirmed QED-203 TRPV6 target engagement in vivo. These studies suggest that the orally active TRPV6 inhibitor QED-203 represents a first-in-class mechanism to treat prostate cancer patients whose tumours have become resistant to current ARTA therapies. Pharmacological inhibitors of TRPV6, could be particularly valuable during the advanced stages of prostate cancer, where there is a clear unmet clinical need. Citation Format: Gregory Monteith, Kimberley Beaumont, Rebecca Pouwer, Rebecca Farrow, Matthew McLachlan, Mei Yeh, Therese Johnson, Raphael Rahmani, Claire Levrier, Hasanthi Wijesekera, Malika Kumarasiri, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Brian Dymock. First-in-class orally active pharmacological inhibitors of TRPV6 for the treatment of advanced prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B119.

Crucial role of hsa-mir-503, hsa-mir-1247, and their validation in prostate cancer.

Prostate cancer (PC) is a common urinary system malignancy, and advanced PC patients had a poor prognosis due to recurrence or distant metastasis. Therefore, it's imperative to reveal more details in tumorigenesis and prognosis of PC patients. The miRNA and mRNA expression profile data of 485 PC patients were obtained from The Cancer Genome Atlas database. The univariate Cox regression was applied to screen miRNAs relating to prognosis of PC. Then miRTarBase was used to predict target mRNAs of miRNAs. The hsa-mir-503/hsa-mir-1247 knockdown in 22RV1 cells was established to evaluate the effect of these two miRNAs on tumor cell migration and invasion ability. Flow cytometry was used to detect the effect of hsa-mir-503/hsa-mir-1247 knockdown on 22RV1 apoptosis rate. Univariate Cox regression analysis identified hsa-mir-503 as a poor and hsa-mir-1247 as a favorable prognostic marker. Totally 649 target mRNAs were screened, among which DUSP19, FGF2, and SLC2A5 had a negative correlation with hsa-mir-503, while FGF2 and VSTM4 had a positive correlation with hsa-mir-1247. In 22RV1 cells, hsa-mir-503 was up-regulated, and hsa-mir-1247 was down-regulated. hsa-mir-503 knockdown attenuated the migration and invasion of 22RV1 cells, while hsa-mir-1247 knockdown exhibited the opposite effect. In addition, hsa-mir-503 knockdown promoted 22RV1 cell apoptosis. hsa-mir-1247 overexpression significantly inhibited the tumor growth of PC in vivo. Herein, we demonstrated that hsa-mir-503 and hsa-mir-1247 could serve as new prognostic markers of PC, and hsa-mir-1247 had great potential to inhibit PC progression by suppressing the migration and invasion ability in vitro and in vivo.

Diagnostic and Prognostic Value of miR-93 in Prostate Cancer: A Meta-Analysis and Bioinformatics Analysis.

Accurate and non-invasive diagnostic and prognostic markers are necessary to improve patient outcomes. MicroRNAs have been proposed as relatively non-invasive and pertinent biomarkers. miR-93 has been studied for its potential as a diagnostic and prognostic marker in prostate cancer (PCa), but findings from individual studies are inconsistent. We conducted a meta-analysis of its overall differential expression in 13 PCa studies and a bioinformatics analysis to provide a comprehensive appraisal of its diagnostic and prognostic role. We searched all published papers on miR-93 expression in PCa up to Nov 30, 2022 using PubMed, Science Direct, Web of Science, Cochrane Central Register of Controlled Trials databases. We used RevMan software to Meta-analyze the included literature. A bioinformatics analysis of genes and pathways that might be target to the effect of the mature miR-93-5p was carried out. The pooled standardized mean difference (SMD) of miR-93 expression in PCa, its area under the curve (AUC) and hazard ratio (HR) were 1.26, 95% CI [-0.34-2.86], 0.84, 95% CI [0.76 -0.93] and 1.67, 95% CI [0.98, 2.84] respectively. Bioinformatics analysis revealed that mature miR-93-5p may regulate genes such as SMAD1, SMAD7 and MAPK and the PI3K-Akt signaling pathways. miR-93 has significant diagnostic and prognostic value in PCa. These findings highlight the potential of miR-93 as a non-invasive biomarker for PCa and may contribute to earlier detection and prognostic assessment. The target genes and signaling pathways regulated by miR-93 may provide insights into the underlying molecular mechanisms of PCa.