Survival In Prostate Cancer Patients Research Articles

Abstract C060: Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors

Abstract Background: Disparities in prostate cancer (PCa) incidence and mortality persist among African Americans. Functional well-being plays a crucial role in the prognosis and survival of PCa patients. Prior studies show the association between African American race and health-related quality of life among PCa patients. However, no studies have examined possible mediational processes linking race to functional well-being in this population. Objective: To assess the association between race and functional well-being and the mediating pathways of clinical, social determinants, and psychological factors in PCa patients. Methods: We used clinic-based cohort data of PCa patients treated with radical prostatectomy from April 2017 through September 2021. We measured functional well-being, socioeconomic factors, social stressors, perceived stress, and primary and secondary appraisal by self-report. We obtained clinical variables such as disease stage, prostate-specific antigen (PSA) levels, and comorbidities through electronic medical records. We first conducted a path analysis based on linear regression to test the direct association between race and functional well-being, adjusting for age, marital status, education level, employment status, and income. We concurrently examined the mediational pathways linking race to functional well-being via mediators, including stage, PSA, primary appraisal, secondary appraisal, perceived stress, and social isolation. Results: A total of 163 participants (48 African American, 115 White) with a mean age of 66.7 years (SD=6.31) were included in the study. Participants' mean score of functional well-being was 20.32 (SD=6.70; Range=0-28). Compared to White individuals, African American participants exhibited significantly lower levels of functional well-being (b [95% CI] = -3.09 [-5.48, -0.72]). Mediation analyses linking race to functional well-being revealed that, compared to Whites, African Americans displayed significantly lower levels of secondary appraisal (b [95% CI] = -1.45 [-2.85, -0.05]), which, in turn, were associated with higher levels of functional well-being (b [95% CI] = 0.27 [0.01, 0.53]). In addition, African Americans also displayed higher levels of social isolation (b [95% CI] = 0.55 [0.14, 0.97]), which were significantly associated with lower levels of functional well-being (b [95% CI] = -0.91 [-1.64, -0.17]). Both indirect effects of race → secondary appraisal → functional well-being (b [95% CI] = -0.39 [-0.88, -0.01]) and race → social isolation → functional well-being (b [95% CI] = -0.50 [-1.06, -0.02]) were significant and explained 12.6% and 16.2%, respectively, of the total relationship between race and functional well-being. Conclusion: Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors. There is a need to understand the lived experiences of Black men and develop interventions that mitigate the impact of social barriers and psychological stressors on functional well-being to advance health equity. Citation Format: Fatimata Sanogo, Junhan Cho, Trista Beard, Chanita Hughes Halbert. Social isolation and secondary appraisal mediate the association between race and functional well-being among prostate cancer survivors [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C060.

Cobalt Serum Level as a Biomarker of Cause-Specific Survival among Prostate Cancer Patients.

Prostate cancer is the most common cancer diagnosed in men and the second leading cause of death in male cancer patients. The WHO suggests that cobalt is involved in the carcinogenesis of prostate cancer. There are, however, no studies associating cobalt levels and prostate cancer patient survival. In this study, 261 Polish prostate cancer (n = 261) patients were recruited into a prospective cohort between 2009 and 2015. Serum cobalt levels were measured using ICP-MS after prostate cancer diagnosis and before treatment. All study participants were assigned into quartiles (QI-QIV) based on the distribution of serum cobalt levels among censored patients. Univariable and multivariable COX regression models were used to calculate hazard ratios (HRs) for each serum cobalt level quartile. We found a significant relationship between high serum cobalt levels and poor prostate cancer patient total survival (HR = 2.60; 95% CI: 1.17-5.82; p = 0.02). In relation to prostate cancer patients who died as a result of other non-cancer causes, the association with high levels of cobalt was even stronger (HR = 3.67; 95% CI: 1.03-13.00; p = 0.04). The impact of high serum cobalt levels on overall survival of prostate cancer-specific-related deaths was not statistically significant.

GPC2 promotes prostate cancer progression via MDK-mediated activation of PI3K/AKT signaling pathway

Prostate cancer is a major medical problem for men worldwide. Advanced prostate cancer is currently incurable. Recently, much attention was paid to the role of GPC2 in the field of oncology. Nevertheless, there have been no investigations of GPC2 and its regulatory mechanism in prostate cancer. Here, we revealed a novel action of GPC2 and a tumor promoting mechanism in prostate cancer. GPC2 was upregulated in prostate cancer tissues and cell lines. Higher expression of GPC2 was correlated with higher Gleason score, lymphatic metastasis, and worse overall survival in prostate cancer patients. Decreased expression of GPC2 inhibited cell proliferation, migration, and invasion in prostate cancer, whereas GPC2 overexpression promoted these properties. Mechanistically, GPC2 promoted the activation of PI3K/AKT signaling pathway through MDK. The rescue assay results in prostate cancer cells demonstrated that overexpression of MDK could attenuate GPC2 knockdown induced inactivation of PI3K/AKT signaling and partly reverse GPC2 knockdown induced inhibition of cell proliferation, migration, and invasion. In all, our study identified GPC2 as an oncogene in prostate cancer. GPC2 promoted prostate cancer cell proliferation, migration, and invasion via MDK-mediated activation of PI3K/AKT signaling pathway. GPC2 might be a promising prognosis predictor and potential therapeutic target in prostate cancer.

Prognosis and diagnosis of prostate cancer based on hypergraph regularization sparse least partial squares regression algorithm.

Prostate cancer (PCa) is a malignant tumor of the male reproductive system, and its incidence has increased significantly in recent years. This study aimed to further identify candidate biomarkers with prognostic and diagnostic significance by integrating gene expression and DNA methylation data from PCa patients through association analysis. To this end, this paper proposes a sparse partial least squares regression algorithm based on hypergraph regularization (HR-SPLS) by integrating and clustering two kinds of data. Next, module 2, with the most significant weight, was selected for further analysis according to the weight of each module related to DNA methylation and mRNAs. Based on the DNA methylation sites in module 2, this paper uses multiple machine learning methods to construct a PCa diagnosis-related model of 10-DNA methylation sites. The results of Receiver Operating Characteristic (ROC) analysis showed that the DNA methylation-related diagnostic model we constructed could diagnose PCa patients with high accuracy. Subsequently, based on the mRNAs in module 2, we constructed a prognostic model for 7-mRNAs (MYH11, ACTG2, DDR2, CDC42EP3, MARCKSL1, LMOD1, and MYLK) using multivariate Cox regression analysis. The prognostic model could predict the disease free survival of PCa patients with moderate to high accuracy (area under the curve (AUC) =0.761). In addition, Gene Set EnrichmentAnalysis (GSEA) and immune analysis indicated that the prognosis of patients in the risk group might be related to immune cell infiltration. Our findings may provide new methods and insights for identifying disease-related biomarkers by integrating DNA methylation and gene expression data.

Impact of comorbidities on prostate cancer-specific mortality: A population-based cohort study.

To assess the impact of comorbidities on prostate cancer mortality. We studied 15,695 South Australian men diagnosed with prostate cancer between 2003 and 2019 from state-wide administrative linked data sets. Comorbidity was measured 1-year before prostate cancer diagnosis using Rx-Risk, a medication-based comorbidity index. Flexible parametric competing risk regression was used to estimate the independent association between comorbidities and prostate cancer-specific mortality. Specific common comorbidities within Rx-Risk (cardiac disorders, diabetes, chronic airway diseases, depression and anxiety, thrombosis, and pain) were also assessed to determine their association with mortality. All models were adjusted for sociodemographic variables, tumor characteristics, and treatment type. Prostate cancer-specific mortality was higher for patients with a Rx-Risk score ≥3 versus 0 (adjusted sub-hazard ratio (sHR) 1.34, 95% CI: 1.15-1.56). Lower comorbidity scores (Rx-Risk score 2 vs. 0 and Rx-Risk score 1 vs. 0) were not significantly associated with prostate cancer-specific mortality. Men who were using medications for cardiac disorders (sHR 1.31, 95% CI: 1.13-1.52), chronic airway disease (sHR 1.20, 95% CI: 1.01-1.44), depression and anxiety (sHR 1.17, 95% CI: 1.02-1.35), and thrombosis (sHR 1.21, 95% CI: 1.04-1.42) were at increased risk of dying from prostate cancer compared with men not on those medications. Use of medications for diabetes and chronic pain were not associated with prostate cancer-specific mortality. All Rx-Risk score categories and the specific comorbidities were also associated with increased risk of all-cause mortality. The findings showed that ≥3 comorbid conditions and specific comorbidities including cardiac disease, chronic airway disease, depression and anxiety, and thrombosis were associated with poor prostate cancer-specific survival. Appropriate management of these comorbidities may help to improve survival in prostate cancer patients.

MKI67 with arterial hypertension predict a poor survival for prostate cancer patients, a real-life investigation.

Prostate cancer is a common urology malignant in males, ranking second globally. The disease is especially severe when diagnosed alongside hypertension. MKI67 is an established marker of neoplastic cell proliferation in humans, but the significance of its prognostic value in patients with prostate cancer and hypertension requires further research. In this retrospective analysis, we evaluated 296 hypertensive prostate cancer patients between March 2, 2012, and November 1, 2015. We used Cox regression models and prediction analysis to assess overall survival. Furthermore, we created a nomogram and verified its accuracy using a calibration curve. Of all participants, 101 (34.12%) died. Our multi-factor analysis revealed that MKI67 expression was associated with an increased hazard ratio of death (> fivefold) (Hazard Ratio 5.829, 95% CI 3.349-10.138, p value < 0.01) and progression (twofold) (HR 2.059, 95% CI 1.368-3.102, p value < 0.01). Our Lasso analysis model displayed that several factors, including heart failure, smoking, ACS, serum albumin, Gealson score, prognostic nutritional index, MKI67 expression, surgery, and stage were high risks of prostate cancer. To ensure each covariate's contribution to cancer prognosis, we created a Cox model nomogram, which accurately predicted the risk of death (C-statistic of 0.8289) and had a proper calibration plot for risk assessment. MKI67 expression predicts poor outcomes for overall mortality in prostate cancer and hypertension patients. Additionally, our cross-validated multivariate score, which includes MKI67, demonstrated accuracy efficacy of predicting prognosis.

IL-38 promotes the development of prostate cancer.

Prostate Cancer (PCa) remains a significant concern in male cancer-related mortality. Tumour development is intricately regulated by the complex interactions between tumour cells and their microenvironment, making it essential to determine which is/are key factor(s) that influence the progression of PCa within the tumour microenvironment. The current study utilised histopathology and immunohistochemistry to determine the expression of IL-38 in PCa and analysed the correlation between the expression level of IL-38 within PCa and clinical pathological characteristics. There was a significant increase in IL-38 expression in PCa tissues compared to adjacent non-PCa tissues (P < 0.0001). In addition, IL-38 expression was significantly higher in tumour cells with a high proliferation index compared to those with a low value-added index. ROC curve analysis demonstrated that IL-38 has high specificity and sensitivity for the diagnosis of PCa (AUC=0.76). Moreover, we Probed the cellular source of IL-38 in prostate cancer tissue by immunofluorescence double staining. Additionally, within PCa, the expression of IL-38 was inversely correlated with the expression levels of CD8 and PD-1. Survival analysis revealed a significantly lower overall survival rate for PCa patients with high IL-38 expression (P=0.0069), and when IL-38 was co-expressed with CD8, the survival rate of the IL-38high/CD8low group was decreased significantly. Multivariate analysis indicated that the expression level of IL-38 and TNM staging were independent predictors of survival in PCa patients. These findings suggest that IL-38 plays a crucial role in the development of PCa, and the exploration of the correlation between IL-38 and various immune factors in the tumour microenvironment further reveals its mechanism of action, making it a potential target for immunotherapy in PCa.

Biochemical Response of

BackgroundIn a subset of patients with oligorecurrent prostate cancer (PCa), salvage surgery with prostate-specific membrane antigen (PSMA) radioguided surgery (PSMA-RGS) seems to be of value. ObjectiveTo evaluate whether a lower level of postoperative prostate-specific antigen (PSA; <0.1 ng/ml) is predictive of therapy-free survival (TFS) following salvage PSMA-RGS. Design, setting, and participantsThis cohort study evaluated patients with biochemical recurrence after radical prostatectomy and oligorecurrent PCa on PSMA positron emission tomography treated with PSMA-RGS in three tertiary care centers (2014–2022). InterventionPSMA-RGS. Outcome measurements and statistical analysisPostsalvage surgery PSA response was categorized as <0.1, 0.1–<0.2, or >0.2 ng/ml. Kaplan-Meier and multivariable Cox regression models evaluated TFS according to PSA response. Results and limitationsAmong 553 patients assessed, 522 (94%) had metastatic soft tissue lesions removed during PSMA-RGS. At 2–16 wk after PSMA-RGS, 192, 62, and 190 patients achieved PSA levels of <0.1, 0.1–<0.2, and >0.2 ng/ml, respectively. At 2 yr of follow-up, TFS rate was 81.1% versus 56.1% versus 43.1% (p < 0.001) for patients with PSA <0.1 versus 0.1–<0.2 versus >0.2 ng/ml. In multivariable analyses, PSA levels of 0.1–0.2 ng/ml (hazard ratio [HR]: 1.9, confidence interval [CI]: 1.1–3.1) and ≥0.2 ng/ml (HR: 3.2, CI: 2.2–4.6, p < 0.001) independently predicted the need for additional therapy after PSMA-RGS. The main limitation is the lack of a control group. ConclusionsFor patients after salvage PSMA-RGS, a lower biochemical response (PSA <0.1 ng/ml) seems to predict longer TFS. This insight may help in counseling patients postoperatively as well as guiding the timely selection of additional therapy. Patient summaryWe studied what happened to prostate cancer patients in three European centers who had salvage surgery using a special method called prostate-specific membrane antigen–targeted radioguidance. We found that patients who had low prostate-specific antigen levels soon after surgery were less likely to need further treatment for a longer time.

Identification and validation of a novel anoikis-related prognostic model for prostate cancer.

Anoikis resistance is a hallmark characteristic of oncogenic transformation, which is crucial for tumor progression and metastasis. The aim of this study was to identify and validate a novel anoikis-related prognostic model for prostate cancer (PCa). We collected a gene expression profile, single nucleotide polymorphism mutation and copy number variation (CNV) data of 495 PCa patients from the TCGA database and 140 PCa samples from the MSKCC dataset. We extracted 434 anoikis-related genes and unsupervised consensus cluster analysis was used to identify molecular subtypes. The immune infiltration, molecular function, and genome alteration of subtypes were evaluated. A risk signature was developed using Cox regression analysis and validated with the MSKCC dataset. We also identify potential drugs for high-risk group patients. Two subtypes were identified. C1 exhibited a higher level of CNV amplification, immune score, stromal score, aneuploidy score, homologous recombination deficiency, intratumor heterogeneity, single-nucleotide variant neoantigens, and tumor mutational burden compared to C2. C2 showed a better survival outcome and had a high level of gamma delta T cell and activated B cell infiltration. The risk signature consisting of four genes (HELLS, ZWINT, ABCC5, and TPSB2) was developed (area under the curve = 0.780) and was found to be an independent prognostic factor for overall survival in PCa patients. Four CTRP-derived and four PRISM-derived compounds were identified for high-risk patients. The anoikis-related prognostic model developed in this study could be a useful tool for clinical decision-making. This study may provide a new perspective for the treatment of anoikis-related PCa.

Abstract 773: Overexpression of phosphoserine phosphatase (PSPH) in prostate cancer and in tumor microenvironment promotes tumor cell proliferation

Abstract Reprogrammed cellular metabolism is one of the key features of cancer and tumor microenvironment. L-3-phosphoserine phosphatase (PSPH) is one of the five rate-limiting enzymes in the biosynthesis of serine from glucose that supports cell proliferation. Here, we aim to study the role of PSPH in prostate cancer (PCa) and its tumor microenvironment. We find that PSPH not only is overexpressed in prostate cancer cell lines compared to normal prostate epithelial cells (PrEC) and benign prostate epithelial cells (BPH-1), but also exhibits a higher level in patient-derived carcinoma-associated fibroblasts (CAFs) compared to the matched benign associated fibroblasts (BAFs), which are derived from fresh radical prostatectomy specimens of African American (AA) and European American (EA) men. Notably, MDAPCa2b cells derived from an AA prostate cancer patient and AA CAFs have even higher expression of PSPH protein. The mRNA levels of PSPH are also significantly elevated in prostate cancer tissues in AA men compared to EA men and predict poor survival in PCa patients. Knock-down of PSPH expression significantly inhibits the proliferation and colony formation of prostate cancer cells. Growth of xenograft tumors derived from PSPH knockdown MDAPCa2b cells has also been suppressed markedly. Gene expression profiling revealed that suppression of PSPH expression by shRNAs in LNCaP and MDAPCa2b cells is associated with the regulation of gene expression related to metabolism, immunity, extracellular matrix remodeling, and Ion channels. Similarly, analysis of publicly available PCa RNA seq databases also demonstrates that PSPH amplification or over-expression is associated with alterations of gene expression related to metabolism and immunity. Our results suggest that PSPH is upregulated in prostate cancer cells and their surrounding fibroblasts to support tumor growth via reprogramming metabolic pathways and transcriptomes. Citation Format: Liankun Song, Noriko Yokoyama, Jun Xie, Yunjie Hu, Zhenyu (Arthur) Jia, Beverly Wang, Dan Mercola, Edward Uchio, Thomas Ahlering, Michael Lilly, Xiaolin Zi. Overexpression of phosphoserine phosphatase (PSPH) in prostate cancer and in tumor microenvironment promotes tumor cell proliferation [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 773.

Abstract 3577: The role of PLXND1 in lineage plasticity and progression to neuroendocrine prostate cancer

Abstract Background: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer and is commonly associated with therapy resistance and poor prognosis. Treatment-induced NEPC (t-NEPC) predominantly develops by lineage plasticity from adenocarcinoma in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the mechanisms underlying the lineage plasticity and progression to NEPC are unclear. PLXND1 (PlexinD1) is a cellular receptor of the semaphorin family and has important functions in modulating the cytoskeleton and cell adhesion. However, the role of PLXND1 in lineage plasticity to NEPC development and progression is not well established. Methods: We performed transcriptomic analysis on NEPC patients’ cohorts and the enzalutamide-resistant prostate cancer cell lines. Correlation of PLXND1 with neuroendocrine feature genes and AR-targeting genes was determined. Kaplan-Meier method and the Cox proportional hazards model was used to estimate the correlation between PLXND1 expression level and patients’ survival. Immunohistochemistry was used to analyze PLXND1 expression in prostate adenocarcinoma and NEPC. Cell viability was determined in C4-2B MDVR, CWR22Rv1, and H660 cells after knocking down PLXND1 using siRNA or knocking out PLXND1 using CRISPR/CAS9. Organoids viability of patient-derived xenografts was measured after knocking down or knocking out PLXND1. Results: Our analysis on different patient cohorts suggests that PLXND1 is highly expressed in NEPC patients, and the expression of PLXND1 is positively correlated with neuroendocrine feature genes (CHGA, ENO2, SYP, and NCAM1). Kaplan-Meier survival analysis shows that high expression of PLXND1 is significantly associated with the poor prognosis of prostate cancer patients. PLXND1 is overexpressed and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells and prostate cancer patients’ cohorts. Furthermore, downregulation of PLXND1 expression suppressed proliferation of the NEPC cells and viability of the PDX tumor organoids. Conclusions: PLXND1 expression is elevated in NEPC and correlated with the poor survival of prostate cancer patients, suggesting it is a potential molecular indicator and therapy target for NEPC. Citation Format: Bo Chen, Pengfei Xu, Joy C. Yang, Shu Ning, Leyi Wang, Christopher Nip, Allen C. Gao, Chengfei Liu. The role of PLXND1 in lineage plasticity and progression to neuroendocrine prostate cancer [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 3577.

Abstract 104: Profiling peripheral blood to predict response to targeted androgen receptor axis therapy in mice

Abstract Background: Targeting the androgen receptor (AR) signaling axis (ARAT) continues to be the mainstay treatment for advanced-stage prostate cancer. Using second-generation antiandrogens like abiraterone acetate (Abi) and apalutamide (Apa) has contributed to the survival of prostate cancer patients. However, resistance to these therapies remains a problem and most of these patients progress to castration-resistant prostate cancer (CRPC). Myeloid-derived suppressor cells (MDSCs) have been shown to drive CRPC. We previously showed that unfavorable responses to androgen deprivation therapy (ADT) or ADT plus Apa were associated with polymorphonuclear MDSCs (PMN-MDSCs) cells enriched in prostate tumors from conditional Pten/Trp53-double knockout (DKO) mice. Here, we explore the association between pre-treatment immune cell subsets blood and antitumor to ARAT therapy DKO mice. Methods: Twenty-eight-week-old DKO mice were surgically castrated and after four weeks were randomized to treatments with vehicle, Apa or Abi for an additional four weeks (n=20). Individual treatment responses were assessed and classified according to tumor burden as follows: high tumor burden (HTB), ≥20% of median; moderate tumor burden (MTB), -20% to 20% of median; or low tumor burden (LTB), ≤-20% of median. Peripheral blood was collected both before and after treatment and analyzed by multi-color flow cytometry panels for lymphoid and myeloid subsets. Blood samples from healthy wildtype and untreated DKO mice with castration-naïve prostate tumors were collected as reference samples. Subsets of PMN-MDSCs and monocytic-MDCSs (m-MDSCs) were represented as % of total abundance and 5 of parental population. revealed a signature that was correlated with treatment responses. Profiles were constructed and the data was used to train supervised learning models to predict treatment responses. Shapely additive explanations (ShAP) were used to determine feature importance. The model was tested and validated on an independent cohort of 20 DKO mice treated with ADT and ADT plus Abi. Results: Moderate prediction from baseline blood could be identified for tumor burden following ARAT using a Naïve Bayes classifier. Model evaluation, using an independent cohort, yielded favorable performance with area under the curve (AUC) mean, 0.707; HTB, 0.627; MTB, 0.750; and LTB, 0.745. The most important features for prediction were identified. Conclusion: Our study revealed that MDSC subsets present in blood were associated with treatment responses to ARAT. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yoshitaka Saito, Takafumi Minami, Kazuhiro Yoshimura, Kazutoshi Fujita, Kazuto Nishio, Hirotsugu Uemura. Profiling peripheral blood to predict response to targeted androgen receptor axis therapy in mice [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 104.

Abstract 6276: In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation

Abstract Recent studies have shown that adrenergic fibers from the sympathetic nervous system (SNS), acting through stromal β2-adrenergic receptors, play an important role in the initial phases of cancer development by promoting tumor cell survival. Recent epidemiological data suggest that β-blocker intake is associated with improved survival of prostate cancer patients. Hypertension and high blood pressure have been suggested to increase prostate cancer development suggesting that the use of β-blockers in these patients could also reduce prostate cancer risk. β-adrenoceptors signal through the cAMP/PKA pathway that is known to promote neuroendocrine differentiation (NED) in LNCaP prostate cancer cell line. While neuroendocrine (NE) cells expressing synaptophysin (SYN) represent a minor cell population in the epithelial compartment of normal prostate glands, the population of NE-like cells, exhibiting NE phenotypes and expressing NE markers, is increased in, and correlates with, cancer progression, androgen-independent state and poor prognosis. Expression of the routine tissue biomarker of prostate cancer AMACR in NE-like cells discriminates them from NE cells. Our aim was to investigate whether NED could also be associated with benign prostatic hyperplasia (BPH) as recent studies showed that an increase in neuroendocrine cell density occurred before development of BPH in hypertensive rats. Our results showed that a 10-day treatment with 100µM IBMX (blocking cAMP degradation) and 10µM forskolin (FSK, adenylate cyclase activator) to trigger sustained activation of the cAMP/PKA pathway led to an increase in SYN and AMACR expression in BPH-1 cells (qPCR and WB). Similar results were observed by combining the effect of the β-adrenoceptor agonist isoproterenol (1µM) and FSK. The same treatments reduced BPH-1 cell proliferation rates by 40% and 60%, respectively, as expected for NED. Effects on AMACR and SYN expression and cell proliferation were fully reversed by the β-blocker carvedilol (5µM). This data suggests that β-adrenoceptors could be linked to the development of NE-like cells in BPH, a non-lethal disease affecting the transition zone (TZ). As 20% of the prostate cancer occur in this TZ, this observation may need further investigation. Citation Format: Natascha Pigat, Laura N. Garrido, Coline Lefevre, Manon Baures, Vincent Goffin, Anne-Sophie Armand, Thierry Capiod. In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation [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 6276.

Abstract 5648: Decoding the non-canonical functions of HO-1 in prostate cancer: A nuclear perspective and its association with a neuroendocrine signature

Abstract Previous studies have demonstrated the non-canonical anti-tumor effect of heme-oxygenase 1 (HO-1) in prostate cancer (PCa). Although HO-1 is crucial for free heme degradation, its nuclear expression unveils non-canonical functions beyond its enzymatic function. Understanding the specifics of its non-canonical role remains a critical unmet need. In this study, we identified nuclear interactors of HO-1 and assessed their association with PCa.PCa cells were treated with hemin (80 µM, 24 h), a specific pharmacological inducer of HO-1. Nuclear HO-1 immunoprecipitation and LC-ESI MS/MS analysis identified 11 differential nuclear associated-HO-1 proteins between control and hemin-treated PCa cells (ILF3, ILF2, BCLAF1, SAFB, DDX17, SLC25A5, CASP14, PRDX1, BRIX1, CCDC175, and GPATCH1). Next, we performed an Ingenuity Pathway Analysis (QIAGEN) showing that ILF3 appears as a master regulator of this signature. To assess the clinical relevance of these factors in PCa, we analyzed overall survival (OS), progression-free survival (PFS), relapse free survival (RFS) in multiple PCa datasets (GSE34312, GSE35988, GSE3933, GSE46602, GSE6956, GSE70768, TCGA-PRAD, GSE70770, GSE16560, GSE24136; n=1064). We performed univariable and multivariable analyses for these factors and identified the ones that significantly and independently affected the OS, RFS, PFS. Next, a risk score model was built based on the expression of 9 genes (∑ni=1(Coefi×Expri)) for the GSE70770 dataset using these factors identifying a subpopulation of PCa patients with high-risk of RFS (HR: 7.39 High vs Low score, p&amp;lt;0.0001); ascertaining the critical role of this signature in PCa. To elucidate the association of these factors with the aggressive phenotype of PCa, we analyzed RNA-seq expression data from the MDA-PCa-PDXs series (PCa Patient Derived Xenografts Program; MD Anderson Cancer Center), capturing PCa heterogeneity. Unsupervised clustering analysis revealed that samples with high expression of HO-1 nuclear interactors corresponded to neuroendocrine tumors, negative for androgen receptor staining. Principal Component Analysis identified ILF3 as the most relevant HO-1 interactor driving PDXs’ samples variance, correlating with a significant decrease in relapse-free survival of PCa patients. Further, we used ChIP-Atlas to assess the epigenomic landscapes for these nuclear HO-1 interactors. Results indicated that 40% of HO-1 nuclear interactors were potential transcription regulators. Strikingly, KEGG pathways analyses revealed that their regulomes were significantly associated with neurodegenerative disorders, highlighting their relevance in neural processes. In conclusion, our findings suggest that HO-1 and its nuclear interactors may play a pivotal role in neuroendocrine PCa, shedding light on potential therapeutic targets for this aggressive form of the disease. Citation Format: Seniuk A. Rocio, Agustina Sabater, Pablo Sanchis, Juan Bizzotto, Gastón Pascual, Estefania Labanca, Nicolas Anselmino, Nora Navone, Elba Vazquez, Pia Valacco, Javier Cotignola, Ayelén Toro, Geraldine Gueron. Decoding the non-canonical functions of HO-1 in prostate cancer: A nuclear perspective and its association with a neuroendocrine signature [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 5648.

A study on the impact of marital status on the survival status of prostate cancer patients based on propensity score matching

Marital status is an independent prognostic factor for survival in many types of cancers, but its prognostic impact on patients with prostate cancer (PCa) has not been established. The aim of this study was to explore the independent prognostic factors of PCa and to investigate the effect of marital status on survival outcomes in patients with different stratified by PCa. Using the surveillance, epidemiology, and end results (SEER) database, we collected data on 584,655 PCa patients diagnosed between 1975 and 2019. Marital status was classified as married, divorced, widowed, and single. We used the Kaplan–Meier analysis and single multivariate Cox proportional hazards regression analysis to determine the effect of marital status on overall survival (OS) and cancer-specific survival (CSS). In addition, we performed subgroup analyses for different ages, Gleason score and PSA values, and performed a 1:1 propensity score matching (PSM) to reduce the impact of confounding factors to obtain more accurate matching results. According to our findings, marital status was an independent prognostic factor for the survival of PCa patients and a better prognosis of married patients. Moreover, we also found that factors such as age, TNM stage, Gleason score, and PSA concentration were also considered as important predictors for the prognosis of PCa. The above findings can facilitate early detection and treatment of high-risk PCa patients, prolong their life and reduce family burden.

CRISPR/Cas9 screenings unearth protein arginine methyltransferase 7 as a novel essential gene in prostate cancer metastasis

Due to the limited effectiveness of current treatments, the survival rate of patients with metastatic castration-resistant prostate cancer (mCRPC) is significantly reduced. Consequently, it is imperative to identify novel therapeutic targets for managing these patients. Since the invasive ability of cells is crucial for establishing and maintaining metastasis, the aim of this study was to identify the essential regulators of invasive abilities of mCRPC cells by conducting two independent high-throughput CRISPR/Cas9 screenings. Furthermore, some of the top hits were validated using siRNA technology, with protein arginine methyltransferase 7 (PRMT7) emerging as the most promising candidate. We demonstrated that its inhibition or depletion via genetic or pharmacological approaches significantly reduces invasive, migratory and proliferative abilities of mCRPC cells in vitro. Moreover, we confirmed that PRMT7 ablation reduces cell dissemination in chicken chorioallantoic membrane and mouse xenograft assays. Molecularly, PRMT7 reprograms the expression of several adhesion molecules by methylating various transcription factors, such as FoxK1, resulting in the loss of adhesion from the primary tumor and increased motility of mCRPC cells. Furthermore, PRMT7 higher expression correlates with tumor aggressivity and poor overall survival in prostate cancer patients. Thus, this study demonstrates that PRMT7 is a potential therapeutic target and potential biomarker for mPCa.

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.

Pretreatment Interstitial Lung Abnormalities Detected on Abdominal Computed Tomography Scans in Prostate Cancer Patients.

Prostate cancer and interstitial lung abnormality (ILA) share similar risk factor, which is men and older age. The purpose of this study was to investigate the prevalence of pretreatment ILA among prostate cancer patients who underwent abdominal computed tomography (CT) within 1 year at their first visit to the urology department. In addition, we aimed to assess the association between pretreatment ILA and long-term survival in prostate cancer patients. This study was conducted in patients who had a first visit for prostate cancer at urology department between 2005 and 2016 and underwent an abdominal CT within 1 year. A thoracic radiologist evaluated the presence of ILA through inspecting the lung base scanned on an abdominal CT. The association between pretreatment ILA and survival was assessed using Kaplan-Meier analysis with log-rank test. Specific survival rates at 12, 36, and 60 months according to the presence of ILA were evaluated using z -test. Cox regression analysis was used to assess the risk factors of mortality. A total of 173 patients were included (mean age, 70.23 ± 7.98 years). Pretreatment ILA was observed in 10.4% of patients. Patients with ILA were more likely to be older and current smokers. Pretreatment ILA was associated with poor survival ( P < 0.001). Age ≥70 years (hazards ratio [HR], 1.98; 95% confidence interval [CI], 1.24-3.16; P = 0.004), metastatic stage (HR, 2.26; 95% CI, 1.36-3.74; P = 0.002), and ILA (HR, 1.96; 95% CI, 1.06-3.60; P = 0.031) were the independent risk factors of mortality. An ILA (HR, 3.94; 95% CI, 1.78-8.72; P = 0.001) was the only independent risk factor of mortality in localized stage prostate cancer patients. This study provides important insights into the unexplored effect of pretreatment ILA in prostate cancer patients. Pretreatment ILAs were observed considerably in the lung bases scanned on the abdominal CT scans among prostate cancer patients. Furthermore, pretreatment ILAs were the risk factor of mortality. Therefore, lung bases should be routinely inspected in the abdominal CT scans of prostate cancer patients. This result may help clinicians in establishing personalized management strategy of prostate cancer patients.

Abstract A025: FANCI regulates Fanconi anemia pathway and counteracts the effects of DNA damaging chemotherapy in prostate cancer

Abstract Prostate cancer is one of the leading causes of death among men worldwide and thus research on the genetic factors enabling the formation of treatment resistant cancer cells is crucial for improving patient outcomes. Here, we report a cell-line specific dependence on FANCI and related signaling pathways to counteract effects of DNA damaging chemotherapy in prostate cancer. Our results reveal that FANCI depletion results in significant downregulation of Fanconi anemia (FA) pathway members in prostate cancer cells indicating that FANCI is an important regulator of FA pathway. Furthermore, we found that FANCI silencing reduces proliferation in p53-expressing prostate cancer cells. This extends the evidence that inactivation of FANCI may convert cancer cells from a resistant to an eradicable state under the stress of DNA-damaging chemotherapy. Our results also indicate that high expression of FA pathway genes correlates with poorer survival in prostate cancer patients. Moreover, genomic alterations of FA pathway members are prevalent in prostate adenocarcinoma patients; mutation and copy number information for the FA pathway genes in seven patient cohorts (N = 1732 total tumor samples) reveals that 1025 (59.2%) tumor samples have an alteration in at least one of the FA pathway genes, suggesting that genomic alteration of the pathway is a prominent feature in patients with the disease. Citation Format: Heidi Kaljunen, Sinja Taavitsainen, Roosa Kaarijärvi, Eerika Takala, Ville Paakinaho, Matti Nykter, G. Steven Bova, Kirsi Ketola. FANCI regulates Fanconi anemia pathway and counteracts the effects of DNA damaging chemotherapy in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A025.

Ferroptosis‐Related LncRNA BCRP3 Promotes the Proliferation and Migration of Prostate Cancer

Background: Long noncoding RNAs (lncRNAs) are reported that play an important role in regulating tumorigenesis. This study aims to develop a ferroptosis‐related lncRNA gene signature for predicting biochemical recurrence of prostate cancer (PCa) and prove a functional lncRNA BCRP3 as a promotor toward PCa progression.Methods: The ferroptosis‐related lncRNA were identified by interoperating the databases of The Cancer Genome Atlas (TCGA) and FerrDb. A predictive model for biochemical recurrence of PCa was established based on the LASSO Cox regression. Kaplan–Meier cures were applied in the measurement of the impact on patients’ survival caused by key lncRNAs. Meanwhile, the molecular assays of CCK8, EdU, wound healing, and Transwell were conducted to evaluate the tumor‐suppressive effect of BCRP3 in vitro.Results: This study presented that 17 differentially expressed ferroptosis‐related lncRNAs were confirmed and further screened out 9 key lncRNAs for the establishment of risk model. The nomogram involved the risk model was also proved with an excellent predictive performance toward 1‐, 3‐, and 5‐year survival with the area of curves (AUC) as 0.77, 0.79, and 0.65 separately. Notably, the lncRNA BCRP3 was significantly correlated with the survival of PCa patients based on multivariate Cox regression. Additionally, downregulation of BCRP3 effectively inhibited the proliferation, migration, and invasion of PC3 cells which further proved its anti‐tumor function.Conclusion: We developed a ferroptosis‐related lncRNA risk model for predicting biochemical recurrence, which assisting in the clinical therapy of patients with PCa.