Advanced Stage Prostate Cancer Research Articles

Proteomic Tissue-Based Classifier for Early Prediction of Prostate Cancer Progression.

Although ~40% of screen-detected prostate cancers (PCa) are indolent, advanced-stage PCa is a lethal disease with 5-year survival rates around 29%. Identification of biomarkers for early detection of aggressive disease is a key challenge. Starting with 52 candidate biomarkers, selected from existing PCa genomics datasets and known PCa driver genes, we used targeted mass spectrometry to quantify proteins that significantly differed in primary tumors from PCa patients treated with radical prostatectomy (RP) across three study outcomes: (i) metastasis ≥1-year post-RP, (ii) biochemical recurrence ≥1-year post-RP, and (iii) no progression after ≥10 years post-RP. Sixteen proteins that differed significantly in an initial set of 105 samples were evaluated in the entire cohort (n = 338). A five-protein classifier which combined FOLH1, KLK3, TGFB1, SPARC, and CAMKK2 with existing clinical and pathological standard of care variables demonstrated significant improvement in predicting distant metastasis, achieving an area under the receiver-operating characteristic curve of 0.92 (0.86, 0.99, p = 0.001) and a negative predictive value of 92% in the training/testing analysis. This classifier has the potential to stratify patients based on risk of aggressive, metastatic PCa that will require early intervention compared to low risk patients who could be managed through active surveillance.

Activation of BDNF/TrkB pathway promotes prostate cancer progression via induction of epithelial-mesenchymal transition and anoikis resistance.

Prostate cancer (PCa) is one of the most common malignant diseases in male worldwide, yet, the molecular mechanisms involved in PCa progression are still poorly understood. This study aimed to investigate the roles of the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) pathway in PCa progression. It was demonstrated by immunohistochemical analysis that both BDNF and TrkB were overexpressed in PCa tissues and elevated TrkB expression was tightly related with lymph node metastasis and advanced stage of PCa. In vitro studies showed that stimulation with rhBDNF or overexpression of TrkB in PCa cells promoted cell migration, invasion, and anoikis resistance. Overexpression of TrkB also resulted in epithelial-mesenchymal transition (EMT)-like transformation in cell morphology, whereas RNA interference-mediated TrkB depletion caused reversion of EMT. Further investigation demonstrated that protein kinase B (AKT) was responsible for BDNF/TrkB signaling-induced pro-migratory and pro-invasive effects, EMT, and anoikis resistance. Finally, in vivo studies confirmed that enhanced TrkB expression facilitated tumor growth, whereas downregulation of TrkB suppressed tumor growth. Our findings illustrate that BDNF/TrkB pathway is crucial for PCa progression, which may provide a novel therapeutic strategy for the treatment of advanced PCa.

PARP inhibitors as a new therapeutic option in metastatic prostate cancer: a systematic review.

A great number of DNA-damage repair (DDR) pathways have been recognized to be frequently dysregulated in advanced stages of prostate cancer. DNA-repair defects in prostate cancer represents a clinically relevant disease subset. Tumors whose ability to repair double-strand DNA breaks by homologous recombination is compromised, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase (PARP). A systematic review of the literature has been conducted in January 2020 using PubMed Medline database in line with the recommendations from the PRISMA guidelines. The following string terms were used for searching clinical trial articles: castration resistant OR castrate resistance OR castration refractory AND prostate cancer AND PARP OR poly(ADP-ribose) polymerase inhibitor OR DNA-repair OR homologous recombination repair. On-going clinical trials with olaparib, niraparib, talazoparib, veliparib, and rucaparib in mCRPC were searched on the clinicalTrials.gov website. From this research 176 articles were identified. After title screening and abstract reading, five papers and four abstract were considered for the systematic review. Thirty-two clinical trials were also identified: from these 16 trials which did not include mCRPC patients or only prostate cancer patients, trials not yet recruiting and trials including radio-metabolic treatments were excluded. Sixteen trials were included and discussed in the paper. Olaparib has been the first agent showing a benefit in terms of rPFS and ORR alone or in combination with abiraterone plus prednisone in patients with DDR deficiency prostate cancer. Also rucaparib showed a benefit in terms of PSA response rate and ORR in patients with BRCA2 and BRCA1 mutation in a phase-II study. Other phase-III clinical trials are evaluating niraparib and talazoparib, alone or in combination with AR signaling inhibitors.

MP51-20 MOLECULAR REPROGRAMMING AND REWIRING OF PROSTATE CANCER CELLS AFTER ENZALUTAMIDE EXPOSURE

INTRODUCTION AND OBJECTIVE:Enzalutamide (ENZU), an androgen receptor (AR) inhibitor, has demonstrated clinical benefit in patients with advance-stage prostate cancer. However, it only provides a tr...

Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer

Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.

Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms.

Androgen deprivation therapy targeting the androgens/androgen receptor (AR) signaling continues to be the mainstay treatment of advanced-stage prostate cancer. The use of second-generation antiandrogens, such as abiraterone acetate and enzalutamide, has improved the survival of prostate cancer patients; however, a majority of these patients progress to castration-resistant prostate cancer (CRPC). The mechanisms of resistance to antiandrogen treatments are complex, including specific mutations, alternative splicing, and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways. In this review, we focus on the major mechanisms of acquired resistance to second generation antiandrogens, including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence. Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.

Integrated analysis of miRNA landscape and cellular networking pathways in stage-specific prostate cancer.

Dysregulation of miRNAs has been demonstrated in several human malignancies including prostate cancer. Due to tissue limitation and variable disease progression, stage-specific miRNAs changes in prostate cancer is unknown. Using chip-based microarray, we investigated global miRNA expression in human prostate cancer LNCaP, PC3, DU145 and 22Rv1 cells representing early-stage, advanced-stage and castration resistant prostate cancer in comparison with normal prostate epithelial cells. A total of 292 miRNAs were differentially expressed with 125 upregulated and 167 downregulated. These miRNAs were involved in pathways including drug resistance drug-efflux, adipogenesis, epithelial-to-mesenchymal transition, bone metamorphosis, and Th1/Th2 signaling. Regulation of miRNAs were interlinked with upstream regulators such as Argonaut 2 (AGO2), Double-Stranded RNA-Specific Endoribonuclease (DICER1), Sjogren syndrome antigen B (SSB), neurofibromatosis 2 (NF2), and peroxisome proliferator activated receptor alpha (PPARA), activated during stage-specific disease progression. Candidate target genes and pathways dysregulated in stage-specific prostate cancer were identified using CS-miRTar database and confirmed in clinical specimens. Integrative network analysis suggested some genes targeted by miRNAs include miR-17, let7g, miR-146, miR-204, miR-205, miR-221, miR-301 and miR-520 having a major effect on their dysregulation in prostate cancer. MiRNA-microarray analysis further identified miR-130a, miR-181, miR-328, miR146 and miR-200 as a panel of novel miRNAs associated with drug resistance drug-efflux and epithelial-to-mesenchymal transition in prostate cancer. Our findings provide evidence on miRNA dysregulation and its association with key functional components in stage-specific prostate cancer.

Inhibition of base excision repair by natamycin suppresses prostate cancer cell proliferation

Prostate cancer (PCa) progression is characterized by increased expression and transcriptional activity of the androgen receptor (AR). In the advanced stages of prostate cancer, AR significantly upregulates the expression of genes involved in DNA repair. Upregulation of expression for base excision repair (BER) related genes is associated with poor patient survival. Thus, inhibition of the BER pathway may prove to be an effective therapy for prostate cancer. Using a high throughput BER capacity screening assay, we sought to identify BER inhibitors that can synergize with castration therapy. An FDA-approved drug library was screened to identify inhibitors of BER using a fluorescence-based assay suitable for HTS. A gel-based secondary assay confirmed the reduction of BER capacity by compounds identified in the primary screen. Five compounds were then selected for further testing in the independently derived, androgen-dependent prostate cancer cell lines, LNCaP and LAPC4, and in the nonmalignant prostate derived cell lines PNT1A and RWPE1. Further analysis led to the identification of a lead compound, natamycin, as an effective inhibitor of key BER enzymes DNA polymerase β (pol β) and DNA Ligase I (LIG I). Natamycin significantly inhibited proliferation of PCa cells in an androgen depleted environment at 1 μM concentration, however, growth inhibition did not occur with nonmalignant prostate cell lines, suggesting that BER inhibition may improve efficacy of the castration therapies.

Incidence of androgen receptor and androgen receptor variant 7 coexpression in prostate cancer.

Prostate cancer (PRCA) is an androgen-driven disease, where androgens act through the androgen receptor (AR) to induce proliferation and survival of tumor cells. Recently, AR splice variant 7 (ARv7) has been implicated in advanced stages of PRCA and clinical recurrence. With the widespread use of AR-targeted therapies, there has been a rising interest in the expression of full-length AR and ARv7 in PRCA progression and how these receptors, both independently and together, contribute to adverse clinicopathologic outcomes. Despite a multitude of studies measuring the expression levels of AR and ARv7 in PRCA progression, the results have been inconsistent and sometimes contradictory due to technical and analytical discrepancies. To circumvent these inconsistencies, we used an automated multiplexed immunostaining platform for full-length AR and ARv7 in human PRCA samples and objectively quantified expression changes with machine learning-based software. With this technology, we can assess receptor prevalence both independently, and coexpressed, within specific tissue and cellular compartments. Full-length AR and ARv7 expression increased in epithelial nuclei of metastatic samples compared to benign. Interestingly, a population of cells with undetectable AR persisted through all stages of PRCA progression. Coexpression analyses showed an increase of the double-positive (AR+ /ARv7+ ) population in metastases compared to benign, and an increase of the double-negative population in PRCA samples compared to benign. Importantly, analysis of clinicopathologic outcomes associated with AR/ARv7 coexpression showed a significant decrease in the double-positive population with higher Gleason score (GS), as well as in samples with recurrence in under 5 years. Conversely, the double-negative population was significantly increased in samples with higher GS and in samples with recurrence in under 5 years. Changes in AR and ARv7 coexpression may have prognostic value in PRCA progression and recurrence. A better understanding of the prevalence and clinicopathologic outcomes associated with changes in these receptors' coexpression may provide a foundation for improved diagnosis and therapy for men with PRCA.

Prediction nomogram for 68Ga-PSMA-11 PET/CT in different clinical settings of PSA failure after radical treatment for prostate cancer.

The objective of this study was to develop a clinical nomogram to predict gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA-11-PET/CT) positivity in different clinical settings of PSA failure. Seven hundred three (n= 703) prostate cancer (PCa) patients with confirmed PSA failure after radical therapy were enrolled. Patients were stratified according to different clinical settings (first-time biochemical recurrence [BCR]: group 1; BCR after salvage therapy: group 2; biochemical persistence after radical prostatectomy [BCP]: group 3; advanced-stage PCa before second-line systemic therapies: group 4). First, we assessed 68Ga-PSMA-11-PET/CT positivity rate. Second, multivariable logistic regression analyses were used to determine predictors of positive scan. Third, regression-based coefficients were used to develop a nomogram predicting positive 68Ga-PSMA-11-PET/CT result and 200 bootstrap resamples were used for internal validation. Fourth, receiver operating characteristic (ROC) analysis was used to identify the most informative nomogram's derived cutoff. Decision curve analysis (DCA) was implemented to quantify nomogram's clinical benefit. 68Ga-PSMA-11-PET/CT overall positivity rate was 51.2%, while it was 40.3% in group 1, 54% in group 2, 60.5% in group 3, and 86.9% in group 4 (p< 0.001). At multivariable analyses, ISUP grade, PSA, PSA doubling time, and clinical setting were independent predictors of a positive scan (all p≤ 0.04). A nomogram based on covariates included in the multivariate model demonstrated a bootstrap-corrected accuracy of 82%. The nomogram-derived best cutoff value was 40%. In DCA, the nomogram revealed clinical net benefit of > 10%. This novel nomogram proved its good accuracy in predicting a positive scan, with values ≥ 40% providing the most informative cutoff in counselling patients to 68Ga-PSMA-11-PET/CT. This tool might be important as a guide to clinicians in the best use of PSMA-based PET imaging.

Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells.

Prostate cancer (PCa) progression is strictly associated with microenvironmental conditions, which can be modified by cancer-released extracellular vesicles (EVs), important mediators of cell-cell communication. However, the role of EVs in the inflammatory cross-talk between cancer cells and microenvironment-residing cells remains largely unknown. To evaluate the role of EVs in the tumour microenvironment, we treated the non-cancerous prostate cell line PNT2 with EVs isolated from advanced-stage prostate cancer PC3 (PC3-EVs). Caspase-1-mediated IL-1β maturation was evaluated after 24 h incubation with EVs. Moreover, the effect of PC3-EVs on differentiated macrophagic THP-1 cells was assessed by analyzing cytokine expression and PC3 cells migration and proliferation profiles. We illustrated that PC3 cells contain active NLRP3-inflammasome cascade and secrete IL-1β. PC3-EVs affect the PNT2 inflammatory response, inducing caspase-1-mediated IL-1β maturation via ERK1/2-mediated lysosomal destabilization and cathepsin B activation. We also verified that PC3-EVs induce a functional TAM-like polarization in differentiated THP-1 cells. Our results demonstrated that cancer-derived EVs induce an inflammatory response in non-cancerous prostate cells, while inducing an immunomodulatory phenotype in immune cells. These apparently contradictory effects are both committed to strengthening the tumour-promoting microenvironment

Genome atlas analysis based profiling of Akt pathway genes in the early and advanced human prostate cancer.

Recent studies conducted in the mouse and cellular models suggest a stage-specific, differential effect of Akt activity modulation on tumor growth and metastasis in various cancers. In prostate cancer (PCa), although the deletion of Akt1 gene in a neuroendocrine model of TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) blunted oncogenic transformation and tumor growth, Akt1 suppression in the advanced PCa resulted in the activation of transforming growth factor-β pathway and enhanced metastasis to the lungs. Such a dual role for the Akt isoforms and its signaling partners has not been investigated in human PCa. In the current study, we performed genomic database analysis of Akt isoforms and associated pathway molecules in human prostate adenocarcinoma, castration-resistant PCa, neuroendocrine PCa and metastatic PCa for mutations, genetic alterations, mRNA and protein expressions and activating phosphorylations from cBioportal. Results from the protein data analysis from the cBioportal were compared to the results of our data on human PCa tissue analysis and the cellular effects of Akt1 suppression using MK-2206 on PCa cell aggressiveness. Our study indicates the existence of a dual role for Akt1 in PCa and warrants a large-scale analysis of the early and advanced stage PCa clinical samples for further clarity.

Abstract 3165: Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data

Abstract Introduction: Although many (~40%) of the screen-detected prostate cancers are indolent (Gleason Score &amp;lt;= 6) and pose minimal risk for progression, advanced stage prostate cancer is a lethal disease with 5-year survival rates around 29%. The challenge is to identify biomarkers for early detection of aggressive disease, when the cancer is still organ confined. Such markers would be also used to better select patients with indolent and low risk cancers for active surveillance. Material and Methods: To identify a panel of protein markers that could predict prostate cancer progression, we developed ultra-sensitive, high-pressure, high-resolution separations coupled with intelligent selection and multiplexing-selected reaction monitoring (PRISM-SRM) assays for 52 protein markers. Candidate protein markers were identified and selected from existing prostate cancer genomics data sets and validated lists of known prostate cancer drivers. The PRISM-SRM assays used heavy isotope-labeled synthetic peptides as internal standards for quantitative proteomics analysis. Study comprised of a prostate cancer patient cohort with organ confined primary tumors (N=338) presenting following post-surgery features: 53 (15.7%) metastatic progression, 124 (36.7%) biochemical recurrence (BCR), and 161 (47.6%) no progression after more than ten years of follow-up after radical prostatectomy. Index tumor region for each case was scraped from representative 10-m sections of formalin-fixed paraffin embedded (FFPE)-whole-mounted prostatectomy specimens and processed for PRISM-SRM analysis. Results: Overall, PRISM-SRM analysis of the FFPE tissue samples enabled the detection of 42 (80.8%) out of 52 biomarker candidates; in comparison regular LC-SRM without the front-end chromatographic enrichment could detect only 21 (40.4%) of these candidates at the protein level. Kruskal-Wallis testing was used for statistical evaluation of the PRISM-SRM results and comparison of relative protein levels between the “no progression”, BCR and “metastatic progression” groups. Several prostate differentiation/androgen receptor signaling related proteins (FOLH1, PSA and NCOA) and tumor progression-related proteins (TGFB1, CCND1 and SPRC) had significantly different expression levels between the three groups, and showed initial promise in predicting progression to invasive cancer, BCR and metastasis. Conclusion: Ultra-sensitive targeted proteomics can be used to select and verify performance of early prognostic markers based on the analysis of prostatectomy specimens. The top performing markers appeared able to predict progression from organ confined cancer to BCR and metastasis. Citation Format: Yuqian Gao, Yi-Ting Wang, Hui Wang, Denise Young, Jennifer Cullen, Yingjie Song, Yongmei Chen, Athena Schepmoes, Gyorgy Petrovics, Thomas Fillmore, Tujin Shi, Wei-Jun Qian, Richard Smith, Sudhir Srivastava, Jacob Kagan, Albert Dobi, Inger Rosner, Karin Rodland, Isabell Sesterhenn, Shiv Srivastava, Tao Liu. Identification of candidate biomarkers for aggressive prostate cancer using targeted proteomics and FFPE tissue samples with outcomes data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3165.

Abstract LB-120: Acetylated Kruppel-like factor 5 and transforming growth factor-β mediated drug resistance in prostate cancer

Abstract Purpose: In this study, we explored the role of Kruppel-like factor 5 (KLF5) and its acetylated form on lysine 369 in transforming growth factor-β (TGFβ) induced drug resistance to promote antitumor synergy and overcome drug resistance in advanced stage prostate cancer. Procedures: Two aggressive prostate cancer cell lines DU 145 and PC-3 were treated with docetaxel to measure cytotoxicity. To assess docetaxel resistance, we used in-vitro cell survival assay, colony survival assay and xenograft mouse model. In addition, TGFβ1 and SB505124 (TGFβ receptor I inhibitor) were used to explore TGFβ induced docetaxel resistance. To measure function of KLF5 and its different acetylation form on lysine 369, stable cell lines were constructed with different KLF5 acetylation status mimics after knocking out endogenous KLF5, utilizing the CRISPR-Cas9 system. Results: We found that KLF5 alone induced docetaxel resistance in vivo, but not in vitro. Moreover, endogenous knocking out of KLF5 inhibited TGFβ induced docetaxel resistance. In addition to previous findings that TGFβ recruits P300 acetyl-transferase to acetylate KLF5 on lysine 369, we further found that TGFβ induced docetaxel resistance depends on acetylation of KLF5. In addition, Mass Spectrometry analysis revealed that JUNB, a downstream target of non-canonical TGFβ pathway, is a direct binding target of acetylated KLF5 but not de-acetylated KLF5. Knocking down of JUNB in acetylated KLF5 mimic cell line inhibited TGFβ induced docetaxel resistance. Conclusions: These suggested that acetylated KLF5 is indispensable in TGFβ induced drug resistance through interaction with JUNB. Our study introduced a novel mechanism of acetylated KLF5 and JUNB mediated docetaxel resistance in prostate cancer and contributed to an advanced therapy combination for advanced prostate cancer patients. Citation Format: Yixiang Li, Baotong Zhang, Jin-Tang Dong. Acetylated Kruppel-like factor 5 and transforming growth factor-β mediated drug resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-120.

IFITM3 promotes bone metastasis of prostate cancer cells by mediating activation of the TGF-\u03b2 signaling pathway

Advanced-stage prostate cancer (PCa) is often diagnosed with bone metastasis, for which there are limited therapies. Transforming growth factor β (TGF-β) is known to induce epithelial–mesenchymal transition (EMT), and abundance of TGF-β in the bone matrix is one of the important growth factors contributing to bone metastasis. TGF-β is reported as a key mediator of bone metastasis, but the underlying mechanism has not been elucidated. It was found in our study that Interferon-inducible Transmembrane Protein 3 (IFITM3) played a key role in the regulation of malignant tumor cell proliferation, invasion, and bone migration by binding to Smad4, thus activating the TGF-β-Smads Signaling Pathway. Lentivirus-mediated short hairpin RNA (shRNA) knockdown of IFITM3 inhibited cell proliferation and colony formation, induced apoptosis and inhibited migration by reversing EMT and downregulating the expression of metastasis-related molecules including FGFs and PTHrP. Microarray analysis showed that IFITM3 knockdown could alter the MAPK pathway associated with TGF-β-Smads signaling. By knocking down and overexpressing IFITM3, we demonstrated that IFITM3 expression level had an effect on MAPK pathway activation, and this change was more pronounced upon exogenous TGF-β stimulation. These results suggest that IFITM3 played an oncogenic role in PCa progression and bone metastasis via a novel TGF-β-Smads-MAPK pathway.

Association of Low Socioeconomic Status With Adverse Prostate Cancer Pathology Among African American Men Who Underwent Radical Prostatectomy.

We tested for associations between socioeconomic status (SES) and adverse prostate cancer pathology in a population of African American (AA) men treated with radical prostatectomy (RP). We retrospectively reviewed data from 2 institutions for AA men who underwent RP between 2010 and 2015. Household incomes were estimated using census tract data, and patients were stratified into income groups relative to the study population median. Pathologic outcomes after RP were assessed, including the postsurgical Cancer of the Prostate Risk Assessment (CAPRA-S) score and a definition of adverse pathology (stage≥ pT3, Gleason score≥ 4+3, or positive lymph nodes), and compared between income groups. We analyzed data of 347 AA men. Median household income was $37,954. Low-SES men had significantly higher prostate-specific antigen values (mean 10.2 vs. 7.3; P< .01) and CAPRA-S scores (mean 3.4 vs. 2.5; P< .01), more advanced pathologic stage (T3-T4 31.8% vs. 21.5%; P= .03), and higher rates of seminal vesicle invasion (17.3% vs. 8.2%; P< .01), positive surgical margins (35.3% vs. 22.1%; P< .01), and adverse pathology (41.4% vs. 30.1%; P= .03). Linear and logistic regression showed significant inverse associations of SES with CAPRA-S score (P< .01) and adverse pathology (P= .03). In a population of AA men who underwent RP, we observed an independent association of low SES with advanced stage or aggressive prostate cancer. By including only patients in a single racial demographic group, we eliminated the potential confounding effect of race on the association between SES and prostate cancer risk. These findings suggest that impoverished populations might benefit from more intensive screening and early, aggressive treatment of prostatic malignancies.

Resistance to anti-hormonal therapy in prostate cancer

Advanced stage prostate cancer is frequently treated with androgen receptor antagonists. Improvement in patients’ survival has been achieved with the anti-androgen enzalutamide. However, there may be an increasing number of point mutations of the androgen receptor during therapy. In addition, ligand-independent activation of truncated androgen receptors may occur during anti-hormonal therapy. In prostate cancer, there is also an increased expression of coactivators and decreased expression of corepressors, thus, contributing to the disease progression. Stromal factors such as interleukins also contribute to therapy resistance. Although preclinical studies with anti-interleukin-6 antibodies opened new possibilities for treatment of prostate cancer, clinical trials have not demonstrated a survival benefit. Increased expression of glucocorticoid receptor has also been associated with advanced prostate cancer. Thus, one can consider the administration of glucocorticoid receptor antagonists in addition to anti-androgens. Stem cells have been described either after androgen treatment or androgen ablation or as a consequence of long-term use of drugs. Taken together, multiple experimental studies provided evidence on the mechanisms that limit usefulness of anti-androgens in prostate cancer.

Racial differences in patterns of treatment among men diagnosed with de novo advanced prostate cancer: A SEER-Medicare investigation.

PurposeApproximately 5% of men were initially diagnosed with (also referred to as de novo) advanced stage prostate cancer and experience far poorer survival compared to men diagnosed with local or regionally advanced disease. Given the number of new therapies targeting metastatic and castrate‐resistant disease, we sought to describe recent treatment patterns by race for de novo AJCC stage IV prostate cancer.MethodsWe used Surveillance, Epidemiology, and End Results (SEER) data linked to Medicare files to identify men aged 66 and older diagnosed in 2004‐2014 with advanced prostate cancer, and examined patterns of treatment among all patients and stratified by race/ethnicity.ResultsThere were 8828 eligible patients identified, and non‐Hispanic black (NHB) patients were more likely to go without treatment (P < 0.001) compared to non‐Hispanic white (NHW) patients, even after accounting for early mortality and TNM stage. The frequency of nearly all forms of treatment was lower among NHB with the exception of orchiectomy, which was significantly higher (10.1% vs 6.1%, P < 0.001), and the use of the progesterone Megace among Medicare Part D enrollees (24.6% vs 15.0%, P < 0.001).ConclusionsResults from this study of elderly Medicare patients presenting with advanced stage prostate cancer suggest that NHB men are less likely to pursue aggressive treatment options. With the reduction in screening for prostate cancer, presumably tied to USPSTF recommendations, and the increasing incidence of men diagnosed with de novo metastatic disease, understanding drivers of treatment‐related decisions are critical in reducing racial disparities in advanced prostate cancer outcomes.

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case-control sets from EPIC.

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow‐up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.

SKP2 Inactivation Suppresses Cell Proliferation and Regulates AR/FOXA1 Expression in PCa Cells

Increased levels of SKP2 (S‐phase kinase‐associated protein 2), an E3 ubiquitin ligase, is frequently seen in advanced stages of prostate cancer (PCa). Correlations between SKP2 and the ubiquitin‐mediated degradation of key cell cycle regulators such as p21 and p27, as well as between SKP2 and the regulation of androgen receptor (AR) activity is frequently observed in PCa progression. Despite these associations, the molecular mechanisms responsible for the proto‐oncogenic effects of SKP2 in PCa remain elusive. The transcription factor FOXA1 (Forkhead box protein A1) is known to induce AR activity, and by doing so cause the activation of AR target genes. Deregulation of the AR/FOXA1 complex has been found to contribute to the progression of PCa and castration‐resistant prostate cancer (CRPC). We hypothesized that SKP2 impacts the function of the AR/FOXA1 complex contributing to the progression of CRPC. Using shRNA technology, we established stable SKP2 knockdown PCa cell lines to investigate the effects of SKP2 on CRPC growth. Our results demonstrate that SKP2 plays a critical role in the regulation of AR and FOXA1 expression in CRPC cell lines. SKP2 knockdown increased AR and FOXA1 levels in C4‐2B and 22RV1 cells, two CRPC cell lines. Furthermore, SKP2 knockdown significantly inhibited cellular proliferation and restored sensitivity to the AR antagonist (MDV3100) in C4‐2B and 22RV1 cells. Combined exposure to the AR antagonist (MDV3100) and a SKP2 inhibitor significantly reduced cellular proliferation, a result of cell cycle arrest and cellular senescence in C4‐2B and 22RV1. Endogenous and Myc‐tagged SKP2 as well as Flag‐tagged FOXA1 immunoprecipitation displayed a physical interaction between SKP2 and FOXA1. In vivo ubiquitination assay was performed using HEK293T cells transfected with HA‐Ub constructs demonstrating a SKP2 E3 ubiquitin ligase function for FOXA1. Our findings present a potential SKP2‐AR/FOXA1 signaling pathway that may be targeted therapeutically to inhibit CRPC malignancy.Support or Funding Information2U54CA163066MVTCP CA163069This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.