High-grade Prostate Research Articles

Cyc-DEP: Cyclic immunofluorescence profiling of particles collected using dielectrophoresis.

Cancer is a highly heterogenous disease that requires precise detection tools and active surveillance methods. Liquid biopsy assays provide an agnostic way to follow the complex trajectory of cancer, providing better patient stratification tools for optimized treatment. Here, we present the development of a low-volume liquid biopsy assay called cyc-DEP (cyclic immunofluorescent imaging on dielectrophoretic chip) to profile biomarkers collected on a dielectrophoretic microfluidic chip platform. To enable on-chip cyclic imaging, we optimized a fluorophore quenching method and sequential rounds of on-chip staining with fluorescently conjugated primary antibodies. cyc-DEP allows for the quantification of a multiplex array of proteins using 25µl of a patient plasma sample. We utilized nanoparticles from a prostate adenocarcinoma (LNCaP) cell line and a panel of six target proteins to develop our proof-of-concept technique. We then used cyc-DEP to quantify blood plasma levels of target proteins from healthy individuals, low-grade and high-grade prostate cancer patients (n=3 each) in order to demonstrate that our platform is suitable for liquid biopsy analysis in its present form. To ensure accurate quantification of signal intensities and comparisons between different samples, we incorporated a signal intensity normalization method (fluorescent beads) and a custom signal intensity quantification algorithm that account for the distribution of signal across hundreds of collection regions on each chip. Our technique enabled a threefold improvement in multiplicity for detecting proteins associated with fluid samples, opening doors for early detection, and active surveillance through quantification of a multiplex array of biomarkers from low-volume liquid biopsies.

Abstract 2270: Hyperlipidemia promotes aggressive variant prostate cancer via RNA-binding protein Quaking

Abstract Introduction: Hyperlipidemia has been associated with increased risk of advanced stage and high Gleason grade prostate cancer (PCa), yet the underlying mechanism is not completely understood. Quaking (QKI) is an RNA-binding protein (RBP) that regulate lipid metabolism. For PCa, QKI overexpression has been associated with increased chance of metastatic recurrence. Method: We performed RNA sequencing of prostate cancer tissues of hyperlipidemia (n = 12) and normolipidemia (n=32). Tissue samples were acquired by MRI-US fusion targeted biopsy. DESeq2 and GSEA was used to identify differently expressed genes and enriched genesets. A web-based RBP motif screening tool TRANSITE was utilized to identify active RBPs in hyperlipidemia-associated PCa. Results: PCa samples of hyperlipidemia patients exhibited poorer histology than normolipidemia PCA. RNA sequencing found that hyperlipidemia-associated PCa is enriched of Myc-regulated genes as well as interferon or innate immunity-associated genes. Interestingly, hyperlipidemia-associated PCa gene expression signature identified PCa samples devoid of common PCa genetic alterations - TMPRSS2-ERG fusion and PTEN deletion/mutation. RBP motif screening found QKI as one of the top enriched RBP in hyperlipidemia-associated PCa transcriptome. In a separate a consecutive radical prostatectomy series (n=190), we found that QKI-high (immunohistochemistry staining score 2-3) tumors had significantly higher serum cholesterol than QKI-low (score 0-1) tumors. Overexpression and knockdown experiments proved that QKI is responsible of rapid cell proliferation and interferon-related inflammatory gene expressions, In silico analysis predicted QKI overexpressing cancer cells are susceptive to stain-mediated ferroptosis-like cell death. Mechanistically, QKI regulates expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), which dictates the sensitivity of QKI overexpressing cells to ferroptosis. Conclusion: Hyperlipidemia was associated with aggressive pathologic characteristics of PCa without TMPRSS2-ERG fusion or PTEN deletion/mutation, and high tissue expression of QKI, an RNA-binding protein. QKI overexpression in PCa increased sensitivity to ACSL4-mediated ferroptosis by statins. This explains the epidemiological associations between hyperlipidemia and PCa, and will guide molecular subtype-driven drug repurposing studies. Citation Format: Hyun Ho Han, Jin Sol Sung, Dong Wook Song, Cheol Keun Park, Nam Hoon Cho, Young Deuk Choi, Woo Jin Ko. Hyperlipidemia promotes aggressive variant prostate cancer via RNA-binding protein Quaking [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2270.

Abstract 1728: Single cell RNA-seq analysis reveals a role of pro-inflammatory tumor-associated macrophages in driving prostate cancer progression

Abstract Genomic amplification and increased expression of C-MYC are found in high-grade intraepithelial neoplasm (HGPIN) and primary prostate adenocarcinoma. What role C-MYC plays in the initiation and progression of prostate cancer remains unclear. A genetically engineered mouse model with a high level of human C-MYC protein expression under a probasin promoter (Hi-Myc model) was developed that captures prostate cancer progression from hyperplasia at 6-week-old, to HGPIN at 3-6 month-old, and ultimately to invasive adenocarcinoma at 8-month-old. Applying single-cell RNA sequencing (scRNA-seq) technology, we have carefully studied the temporal transcriptional change in MYC-expressing tumor-initiating cells and the tumor-infiltrating immune cells to understand the cell-intrinsic and -extrinsic mechanisms by which C-MYC promotes the transition from HGPIN to invasive prostate cancer. We have identified a particular type of luminal cells, Prom1+ L1 cells, as the likely tumor initiating cells in the Hi-Myc model. The MYC-expressing L1 tumor initiating cells were more abundant and cycling more often in the invasive cancer at 8-month-old, compared to the pre-invasive stage. Interestingly, significant infiltration of novel M1-like tumor-associated macrophages (TAMs) correlated with the histologic tumor progression from HGPIN to invasive cancer. Targeting TAMs with anti-CSF1R antibody delayed prostate cancer progression and invasion, which appears to be independent of CD8 T-cells. Mechanistically, TAMs expressed a high level of IL-1b, which stimulated Hi-Myc prostate cell proliferation in an organoid co-culture system. More importantly, depleting IL-1b with a neutralizing antibody slowed prostate cancer progression in Hi-Myc mice. Lastly, we found that increased macrophage gene expression was associated with higher Gleason scores and worse disease-free survival in a TCGA clinical patient cohort. In summary, we have identified a molecular mechanism involving pro-inflammatory TAMs and IL-1b in driving early prostate cancer progression in a MYC-driven prostate cancer model, opening a potential therapeutic avenue to target TAMs and pro-inflammatory cytokine in preventing early prostate cancer progression. Citation Format: Jimmy L. Zhao, Joseph Chan, Max Land, Perianne Smith, Anuradha Gopalan, Michael Haffner, Dana Pe'er, Charles Sawyers. Single cell RNA-seq analysis reveals a role of pro-inflammatory tumor-associated macrophages in driving prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1728.

Abstract 2297: Profound anti-tumor efficacy of dual CDK7 and PD1 blockade in novel syngeneic prostate cancer models

Abstract Background: Anti-PD1 immune checkpoint blockade (ICB) has largely failed as a monotherapy for metastatic prostate cancer likely due to inadequate tumor neoantigen load and inadequate T cell filtration (TILs). Strategies to increase TILs that can be tested in novel syngeneic mouse models are needed in order to fulfill this critical medical need. CDK7 is a major regulator of the cell cycle that is under investigation as a novel therapeutic target. CDK7 inhibition can trigger robust anti-tumor immunity by causing genomic instability and DNA damage in lung cancer mouse models. Herein, we characterize our novel syngeneic mouse models and report on the anti-tumor activity of CDK7 alone and in combination with anti-PD1 ICB as an immunotherapeutic strategy. Methods: We generated two models of prostate cancer organoids and syngeneic mouse models. APC and PTEN are tumor suppressor genes commonly lost in metastatic prostate cancer and are emerging as a putative mechanism of resistance to immunotherapy. The MPA and MPP models were established by ex-vivo Lenti-Cas9-sgRNA knock-out of APC or PTEN from the prostate organoids grown in 3D cultures established from the prostate of a MYCT/TP53-/- GEMM. Results: Organoids from the MPA and MPP models form orthotopic high grade prostate adenocarcinoma from 2 to 3 weeks post-implantation and spontaneously develop lung metastases 10-12 weeks after orthotopic implantation. In addition, the MPA model developed immediate castration resistance and neuroendocrine transformation following hormone deprivation in vivo. By contrast, the MPP tumors significantly regressed after in vivo androgen deprivation. Baseline immunoprofiling of the MPA and MPP orthotopic tumors showed increased infiltration from monocytic MDSCs and expression of T cell exhaustion markers. Treatment of the MPA and MPP orthotopic models with YKL-5-124, a CDK7 inhibitor, led to substantial in vivo tumor growth inhibition, which was further augmented by the addition of anti-PD-1 ICB. Immunoprofiling of tumors treated with combined YKL-5-124 and PD-1 blockade showed activation of CD4+ and CD8+ T cells, and a decrease in the Treg, B cell and NK cell population. Conclusions: The MPA and MPP orthotopic models recapitulate the biology and immune suppressive microenvironment of advanced prostate cancer and provide useful tools for immunotherapy drug development. Combination of CDK7 inhibition with anti-PD-1 blockade profoundly inhibited in vivo orthotopic tumor growth in both MPA and MPP model, providing a rationale for exploring CDK7 in combination with PD-1 checkpoint immunotherapy as a novel therapeutical strategy for advanced prostate cancer. Funding Acknowledgements: DRW is funded through 2018YI2295 Prostate Cancer Foundation Young Investigator Award and PC160944 Department of Defense Physician Research Career Development Award. Citation Format: David Wise, Luiza Doro Pereira, Jiansheng Wu, Victor R. Adorno Febles, Jonathan Melamed, Fang-Ming Deng, Hua Zhang, Kwok-Kin Wong. Profound anti-tumor efficacy of dual CDK7 and PD1 blockade in novel syngeneic prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2297.

Abstract 5008: The potential role of hsa-miR-3157-3p in prostate cancer pathogenesis

Abstract Prostate cancer remains a major area of concern as it is the second leading cause of cancer mortalities amongst American men. Our study aimed to find the role of differentially expressed microRNAs that play a role in prostate cancer etiopathology. With the use of the National Center for Biotechnology Information (NCBI), we narrowed down a desired dataset (GSE138740). While analyzing the dataset, we found the expression pattern of hsa-miR-3157-3p (adjusted p-value 0.04797) to be significantly upregulated in low grade tumor samples (Gleason Score 6 and n=88) compared to high grade tumor samples (Gleason Score 8,9 and n=13). Furthermore, the role of hsa-miR-3157-3p in prostate cancer remains a novel finding. We have identified target genes such as E2F3, UBE2M, ABCF1, PKN3 and VANGL1 using the RNA Central website portal. Further studies are underway to elucidate the expression pattern of this miRNA and it’s target genes that would correlate with the disease progression observed among tumor samples in The Cancer Genome Atlas (TCGA) database. The Ingenuity Pathway Analysis (IPA) software generated report will be presented at the meeting to describe gene networks and pathways implicated in Prostate Cancer. Overall, these studies are designed to further validate whether this miRNA and its target genes can serve as potential biomarkers to predict the onset and progression from low to high grade prostate cancer. Citation Format: Akhil Wali, Hari Koul. The potential role of hsa-miR-3157-3p in prostate cancer pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5008.

Abstract 999: Epigenetic loss of heterogeneity from low to high grade localized prostate tumors

Abstract Identifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequenced the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumors. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumors. Despite this loss, high-grade tumors exhibit an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites, indicating a shared trans-regulatory program. We identify two unique genes encoding neuronal adhesion molecules that are highly accessible in high-grade prostate tumors. We show NRXN1 and NLGN1 expression in epithelial, endothelial, immune and neuronal cells in prostate cancer using cyclic immunofluorescence. Our results provide a deeper understanding of the active gene regulatory networks in primary prostate tumors, critical for molecular stratification of the disease. Citation Format: Ece Sebnem Eksi, Zeynep Sayar, Alex Chitsazan, George T. Thomas, Andrew Adey, Paul T. Spellman, Ryan Kopp. Epigenetic loss of heterogeneity from low to high grade localized prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 999.

Abstract 394: Elevated aryl hydrocarbon receptor and leptin receptor expression correlates with prostate cancer progression and may be associated with obesity-associated leptin-mediated chemoresistance

Abstract The aryl hydrocarbon receptor (AhR) is a nuclear transcription factor and xenobiotic sensor reported to mediate diet-induced obesity and is upregulated in high-grade prostate cancer (PCa). Previously published data from our lab shows that AhR protein is overexpressed and constitutively active in castration-resistant prostate cancer cells. Physiologically relevant leptin concentration is proportional to BMI and it is secreted by adipose cells to inhibit hunger under normal circumstances. Our preliminary results suggest that obesity-associated leptin concentrations desensitize PCa cells to cancer drugs however, the underlying mechanisms must be elucidated and may require sustained AhR signaling. In this study, we conducted an integrative bioinformatics analysis to explore the role of AHR and LEPR in PCa, which revealed AHR and LEPR mRNA expression positively correlates in prostate cancer (P<0.05, Pearson: 0.68, R^2=0.46). The mRNA expression levels of AHR and LEPR in PCa tissue samples (i.e. solid tissue normal samples from individuals with cancer in TCGA, N=498) were analyzed using the cBioPortal and Xena online tools. We will further investigate if the decrease in drug response is seen in the presence of obesity-associated leptin concentrations. Further understanding of the potential interaction(s) between adipokines, AhR, and chemoresistance can promote improved treatments for patients with prostate cancer. Citation Format: Kofi Kyenku Khamit-Kush, Joann B. Powell, Jeffrey A. Handy, Nathan Bowen, Daqing Wu, Valerie Odero-Marah. Elevated aryl hydrocarbon receptor and leptin receptor expression correlates with prostate cancer progression and may be associated with obesity-associated leptin-mediated chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 394.

Abstract 520: MYB exhibits racially disparate overexpression and clinicopathologic association in prostate cancer: significance as a predictor of biochemical recurrence

Abstract Prostate cancer (PCa) is the most diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death in American men. Significant racial disparities also exist in incidence and clinical outcome. African American (AA) men are nearly two times more likely to be diagnosed with PCa and have more than twice mortality rate than their Caucasian American (CA) counterparts. Despite an early diagnosis in majority of the cases, about one-third patients face biochemical recurrence following local therapy, with a likelihood of developing distant metastasis. Gleason score used as a prognosticator exhibits discrepancy between AA and CA men highlighting the need for better predictive markers. We previously demonstrated functional significance of MYB in PCa growth, aggressiveness, and castration-resistance. We also showed a role of MYB in sustained androgen receptor (AR) signaling under androgen-deprived condition and prostate-specific antigen (PSA) expression. Here, we studied the expression of MYB in PCa by immunohistochemistry and examined if it varied between AA and CA PCa cases and had any clinicopathological correlation. A total of 105 PCa [CA (n=50) and AA (n=55)] cases with available clinicopathologic data were included. MYB expression was also studied in adjacent benign prostatic hyperplasia (BPH) and high-grade prostate intraepithelial neoplastic (HGPIN) lesions. Stained slides were scanned and digitally analyzed for the measurement of percent positivity (0-100%) and staining intensity (1+, 2+ and 3+). Significant overexpression of MYB (p<0.0001) was reported in PCa relative to HGPIN and BPH. PCa predominantly exhibited moderate to strong staining, compared to weak to moderate staining with low precent positivity rate in HGPIN and weak MYB staining with low percent positivity in BPH. A significantly higher expression of MYB (p<0.0001) was noted in high Gleason score (8-9) PCa, compared to the low-medium Gleason score (≤7) PCa. Interestingly, MYB expression was significantly (p= 0.024) higher in AA PCa than CA PCa in overall and Gleason score wise comparisons. Correlation analysis of MYB showed its inverse association with time to BCR (r =-0.467, 95% CI=-0.675 to -0.190, p=0.002). Altogether, our findings establish MYB as a potentially useful biomarker for PCa diagnosis and prognosis and provide clinical support to our prior findings on the pathobiological role of MYB in PCa. Citation Format: Mohammad Aslam Khan, Srijan Acharya, Shashi Anand, Fnu Sameeta, James E. Carter, Oliver J. Semmes, Dean A. Troyer, Seema Singh, Santanu Dasgupta, Ajay P. Singh. MYB exhibits racially disparate overexpression and clinicopathologic association in prostate cancer: significance as a predictor of biochemical recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 520.

SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells

Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a matricellular protein that modulates interactions between cells and their microenvironment. SPARC is expressed during extracellular matrix remodeling and is abundant in bone marrow and high-grade prostate cancer (PCa). In PCa, SPARC induces changes associated with epithelial–mesenchymal transition (EMT), enhancing migration and invasion and increasing the expression of EMT transcriptional factor Zinc finger E-box-binding homeobox 1 (ZEB1), but not Zinc finger protein SNAI1 (Snail) or Zinc finger protein SNAI2 (Slug). It is unknown whether the SPARC-induced downregulation of E-cadherin in PCa cells depends on ZEB1. Several integrins are mediators of SPARC effects in cancer cells. Because integrin signaling can induce EMT programs, we hypothesize that SPARC induces E-cadherin repression through the activation of integrins and ZEB1. Through stable knockdown and the overexpression of SPARC in PCa cells, we demonstrate that SPARC downregulates E-cadherin and increases vimentin, ZEB1, and integrin β3 expression. Knocking down SPARC in PCa cells decreases the tyrosine-925 phosphorylation of FAK and impairs focal adhesion formation. Blocking integrin αvβ3 and silencing ZEB1 revert both the SPARC-induced downregulation of E-cadherin and cell migration enhancement. We conclude that SPARC induces E-cadherin repression and enhances PCa cell migration through the integrin αvβ3/ZEB1 signaling pathway.

Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells

BackgroundAccumulating evidence supports that prostate cancer stem-like cells (PCSCs) play significant roles in therapy resistance and metastasis of prostate cancer. Many studies also show that nitric oxide (NO) synthesized by NO synthases can function to promote tumor progression. However, the exact roles of NOSs and NO signaling in the growth regulation of PCSCs and castration-resistant prostate cancer (CRPC) are still not fully understood.MethodsThe regulatory functions of NOS-NO signaling were evaluated in prostate cancer cells, especially in PCSCs enriched by 3D spheroid culture and CD133/CD44 cell sorting. The molecular mechanisms of NOS-NO signaling in PCSCs growth regulation and tumor metastasis were investigated in PCSCs and mice orthotopic prostate tumor model.ResultsEndothelial NOS (eNOS) exhibited a significant upregulation in high-grade prostate cancer and metastatic CRPC. Xenograft models of CRPC exhibited notable increased eNOS expression and higher intracellular NO levels. PCSCs isolated from various models displayed significant enhanced eNOS-NO signaling. Functional analyses demonstrated that increased eNOS expression could promote in vivo tumorigenicity and metastatic potential of prostate cancer cells. Characterization of eNOS-NO involved downstream pathway which confirmed that enhanced eNOS signaling could promote the growth of PCSCs and antiandrogen-resistant prostate cancer cells via an activated downstream NO-sGC-cGMP-PKG effector signaling pathway. Interestingly, eNOS expression could be co-targeted by nuclear receptor ERRα and transcription factor ERG in prostate cancer cells and PCSCs.ConclusionsEnhanced eNOS-NO signaling could function to promote the growth of PCSCs and also the development of metastatic CRPC. Besides eNOS-NO as potential targets, targeting its upstream regulators (ERRα and ERG) of eNOS-NO signaling could also be the therapeutic strategy for the management of advanced prostate cancer, particularly the aggressive cancer carrying with the TMPRSS2:ERG fusion gene.

Experimental Support for the Possibility of Retrograde Genesis of Intraductal Carcinoma of the Prostate.

Background. Historically, intraductal carcinoma of the prostate (IDC-P) was postulated to be a retrograde spread of high-grade invasive prostate cancer. There is evidence that IDC-P can primarily originate in the prostatic ducts. The retrograde genesis has never been experimentally or clinically confirmed before. Methods. Biopsy proven intermediate or high-risk prostate cancer was orthotopically grafted in the prostate of severe combined immunodeficiency gamma mice. Cancer growth was monitored by serum PSA levels. The animals were sacrificed and grafted areas were histological examined. Results. Twenty-one of 23 mice survived and demonstrated rising serum PSA. In 10 of 21 animals, human prostate cancer was identified orthotopically. Except for one case where the human biopsy showed a Grade Group 2 prostate cancer and mouse graft was Grade Group 5, other 9 specimens showed comparable grades. One of the specimens demonstrated a cribriform invasive prostate cancer and adjacent IDC-P. Conclusion. These experimental data offer some evidence that invasive prostate cancer can demonstrate a retrograde spread in the prostatic ducts as IDC-P. Its ability to primarily arise in the ducts has been demonstrated in other studies. However, the issue which remains unresolved is in its most common presentation of IDC-P intermixed with high-grade invasive cancer if it is the former or the latter which came first. Possibly resolving this dilemma will shed some light on the existing controversies if IDC-P should or should not be graded when invasive cancer is present.

68Ga-PSMA-11 PET/MRI in Patients with Newly Diagnosed Intermediate- or High-Risk Prostate Adenocarcinoma: PET Findings Correlate with Outcomes After Definitive Treatment.

Prostate-specific membrane antigen (PSMA) PET offers an accuracy superior to other imaging modalities in initial staging of prostate cancer and is more likely to affect management. We examined the prognostic value of 68Ga-PSMA-11 uptake in the primary lesion and presence of metastatic disease on PET in newly diagnosed prostate cancer patients before initial therapy. Methods: In a prospective study from April 2016 to December 2020, 68Ga-PSMA-11 PET/MRI was performed in men with a new diagnosis of intermediate- or high-grade prostate cancer who were candidates for prostatectomy. Patients were followed up after initial therapy for up to 5 y. We examined the Kendall correlation between PET (intense uptake in the primary lesion and presence of metastatic disease) and clinical and pathologic findings (grade group, extraprostatic extension, nodal involvement) relevant for risk stratification, and examined the relationship between PET findings and outcome using Kaplan-Meier analysis. Results: Seventy-three men (age, 64.0 ± 6.3 y) were imaged. Seventy-two had focal uptake in the prostate, and in 20 (27%) PSMA-avid metastatic disease was identified. Uptake correlated with grade group and prostate-specific antigen (PSA). Presence of PSMA metastasis correlated with grade group and pathologic nodal stage. PSMA PET had higher per-patient positivity than nodal dissection in patients with only 5-15 nodes removed (8/41 vs. 3/41) but lower positivity if more than 15 nodes were removed (13/21 vs. 10/21). High uptake in the primary lesion (SUVmax > 12.5, P = 0.008) and presence of PSMA metastasis (P = 0.013) were associated with biochemical failure, and corresponding hazard ratios for recurrence within 2 y (4.93 and 3.95, respectively) were similar to or higher than other clinicopathologic prognostic factors. Conclusion: 68Ga-PSMA-11 PET can risk-stratify patients with intermediate- or high-grade prostate cancer before prostatectomy based on degree of uptake in the prostate and presence of metastatic disease.

PGC1 alpha coactivates ERG fusion to drive antioxidant target genes under metabolic stress

The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis1–3. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.

Comparison of a Personalized Prostate Biopsy Pattern With Traditional Transrectal Prostate Biopsy: Different Cancer Detection Rate.

Background: In terms of prostate biopsy approaches, it is difficult to reach the ventral central region of the prostate with the traditional transrectal prostate biopsy, while with the transperineal biopsy, the tumor in the dorsolateral region of the prostate is easily missed. However, until now, no studies have investigated the biopsy accuracy in the selective application of transrectal or transperineal biopsies according to the lesion site. Methods: We developed a personalized prostate biopsy pattern and the biopsy approach was selected individually according to the lesion site. We compared it with the traditional transrectal prostate biopsy method to evaluate the efficiency. Patients (n = 351) who underwent prostate biopsy at Qilu Hospital of Shandong University from January 2018 to October 2020 were divided into two groups, including the traditional transrectal prostate biopsy group (n = 236) and the personalized group (n = 115). The data from patients, including clinical characteristics, biopsy results, and complications, were analyzed. Results: The clinical characteristics of the two groups were similar. The total detection rate of prostate cancer in the personalized group was 49.6%, which was significantly higher than 38.1% in the traditional group (p = 0.023). When prostate-specific antigen was <20 ng/ml, the detection rates of the two groups were 30.4 and 19.3%, respectively (p = 0.039). The PI-RADS was positively associated with high-grade prostate cancer in the personalized group. Patients with complications in the traditional transrectal systematic method group accounted for 6.8%, and those in the personalized group complications through the transrectal and transperineal approaches accounted for 7.1 and 4.1%, respectively. The most common complications in the transrectal group were fever and rectal bleeding, and those in the transperineal group were hematuria and urinary retention. Conclusion: Compared with traditional transrectal prostate biopsy, the personalized biopsy pattern improved the detection rate of prostate cancer. The complications of the transrectal approach were much higher than those in the transperineal approach.

MP38-14 GUT MICROBIOME ASSOCIATED WITH BLOOD TESTOSTERONE LEVELS IN ELDERLY MEN

You have accessJournal of UrologyCME1 May 2022MP38-14 GUT MICROBIOME ASSOCIATED WITH BLOOD TESTOSTERONE LEVELS IN ELDERLY MEN Kazutoshi Fujita, Makoto Matsushita, Koji Hatano, Mitsuhisa Nishimoto, Daisuke Motooka, Eri Banno, Junya Hata, Takafumi Minami, Masahiro Nozawa, Shota Nakamura, Akira Tsujimura, Wataru Obara, Kazuhiro Yoshimura, Hirotsugu Uemura, and Norio Nonomura Kazutoshi FujitaKazutoshi Fujita More articles by this author , Makoto MatsushitaMakoto Matsushita More articles by this author , Koji HatanoKoji Hatano More articles by this author , Mitsuhisa NishimotoMitsuhisa Nishimoto More articles by this author , Daisuke MotookaDaisuke Motooka More articles by this author , Eri BannoEri Banno More articles by this author , Junya HataJunya Hata More articles by this author , Takafumi MinamiTakafumi Minami More articles by this author , Masahiro NozawaMasahiro Nozawa More articles by this author , Shota NakamuraShota Nakamura More articles by this author , Akira TsujimuraAkira Tsujimura More articles by this author , Wataru ObaraWataru Obara More articles by this author , Kazuhiro YoshimuraKazuhiro Yoshimura More articles by this author , Hirotsugu UemuraHirotsugu Uemura More articles by this author , and Norio NonomuraNorio Nonomura More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002592.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Testosterone levels have been implicated in a variety of male diseases, such as hypogonadism and sexual funciton. Patients with high-grade prostate cancer had a unique microbiota composition, suggesting that intestinal bacteria could influence the prostate cancer progression via testosterone metabolism. In this study, we determined the relationship between testosterone levels and gut microbiota. METHODS: Fifty-four Japanese men who had negative prostate biopsies were included in the study. The gut microbiota was analyzed by 16S rRNA gene sequencing of bacterial DNA extracted from rectal swabs. The gut microbiota compositions were compared in two groups according to serum testosterone levels above or below 3.5 ng /ml. RESULTS: No significant difference in alpha or beta diversity was observed, but some bacteria belonging to the phylum Firmicutes (Clostridiales, Turicibacter, and Gemella) were increased in the high testosterone group. Serum testosterone level were positively correlated with the relative amount of Firmicutes (rS=0.33, P=0.01), and Firmicutes amount affected serum testosterone levels independent of host factors (Age, BMI, triglyceride, and total cholesterol (β=0.770, P=0.040)). CONCLUSIONS: These results suggest that some intestinal bacteria belonging to phylum Firmicutes influence the testosterone metabolism of elderly men and may affect the pathology of various testosterone-induced diseases, especially male hypogonadism. Source of Funding: Kaken, Yakulto-Bioscience, Japanese Urological Association © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e623 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kazutoshi Fujita More articles by this author Makoto Matsushita More articles by this author Koji Hatano More articles by this author Mitsuhisa Nishimoto More articles by this author Daisuke Motooka More articles by this author Eri Banno More articles by this author Junya Hata More articles by this author Takafumi Minami More articles by this author Masahiro Nozawa More articles by this author Shota Nakamura More articles by this author Akira Tsujimura More articles by this author Wataru Obara More articles by this author Kazuhiro Yoshimura More articles by this author Hirotsugu Uemura More articles by this author Norio Nonomura More articles by this author Expand All Advertisement PDF DownloadLoading ...

Comparison of TransPerineal Prostate Biopsy Using Novel Affordable VY Probe (TPPB-VY) and TransRectal Prostate Biopsy (TRPB) in Detection of Prostate Cancer on Hypoechoic Lesions.

Introduction:Prostate cancer is one of the most commonly encountered urologic malignancy. Biopsy samples may be attained using TPPB-VY or TRPB; both of the approaches are relatively comparable in terms of accuracy. Transperineal Access System revolutionizes the methodology for obtaining prostate biopsies. But in Indonesia this device is not available and expensive, we developed VY probe mounted needle guide device. The study was aimed to compare cancer detection rate and rates of cancer detection in Grade Groups (GG) between these two approaches, particularly in prostate cancer patients. Methods:A cross-sectional study with retrospective data from patients diagnosed with prostate cancer in Hasan Sadikin General Hospital in 2019 – 2020 was performed. Ethical approval of this study was sought from the hospital authorities (IRB number: LB.02.01/X.6.5/ 55/2020). The patient was included to the study if PSA ≥ 4 ng/ml, DRE results suggestive of prostate cancer. The diagnostic accuracy of both approaches was compared using histopathological analysis. Results:There were 44 patients included in the study; 22 patients had received TRPB and 22 patients had TPPB-VY. Higher degree of cancer detection rates was found in patients receiving TPPB-VY. Patient with Prostatic adenocarcinoma were all found having hypoechoic lesion in TPPB-VY. On the other hand, half of the patient with Prostatic adenocarcinoma shown having no lesion in TRPB. Prostate cancer with hypoechoic lesion can be detected better by TPPB-VY than TRPB. Cancer detection rates on TPPB-VY were significantly higher than on TRPB for each grade group. Conclusion:Among patient with hypoechoic lesions, TPPB-VY led to more detectionof prostate cancer, it provides detection of all grade groups and high-grade prostate cancer, this showed a non-inferior TPPB-VY compared to TRPB. TPPB-VY should be considered as an option for all men in whom a prostate biopsy is indicated.

Therapeutic value of pelvic lymph node dissection in high-grade prostate cancer

Objective: This study aimed to assess the therapeutic value of pelvic lymph node dissection (PLND) in high-grade margin-negative prostate cancer without and with lymph node metastases. Methods: We retrospectively reviewed cases in the Western Australian radical prostatectomy (RP) database between January 1, 2010, and December 31, 2017. We identified men who had RP only (no PLND) and those had RP with PLND. Further, a subset of high-grade (Gleason score (GS) ⩾8) margin-negative cancers were identified. We assessed the therapeutic impact of PLND in this high-risk but potentially curable subset. Results: A total of 5648 prostatectomies were performed, and 1209 of these had concurrent PLND, negative surgical margins, and follow-up prostate-specific antigen (PSA) data. Of 558 men with high-grade margin-negative prostate cancer, 395 men had PLND, while 163 did not. There were significantly more patients with T3/T4 disease in the PLND group compared to those without PLND. Preoperative PSA did not differ significantly between the two groups. However, when stage matched, PLND had no impact on the numbers of men who were cured compared to those who failed surgical intervention. Conclusion: PLND has value in staging high-grade prostate cancer but has limited impact on producing a durable PSA cure or avoiding adjuvant therapy. Level of evidence: Not applicable for this multicenter audit.

Histopathological and genetic features of mismatch repair-deficient high-grade prostate cancer.

Mismatch repair (MMR) deficiency is commonly caused by functional inactivation of MLH1, PMS2, MSH2 or MSH6. The morphological and molecular correlates of MMR deficiency have been extensively characterized in certain tumour types such as colorectal and endometrial adenocarcinoma. In contrast, the histological and molecular features of MMR-deficient prostate cancer remain incompletely described. In this study, we evaluated 19 MMR-deficient prostate cancers, including 11 cases without prior systemic treatment. All treatment-naive cases (11 of 11, 100%) were grade group 4-5 and had predominant cribriform and/or solid growth patterns. Solid components (any amount) and tumour infiltrating lymphocytes were 7 cases each (7 of 11, 64%). In 68 MMR-proficient grade group 5 prostate cancers, predominant cribriform or solid growth patterns, solid components (any amount) and tumour infiltrating lymphocytes were seen at significantly lower frequencies (31 of 68, 46%; 9 of 68, 13% and 6 of 62, 9%, respectively; P < 0.001 for all comparisons). Molecular evaluation of 19 cases demonstrated that MMR-deficiency was secondary to functional loss of MSH2/MSH6 and MLH1/PMS2 in 15 (79%) and 4 cases (21%), respectively. Definite or probable germline mutations were present in 4 cases (4 of 19, 21%). TMPRSS2::ERG rearrangements were identified in 2 cases (2 of 19, 11%). Recurrent cancer-relevant somatic mutations included (but were not limited to) ATM, TP53, FOXA1, RB1, BRCA2 and PTEN. MMR deficiency was most commonly secondary to inactivation of MSH2/MSH6 in this study. Importantly, MMR-deficient high-grade prostatic adenocarcinomas had morphological features that might be useful to identify selected cases for MMR immunohistochemistry.

Integrating Information from Existing Risk Prediction Models with No Model Details.

Consider the setting where (i) individual-level data are collected to build a regression model for the association between an event of interest and certain covariates, and (ii) some risk calculators predicting the risk of the event using less detailed covariates are available, possibly as algorithmic black boxes with little information available about how they were built. We propose a general empirical-likelihood-based framework to integrate the rich auxiliary information contained in the calculators into fitting the regression model, to make the estimation of regression parameters more efficient. Two methods are developed, one using working models to extract the calculator information and one making a direct use of calculator predictions without working models. Theoretical and numerical investigations show that the calculator information can substantially reduce the variance of regression parameter estimation. As an application, we study the dependence of the risk of high grade prostate cancer on both conventional risk factors and newly identified molecular biomarkers by integrating information from the Prostate Biopsy Collaborative Group (PBCG) risk calculator, which was built based on conventional risk factors alone.

Associations Between Vertebral Marrow Proton Density Fat Fraction and Risk of Prostate Cancer.

Bone marrow adipocytes may be responsible for cancer progression. Although marrow adipogenesis is suspected to be involved in prostate carcinogenesis, an association between marrow adiposity and prostate cancer risk has not been clearly established in vivo. This work included 115 newly diagnosed cases of histologically confirmed prostate cancer (range, 48–79 years) and 87 age-matched healthy controls. Marrow proton density fat fraction (PDFF) was measured by 3.0-T MR spectroscopy at the spine lumbar. Associations between marrow PDFF and risk of prostate cancer by stage of disease and grade sub-types were performed using multivariable polytomous logistic regression. There were no significant group differences in the vertebral marrow PDFF, despite prostate cancer patients having 6.6% higher marrow PDFF compared to the healthy controls (61.7 ± 9.8% vs. 57.9 ± 6.5%; t = 1.429, p = 0.161). After adjusting for various clinical and demographic characteristics, we found that elevated marrow PDFF was related to an increased risk of high-grade prostate cancer [odds ratios (OR) = 1.31; 95% confidence interval (CI), 1.08–1.57; p = 0.003]. Likewise, increased marrow PDFF had a significantly positive correlation with aggressive prostate cancer risk (OR = 1.54; 95% CI, 1.13–1.92; p <0.001). There were no associations between marrow PDFF and low-grade (p = 0.314) or non-aggressive (p = 0.435) prostate cancer risk. The data support the hypothesis that marrow adiposity was correlated with increased risk of aggressive prostate cancer, supporting a link between adipogenesis and prostate cancer risk.