Different Stages Of Prostate Cancer Research Articles

Role of MicroRNA-21 in Prostate Cancer Progression and Metastasis: Molecular Mechanisms to Therapeutic Targets.

The role of noncoding RNA has made remarkable progress in understanding progression, metastasis, and metastatic castration-resistant prostate cancer (mCRPC). A better understanding of the miRNAs has enhanced our knowledge of their targeting mainly at the therapy level in solid tumors, such as prostate cancer (PCa). microRNAs (miRNAs) belong to a class of endogenous RNA that deficit encoded proteins. Therefore, the role of miRNAs has been well-coined in the progression and development of PCa. miR-21 has a dual nature in its work both as a tumor suppressor and oncogenic role, but most of the recent studies showed that miR-21 is a tumor promoter and also is involved in castration-resistant prostate cancer (CRPC). Upregulation of miR-21 suppresses programmed cell death and inducing metastasis and castration resistant in PCa. miR-21 is involved in the different stages, such as proliferation, angiogenesis, migration, and invasion, and plays an important role in the progression, metastasis, and advanced stages of PCa. Recently, various studies directly linked the role of high levels of miR-21 with a poor therapeutic response in the patient of PCa. In the present review, we have explained the molecular mechanisms/pathways of miR-21 in PCa progression, metastasis, and castration resistant and summarized the role of miR-21 in diagnosis and therapeutic levels in PCa. In addition, we have spotlighted the recent therapeutic strategies for targeting different stages of PCa.

Assessment of PSMA Expression of Healthy Organs in Different Stages of Prostate Cancer Using [68Ga]Ga-PSMA-11-PET Examinations.

The efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is currently being investigated for its application in patients with early-stage prostate cancer (PCa). However, little is known about PSMA expression in healthy organs in this cohort. Collectively, 202 [68Ga]Ga-PSMA-11 positron emission tomography (PET) scans from 152 patients were studied. Of these, 102 PET scans were from patients with primary PCa and hormone-sensitive biochemically recurrent PCa and 50 PET scans were from patients with metastatic castration-resistant PCa (mCRPC) before and after three cycles of [177Lu]Lu-PSMA-RLT. PSMA-standardized uptake values (SUV) were measured in multiple organs and PSMA-total tumor volume (PSMA-TTV) was determined in all cohorts. The measured PET parameters of the different cohorts were normalized to the bloodpool and compared using t- or Mann-Whitney U tests. Patients with early-stage PCa had lower PSMA-TTVs (10.39 mL vs. 462.42 mL, p < 0.001) and showed different SUVs in the thyroid, submandibular glands, heart, liver, kidneys, intestine, testes and bone marrow compared to patients with advanced CRPC, with all tests showing p < 0.05. Despite the differences in the PSMA-TTV of patients with mCRPC before and after [177Lu]Lu-PSMA-RLT (462.42 mL vs. 276.29 mL, p = 0.023), no significant organ differences in PET parameters were detected. These suggest different degrees of PSMA-ligand binding among patients with different stages of PCa that could influence radiotoxicity during earlier stages of disease in different organs when PSMA-RLT is administered.

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

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

Abstract 7344: Role of ubiquitin receptor ADRM1 (Rpn13) in prostate cancer

Abstract Adhesion-regulating molecule 1 (ADRM1)/Rpn13 is a component of the 19S regulatory subunit of the 26S proteasome [1]. ADRM1 plays a crucial role in the recognition of polyubiquitinated substrates of the proteasome and their subsequent deubiquitination and degradation [2]. ADRM1 transcript levels are commonly upregulated in diverse tumor types [3]. The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. In this study, we investigated the expression of ADRM1/Rpn13 in different stages of prostate cancer and its association with AR expression. TCGA data from UALCAN was used for understanding ADRM1 expression on different stages of diseases and single-cell RNA-sequencing data of prostate cancer cell line was obtained from Prostate Cancer Atlas. TCGA (cell, 2015) data set was used for investigating the correlation between ADRM1 and AR by using R programming. Our study from the TCGA dataset reveals that ADRM1 expression increased significantly with the aggressiveness of prostate cancer (increase consistently with the Gleason score) from the TCGA dataset. We analyzed ADRM1 and AR expression in different prostate cancer cell lines and obtained that ADRM1 expressed significantly higher in prostate cancer cell lines which had lower AR expression. TCGA (cell, 2015) dataset indicated a negative correlation between ADRM1 and AR expression in prostate cancer. Our preliminary analysis indicated that ADRM1 inhibitor might be a potential therapeutic option for AR-independent prostate cancer. Citation Format: Shahjalal Chowdhury, Honghe Wang, Chitra Nayak, Balasubramanyam Karanam. Role of ubiquitin receptor ADRM1 (Rpn13) in 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 7344.

A Prospective Randomised Trial to Determine the Effect of a Reduced Versus Standard Dose of Enzalutamide on Side Effects in Frail Patients with Prostate Cancer

Background and objectiveEnzalutamide is a potent antiandrogen inhibitor, effectively used for the treatment of different stages of prostate cancer. Side effects occur frequently at the registered dose, whilst a lower dose might be equally effective. Therefore, the aim of this study is to determine the effect of a reduced dose of enzalutamide on side effects in frail patients with prostate cancer. MethodsThis multicentre randomised trial compared the standard enzalutamide dose of 160 mg once daily (OD) with a reduced dose of 120 mg OD in frail patients with prostate cancer. Fatigue, cognitive side effects, and depressive symptoms were measured by the Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-Fatigue) questionnaire, Functional Assessment of Cancer Therapy—Cognitive Function (FACT-Cog) questionnaire, and Geriatric Depression Scale—15 (GDS-15). Linear mixed-effect models were used to study differences in side effects over time between both groups. Key findings and limitationsIn total, 52 patients were included in the analysis (25 reduced dose and 27 standard dose). Patients treated with the reduced dose had significantly lower fatigue after 24 wk than those with the standard dose (difference FACIT-Fatigue 6.2; 95% confidence interval 1.4–11.0; p = 0.01). Patients treated with the reduced dose showed stable fatigue, cognitive side effects, and depressive symptoms over time, whilst patients with the standard dose showed significantly worse side effects after 24 wk than at baseline. Conclusions and clinical implicationsA reduced dose of enzalutamide results in less fatigue, cognitive side effects, and depressive symptoms in frail patients with prostate cancer than the standard dose, without any indication of interference with efficacy endpoints. Patient summaryIn this report, we looked at the side effects of enzalutamide at two dose levels. We found that, in frail patients, three tablets a day result in less fatigue than four tablets a day. Patients treated with four tablets a day showed an increase in fatigue, cognitive side effects, and depression. We conclude that a lower dose of three tablets can be used to alleviate side effects without indications for less efficacy.

Predicting prostate cancer progression with a Multi-lncRNA expression-based risk score and nomogram integrating ISUP grading

Prostate cancer is a highly heterogeneous disease; therefore, estimating patient prognosis accurately is challenging due to the lack of biomarkers with sufficient specificity and sensitivity. One of the current challenges lies in integrating genomic and transcriptomic data with clinico-pathological features and in incorporating their application in everyday clinical practice. Therefore, we aimed to model a risk score and nomogram containing long non-coding RNA (lncRNA) expression and clinico-pathological data to better predict the probability of prostate cancer progression. We performed bioinformatics analyses to identify lncRNAs differentially expressed across various prostate cancer stages and associated with progression-free survival. This information was further integrated into a prognostic risk score and nomogram containing transcriptomic and clinico-pathological features to estimate the risk of disease progression. We used RNA-seq data from 5 datasets from public repositories (total n = 178) comprising different stages of prostate cancer: pre-treatment primary prostate adenocarcinomas, post-treatment tumors and metastatic castration resistant prostate cancer. We found 30 lncRNAs with consistent differential expression in all comparisons made using two R-based packages. Multivariate progression-free survival analysis including the ISUP group as covariate, revealed that 7/30 lncRNAs were significantly associated with time-to-progression. Next, we combined the expression of these 7 lncRNAs into a multi-lncRNA score and dichotomized the patients into low- or high-score. Patients with a high-score showed a 4-fold risk of disease progression (HR = 4.30, 95 %CI = 2.66–6.97, p = 3.1e-9). Furthermore, we modelled a combined risk-score containing information on the multi-lncRNA score and ISUP group. We found that patients with a high-risk score had nearly 8-fold risk of progression (HR = 7.65, 95 %CI = 4.05–14.44, p = 3.4e-10). Finally, we created and validated a nomogram to help uro-oncologists to better predict patient's risk of progression at 3- and 5-years post-diagnosis. In conclusion, the integration of lncRNA expression data and clinico-pathological features of prostate tumors into predictive models might aid in tailored disease risk assessment and treatment for patients with prostate cancer.

Cytochrome P450 genes expression in human prostate cancer

CYP-dependent metabolites play a critical role in regulating the cell cycle, as well as the proliferative, invasive, and migratory activity of cancer cells. We conducted a study to analyze the relative gene expression of various CYPs (CYP7B1, CYP27A1, CYP39A1, CYP51, CYP1B1, CYP3A5, CYP4F8, CYP5A1, CYP4F2, CYP2J2, CYP2E1, CYP2R1, CYP27B1, CYP24A1) in 41 pairs of prostate samples (tumor and conventional normal tissues) using qPCR. Our analysis determined significant individual variability in the expression levels of all studied CYPs, both in the tumor and in conventionally normal groups. However, when we performed a paired test between the tumor and normal groups, we found no significant difference in the expression of the studied genes. We did observe a tendency to increase the level of CYP1B1 expression in the tumor group. We also did not find any significant difference between the levels of the studied CYPs in the tumor and conventional normal groups at different stages of prostate cancer and pathomorphological indicators. Correlation analysis revealed the presence of a positive relationship between the expressions of some cholesterol-metabolizing CYP genes, as well as between genes responsible for vitamin D biosynthesis and cholesterol biosynthesis. We observed significant correlative relationships between the expression of CYPs and some prostate cancer-related genes (CDH2, MMP9, SCHLAP1, GCR, CYP17A1, ACTA2, CXCL14, FAP, CCL17, MSMB, IRF1, VDR). Therefore, the expression of CYPs is not directly associated with prostate cancer but is largely determined by genetic, epigenetic factors, as well as endogenous substrates and xenobiotics. The significant correlative relationship between CYPs and genes associated with cancer may indicate common regulatory pathways that may have a synergistic effect on the tumor, ensuring the survival of cancer cells.

Identification of differentially expressed circRNAs in prostate cancer of different clinical stages by RNA sequencing

Circular RNAs (circRNAs) are linked to cancer, but it's still not clear what role they play in prostatic cancer. Through high-throughput sequencing, the goal of this study was to compare how circRNAs are expressed at different stages of prostate cancer. 12 patients attending the Department of Urology at the Second Affiliated Hospital of Nanchang University between June 2020 and October 2021 were used for RNA sequencing, and 14 patients were used for real-time fluorescent quantitative PCR (qRT-PCR). The expression profiles of prostate cancer circRNAs were constructed by sequencing with the help of next-generation high-throughput sequencing technology, and the differentially expressed circRNAs were analyzed by targeting microRNA (miRNA) loci and Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the genes from which circRNAs originated. Finally, the expression of target circRNAs in two prostate tissues was verified by qRT-PCR. Following high-throughput sequencing, 13,047 circRNAs were identified, and 605 circRNAs with significant differential expression were identified, of which 361 circRNAs were up-regulated, and 244 circRNAs were down-regulated. Analysis of circRNA-originated genes using GO and the KEGG enrichment analysis showed that circRNA host genes can regulate and influence multiple signaling pathways in prostate cancer with important biological functions. And the circRNA–miRNA network was constructed. The highest number of differentially expressed circRNA-binding miRNAs were: hsa_circ_000 7582 (52), hsa_circ_000 6198 (37), hsa_circ_000 6759 (28), hsa_circ_000 5675 (25), and hsa_circ_000 2172 (22). Moreover, we further screened out the circRNA (hsa_circ_0005692) that was significantly differentially expressed and common to all groups and verified by qRT-PCR that the expression of the target circRNA (hsa_circ_0005692) was significantly downregulated in prostate cancer compared with benign prostatic hyperplasia (BPH) tissues.

Lysosome-dependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer.

Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive post-translational FOXA1 regulating mechanisms. Here, we show that SKP2 (S-phase kinase-associated protein 2) catalyzes K6- and K29-linked polyubiquitination of FOXA1 for lysosomal-dependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages I-III, together with a strong inverse correlation (r = -0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2-FOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2-Foxa1-Pcna signaling and colocalization, whereas disruption of the Skp2-Foxa1 interplay in Pten/Trp53/Skp2 triple-null mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1-41 decreased tumor proliferation, SKP2:FOXA1 ratios, and colocalization. Thus, our results highlight the significance of the SKP2-FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control.

The Impact of PSMA PET/CT on Modern Prostate Cancer Management and Decision Making—The Urological Perspective

Prostate-specific membrane antigen (PSMA) PET use in prostate cancer treatment has recently become a routinely used imaging modality by urologists. New, established data regarding its performance in different stages of prostate cancer, as well as gaining clinical knowledge with new tracers, drives the need for urologists and other clinicians to improve the utilization of this tool. While the use of PSMA PET/CT is more common in metastatic disease, in which it outperforms classical imaging modalities and drives treatment decisions and adjustments, recently, it gained ground in localized prostate cancer as well, especially in high-risk disease. Still, PSMA PET/CT might reveal lesions within the prostate or possibly locoregional or metastatic disease, not always representing true cancer when utilized in earlier stages of the disease, potentially adding diagnostic burden and changing treatment decisions. As urological treatment options advance toward focal treatments in localized organ-confined prostate cancer, recent reports suggest the utilization of PSMA PET/CT in treatment planning and follow-up and even when choosing active surveillance. This review aims to reveal the current perspective of urologists regarding its daily use.

The Relationship between Telomere Length and Nucleoplasmic Bridges and Severity of Disease in Prostate Cancer Patients

Telomeres are repetitive nucleotide (TTAGGG) sequences that stabilize the chromosome ends and play an important role in the prevention of cancer initiation and progression. Nucleoplasmic bridges (NPBs) are formed when chromatids remain joined together during mitotic anaphase either due to mis-repair of DNA breaks or due to chromatid end fusion as a result of telomere loss or telomere dysfunction. We tested the hypotheses that (i) telomere length (TL) is shorter in prostate cancer (PC) patients relative to healthy age-matched individuals, (ii) TL differs in different stages of PC and (iii) shorter TL is significantly correlated with NPBs formation in PC cases. TL was measured in whole blood by well-established quantitative PCR method and the frequency of NPBs was measured in lymphocytes using cytokinesis-block micronucleus cytome (CBMNcyt) assay. Our results indicate that TL is shorter and NPBs are increased in PC patients relative to age-matched healthy controls. Furthermore, TL was significantly shorter (p = 0.03) in patients with a Gleason score more than 7 and there was also a significant trend of decreasing TL across all three stages (p trend = 0.01; Gleason score &lt;7, 7 and &gt;7). Furthermore, TL was significantly inversely correlated with NPB frequency in PC patients (r = −0.316; p = 0.001) but not in controls (r = 0.163; p = 0.06) and their relationships became stronger with higher Gleason scores. More studies are required that can confirm our observations and explore mechanistic differences in the role of telomeres in NPB formation in PC cases relative to non-cancer cases.

Deregulation of miR-10b and miR-21 Correlate with Cancer Stem Cells Expansion through the Apoptotic Pathway in Prostate Cancer.

MicroRNAs are small, non-coding RNA molecules that regulate important cellular processes such as tumorigenesis, cell proliferation, and apoptosis. Cancer stem cells are a subset of cells that control metastasis and cell proliferation. In this study, we focus on the roles of miR-10b, miR-21 and correlate with cancer stem cells through the apoptotic pathway in different stages of prostate cancer (PCa). In total, 45 patients, each group with Benign prostatic hyperplasia (BPH), localised PCa, and metastatic PCa, were recruited. MicroRNA and gene expression were estimated through quantitative polymerase chain reaction. Flow cytometry was used to characterise prostate cancer stem cells (PCSCs), estimate reactive oxygen species (ROS), apoptosis and chemiluminescent immunoassay was used to estimate interleukin 6 (IL-6), tumour necrosis factor (TNF-α), prostate-specific antigen (PSA), and testosterone. The fold change mean expressions of miR-21, miR-10b, Cytochrome C, and B-cell lymphoma 2 (BCL-2) were significantly upregulated in localised and metastatic PCa compared with BPH. In contrast, the mean fold change expressions of Bcl-2-associated X protein (BAX), Caspase-3, Caspase-9, and Second mitochondria-derived activator of caspase (SMAC) were lower in localised and metastatic PCa compared to BPH. The levels of IL-6, TNF-α, ROS, PSA and testosterone also showed a significant increase while apoptosis was decreased in both localized PCa and metastatic PCa as compared with BPH. In bioinformatics analyses, we found a similar pattern of miRNAs and gene expression in PCa databases. Our study also found a high expression of CD44+/CD24- and CD44+/CD133+ in localised and metastatic PCa compared with BPH. Our findings suggest miR-10b and miR-21 promote PCSCs and may target apoptotic genes involved in PCa pathogenesis; these miRNAs could be used as diagnosis biomarkers of PCa. In PCa pathogenesis and PCSCs regulation, the interaction between these two players is crucial and will help develop new PCa therapeutic targets.

MRI for detection, staging, and follow-up of prostate cancer: Synthesis of the PI-RADS v2.1, MET-RADS, PRECISE, and PI-RR guidelines

Prostate cancer is very common among men. Radiology, mainly through MRI, plays a key role in the different stages of prostate cancer: diagnosis, staging and treatment assessment. The correct management of MRI requires knowledge and proper use of the different guidelines developed for the acquisition, interpretation and reporting of MRI in diagnosis (PI-RADS guide), whole body staging (MET-RADS guide), active surveillance (PRECISE guide) and local recurrence (PI-RR guide) in prostate cancer. The objective of this article is to show an update and synthesis of the most relevant aspects of these MRI guidelines for an optimal use and thus providing a more effective management of prostate cancer.

A systematic method introduced a common lncRNA-miRNA-mRNA network in the different stages of prostate cancer.

The present study aimed to investigate the interaction of the common lncRNA-miRNA-mRNA network involved in signaling pathways in different stages of prostate cancer (PCa) by using bioinformatics and experimental methods. Seventy subjects included sixty PCa patients in Local, Locally Advanced, Biochemical Relapse, Metastatic, and Benign stages, and ten healthy subjects were entered into the current study. The mRNAs with significant expression differences were first found using the GEO database. The candidate hub genes were then identified by analyzing Cytohubba and MCODE software. Cytoscape, GO Term, and KEGG software determined hub genes and critical pathways. The expression of candidate lncRNAs, miRNAs, and mRNAs was then assessed using Real-Time PCR and ELISA techniques. 4 lncRNAs, 5 miRNAs, and 15 common target genes were detected in PCa patients compared with the healthy group. Unlike the tumor suppressors, the expression levels of common onco-lncRNAs, oncomiRNAs, and oncogenes showed a considerable increase in patients with advanced stages; Biochemical Relapse and Metastatic, in comparison to the primary stages; Local and Locally Advanced. Additionally, their expression levels significantly increased with a higher Gleason score than a lower one. Identifying a common lncRNA-miRNA-mRNA network associated with prostate cancer may be clinically valuable as potential predictive biomarkers. They can also serve as novel therapeutic targets for PCa patients.

Abstract 5792: The novel therapeutic diiminoquinone exhibits anticancer effects on human prostate cancer cells in 2D and 3D in vitro models

Abstract Aim: To investigate the anticancer potential of the novel quinone DIQ on prostate cancer (PCa) cells in two-dimensional (2D) and three-dimensional (3D) in vitro. Methods: The anti-proliferative effect of DIQ on PC3 and DU145 PCa cell lines was determined in vitro by using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion assays. In addition, the potency of DIQ was tested on the formation and size of PCa cell-derived prostatospheres and organoids grown in a specialized 3D-culture system. Also, 3D organoids were established from fresh tissue samples representing different stages of PCa obtained from consented patients who underwent radical prostatectomy at the American University of Beirut Medical Center (AUBMC) according to appropriate Institutional Review Board (IRB) approval guidelines. This model was used to assess DIQ individualized tumor response on organoids growth and the effect was evaluated by quantifying the number of organoids formed (OFC) and calculating the average size (diameters). Results: Our results showed that DIQ significantly attenuated cell proliferation and viability in PC3 and DU145 PCa cell lines. DIQ also reduced the formation ability and size of PC3 and DU145 prostatospheres and organoids at sub-toxic doses of 1 µM. Potently, DIQ displayed a significant decrease in both the count and the size of the different patient-derived organoids as compared to their respective control. Conclusion: This study provides promising clues for the use of the novel anticancer therapeutic DIQ in targeting CSCs, findings that may have promising therapeutic implications for PCa patients. Citation Format: Amani Yehya, Alissar Monzer, Kevork Wakimian, Fatima Ghamlouche, Nour Saheb, Ayman Tawil, Hala Gali-Muhtasib, Deborah Mukherji, Albert El-Hajj, Wassim G. Abou-Kheir. The novel therapeutic diiminoquinone exhibits anticancer effects on human prostate cancer cells in 2D and 3D in vitro models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5792.

Abstract 1343: Mesenchymal cell populations associated with different stages of prostate cancer progression in mice and human

Abstract Mesenchymal cells in the prostate cancer (PCa) tumor microenvironment (TME) contribute to the biological and clinical history of PCa. Indeed, mesenchymal cells heavily interact with cancer cells, immune cells, and the other cellular and non-cellular components of the TME to favor or hinder carcinogenesis and tumor progression. Using a comprehensive array of genetically engineered mouse models (GEMMs) of prostate cancer, 8 mesenchymal populations with different transcriptional programs are preferentially enriched in specific GEMMs at different stages of PCa. Here, we determine the transferability of this mesenchymal cluster designation from mice PCa models to human PCa cases. To this end, we compared: a) Tmprss2-ERG (T-ERG) mouse and ERG+ human cases; b) Pb4-Cre+/-;Ptenf/f;LSL-MYCN+/+;Rb1f/f (PRN) mouse and PCa bone metastasis. We generated scRNA-seq data for &amp;gt; 8000 mesenchymal cells from ERG+ (n=6) and ERG- (n=3) PCa patients, and we retrieved data for bone metastasis mesenchymal cells (osteoblasts, osteoclasts, endothelial cells, pericytes; 1,872 total cells) from GSE143791. To transfer the stromal mouse clusters’ labels to human data, human gene symbols were converted to their mouse counterparts, then both datasets were restricted to overlapping genes. For the human PCa cases, label transfer was performed through ‘ingest’ using the scRNA-seq data from the mouse T-ERG model as reference for the human ERG+ cases and data from the remaining GEMMs as reference for the human ERG- cases. For bone metastases cases, mouse stromal data from all GEMMs were used to project the 8 stromal clusters to the mesenchymal cells in the bone metastases microenvironment. Not surprisingly, ERG+ human samples were enriched (&amp;gt; 60% of total stromal cells) in mouse stroma clusters predominantly present in T-ERG mouse model, characterized by the expression of Wnt regulators and AR. Common populations to all murine models, representing myofibroblasts and immunomodulatory fibroblasts (expressing Gpx3, C3, C7, Cfh), were also commonly present in patients, irrespectively to the ERG status. In the PCa bone metastases, mesenchymal clusters enriched in the PRN model were strongly represented in human bone metastases, comprising &amp;gt; 60% of total stromal cells. These cells were characterized by high expression of POSTN and MKI67, as well as bone-specific genes like BGN. Altogether, these findings suggest that our mesenchymal cluster designation developed using GEMMs can be meaningfully applied to human PCa, and that the different transcriptional programs we identified in distinct mesenchymal population are conserved across species. This lays the foundation for the utilization of defined genetically-engineered models in defining the interactions and cross-talks between different mesenchymal populations in relation to cancer and immune cells and other components of the TME in human prostate cancer. Citation Format: Mohamed Omar, Hubert Pakula, Filippo Pederzoli, Giuseppe N. Fanelli, Tania Panellinni, Ryan Carelli, Silvia Rodrigues, Caroline Fidalgo-Ribeiro, Pier V. Nuzzo, Lucie V. Emmenis, Mohammad Mohammad, Madhavi Jere, Caitlin Unkenholz, David Rickman, Christopher Barbieri, Brian Robinson, Luigi Marchionni, Massimo Loda. Mesenchymal cell populations associated with different stages of prostate cancer progression in mice and human [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1343.

Abstract 6023: Plasma methylome landscape across the spectrum of prostate cancer progression, and differentially methylated region (DMR) based biomarkers of hormonal therapy failure in metastatic hormone-sensitive prostate cancer

Abstract Background: DNA silencing of gene expression can affect tumorigenesis, treatment outcomes and prognosis. Epigenetic silencing of tumor suppressor genes in prostate cancer detected in plasma at different stages of progression and its effect on clinical outcomes has not been determined. In a cohort study across different stages of prostate cancer (PC) progression, we performed plasma cell-free DNA (cfDNA)-based epigenomic profiling for determining the landscape of methylation and Differentially Methylated Region (DMR) classifiers and the potential impact on clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) state. Methods: Plasma was collected prospectively in a longitudinal cohort study of 108 PC patients (pts) of which 24 had non-metastatic Local PC; 28 had mHSPC; 56 had mCRPC. cfDNA was used for enzymatic methylation sequencing (EM-seq) of a targeted panel of genes (N=441) implicated in prostate cancer biology. Methylation status at CpG islands of these genes were examined using Twist targeted cfDNA methylation assay. The Bismark program was used for methylation calls. Temporal trends of differentially methylated regions (DMRs) were identified in different states of progression by comparing the methylation status of target genes in localized PC, mHSPC and mCRPC states using a False Discovery Rate (FDR-q-value) of 0.2 or less. DMRs uniquely associated with mHSPC state were identified and determination of genes with DMRs in pts experiencing early failure of androgen deprivation therapy (ADT)-based therapies was performed. Early failure was defined as progression on ADT within 12 months. Results: We identified 304/441 genes that were differentially methylated between localized PC and advanced PC (mHSPC and mCRPC) (FDR&amp;lt;0.2), of which 237 genes differed between mHSPC and mCRPC (p&amp;lt;0.05) states. mHSPC pts were serially profiles before and after 3 months of ADT-based therapies. All 28 pts experienced a PSA response at 3-months and 112/237 genes showed significant change in methylation status in these serial samples taken before/after 3 months of ADT-based therapies. The median follow up of the cohort was 18 months (range 10-24). 6/28 mHSPC pts experienced early ADT failure (&amp;lt;12 months; median 10 months). 8/112 genes were significantly associated with early failures and included DMRs in RB1, FOXA1, SOX11. GSC, ALDH1L1, SCGB3A1, FLT4, and PTPRN2. Conclusions. A targeted cfDNA plasma liquid-biopsy based epigenomic profiling of PC cancer related genes was able to capture significant differences in DMRs across different states of cancer progression. Candidate differentially expressed CpG methylome gene biomarkers detected in plasma also identified biomarkers associated with early ADT-based treatment failure in mHSPC. Citation Format: Manish Kohli, Jodie Wong, Yijun Tian, Amir Bitaraf, Claire Hanson, Matt Larsen, Jennifer Lloyd, Julia Batten, Neeraj Agarwal, Umang Swami, Benjamin Maughan, Sumati Gupta, Jonathan Tward. Plasma methylome landscape across the spectrum of prostate cancer progression, and differentially methylated region (DMR) based biomarkers of hormonal therapy failure in metastatic hormone-sensitive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6023.

Literature review: Imaging in prostate cancer

Imaging plays an increasingly important role in the detection and characterization of prostate cancer (PC). This review summarizes the key conventional and advanced imaging modalities including multiparametric magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging and tries to instruct clinicians in finding the best image modality depending on the patient`s PC-stage. We aim to give an overview of the different image modalities and their benefits and weaknesses in imaging PC.Emphasis is put on primary prostate cancer detection and staging as well as on recurrent and castration resistant prostate cancer. Results from studies using various imaging techniques are discussed and compared. For the different stages of PC, advantages and disadvantages of the different imaging modalities are discussed. Moreover, this review aims to give an outlook about upcoming, new imaging modalities and how they might be implemented in the future into clinical routine.Imaging patients suffering from PC should aim for exact diagnosis, accurate detection of PC lesions and should mirror the true tumor burden. Imaging should lead to the best patient treatment available in the current PC-stage and should avoid unnecessary therapeutic interventions. New image modalities such as long axial field of view PET/CT with photon-counting CT and radiopharmaceuticals like androgen receptor targeting radiopharmaceuticals open up new possibilities. In conclusion, PC imaging is growing and each image modality is aiming for improvement.

Potential role for protein kinase D inhibitors in prostate cancer.

Protein kinase D (PrKD), a novel serine-threonine kinase, belongs to a family of calcium calmodulin kinases that consists of three isoforms: PrKD1, PrKD2, and PrKD3. The PrKD isoforms play a major role in pathologic processes such as cardiac hypertrophy and cancer progression. The charter member of the family, PrKD1, is the most extensively studied isoform. PrKD play a dual role as both a proto-oncogene and a tumor suppressor depending on the cellular context. The duplicity of PrKD can be highlighted in advanced prostate cancer (PCa) where expression of PrKD1 is suppressed whereas the expressions of PrKD2 and PrKD3 are upregulated to aid in cancer progression. As understanding of the PrKD signaling pathways has been better elucidated, interest has been garnered in the development of PrKD inhibitors. The broad-spectrum kinase inhibitor staurosporine acts as a potent PrKD inhibitor and is the most well-known; however, several other novel and more specific PrKD inhibitors have been developed over the last two decades. While there is tremendous potential for PrKD inhibitors to be used in a clinical setting, none has progressed beyond preclinical trials due to a variety of challenges. In this review, we focus on PrKD signaling in PCa and the potential role of PrKD inhibitors therein, and explore the possible clinical outcomes based on known function and expression of PrKD isoforms at different stages of PCa.

Resonancia magnética en la detección, estadificación y seguimiento del cáncer de próstata: síntesis de las guías PI-RADS v2.1, MET-RADS, PRECISE y PI-RR

Prostate cancer is very common among men. Radiology, mainly through MRI, plays a key role in the different stages of prostate cancer: diagnosis, staging and treatment assessment. The correct management of MRI requires knowledge and proper use of the different guidelines developed for the acquisition, interpretation and reporting of MRI in diagnosis (PI-RADS guide), whole body staging (MET-RADS guide), active surveillance (PRECISE guide) and local recurrence (PI-RR guide) in prostate cancer. The objective of this article is to show an update and synthesis of the most relevant aspects of these MRI guidelines for an optimal use and thus providing a more effective management of prostate cancer.