The Prostate最新文献

{"title":"Minimally invasive surgical therapies for benign prostatic hyperplasia in the geriatric population: A systematic review.","authors":"A. Abid, H. Piperdi, M. Babar, J. Loloi, Ahmed Moutwakil, Umair Azhar, P. Maria, A. Small","doi":"10.1002/pros.24717","DOIUrl":"https://doi.org/10.1002/pros.24717","url":null,"abstract":"BACKGROUND\u0000Geriatric patients, prone to adverse events (AEs) and low compliance with drugs, may benefit from minimally invasive surgical therapies (MISTs) for managing benign prostatic hyperplasia (BPH). We evaluated the efficacy, safety, and procedural characteristics of MISTs in geriatric patients with BPH.\u0000\u0000\u0000METHODS\u0000PubMed/MEDLINE database was systematically searched for relevant articles through October 1, 2023. Eligible studies focused on geriatric patients (≥65 years) with BPH who were treated with MISTs and evaluated follow-up surgical, micturition, and/or sexual outcomes. Studies were included if there was separate reporting for age subgroups ≥65 years, or if the mean age minus standard deviation was ≥65 years, or if the first quartile was ≥65 years.\u0000\u0000\u0000RESULTS\u0000Out of 292 screened studies, 32 (N = 3972 patients) met inclusion criteria and assessed prostatic artery embolization (PAE), Rezum, GreenLight, holmium laser enucleation of the prostate (HoLEP), thulium laser enucleation of the prostate (ThuLEP), diode laser enucleation of the prostate (DiLEP), and Aquablation. Except for Rezum, all MISTs required a planned overnight stay. While PAE and Rezum could be performed under local anesthesia, the other MISTs needed general or spinal anesthesia. Postoperative catheterization duration was longest for PAE (median 14 days) and Rezum (21 days) and shortest for GreenLight (1.9 days). At 12 months postoperatively, all MISTs exhibited significant percent changes in International Prostate Symptom Score (median -69.9%) and quality of life (median -72.5%). Clavien-Dindo Grade 1 AEs ranged widely, with PAE (5.8%-36.8%), Rezum (0%-62.1%), and GreenLight (0%-67.6%) having the largest range, and HoLEP (0%-9.5%), ThuLEP (2%-6.9%), and DiLEP (5%-17.5%) having the smallest. PAE, Rezum, DiLEP, and Aquablation reported no significant changes in the International Index of Erectile Function.\u0000\u0000\u0000CONCLUSIONS\u0000Although all the MISTs reviewed in this study effectively treat BPH in geriatric patients, differences in procedural characteristics and safety profiles across MISTs were considerable. Physicians should use shared decision-making processes, considering risks and patient characteristics, when choosing a suitable treatment option for their patients.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"25 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140660955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular analysis of archival diagnostic prostate cancer biopsies identifies genomic similarities in cases with progression post‐radiotherapy, and those with de novo metastatic disease","authors":"Philip Vincent Charlton, Dawn O'Reilly, Yiannis Philippou, Srinivasa Rao Rao, Alastair David Gordon Lamb, Ian Geoffrey Mills, Geoff Stuart Higgins, Freddie Charles Hamdy, Clare Verrill, Francesca Meteora Buffa, Richard John Bryant","doi":"10.1002/pros.24715","DOIUrl":"https://doi.org/10.1002/pros.24715","url":null,"abstract":"BackgroundIt is important to identify molecular features that improve prostate cancer (PCa) risk stratification before radical treatment with curative intent. Molecular analysis of historical diagnostic formalin‐fixed paraffin‐embedded (FFPE) prostate biopsies from cohorts with post‐radiotherapy (RT) long‐term clinical follow‐up has been limited. Utilizing parallel sequencing modalities, we performed a proof‐of‐principle sequencing analysis of historical diagnostic FFPE prostate biopsies. We compared patients with (i) stable PCa (sPCa) postprimary or salvage RT, (ii) progressing PCa (pPCa) post‐RT, and (iii) de novo metastatic PCa (mPCa).MethodsA cohort of 19 patients with diagnostic prostate biopsies (<jats:italic>n</jats:italic> = 6 sPCa, <jats:italic>n</jats:italic> = 5 pPCa, <jats:italic>n</jats:italic> = 8 mPCa) and mean 4 years 10 months follow‐up (diagnosed 2009–2016) underwent nucleic acid extraction from demarcated malignancy. Samples underwent 3′RNA sequencing (3′RNAseq) (<jats:italic>n</jats:italic> = 19), nanoString analysis (<jats:italic>n</jats:italic> = 12), and Illumina 850k methylation (<jats:italic>n</jats:italic> = 8) sequencing. Bioinformatic analysis was performed to coherently identify differentially expressed genes and methylated genomic regions (MGRs).ResultsEighteen of 19 samples provided useable 3′RNAseq data. Principal component analysis (PCA) demonstrated similar expression profiles between pPCa and mPCa cases, versus sPCa. Coherently differentially methylated probes between these groups identified ~600 differentially MGRs. The top 50 genes with increased expression in pPCa patients were associated with reduced progression‐free survival post‐RT (<jats:italic>p</jats:italic> &lt; 0.0001) in an external cohort.Conclusions3′RNAseq, nanoString and 850k‐methylation analyses are each achievable from historical FFPE diagnostic pretreatment prostate biopsies, unlocking the potential to utilize large cohorts of historic clinical samples. Profiling similarities between individuals with pPCa and mPCa suggests biological similarities and historical radiological staging limitations, which warrant further investigation.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"102 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140798487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translation and validation of a lifestyle questionnaire related to prostate cancer.","authors":"Reyhane Karegar-Niavol, Fatemeh Ghaffari, Ali Saravi, Z. Fotokian, F. Kheirkhah","doi":"10.1002/pros.24713","DOIUrl":"https://doi.org/10.1002/pros.24713","url":null,"abstract":"BACKGROUND\u0000Valid and reliable instruments are needed to measure prostate cancer-related lifestyle changes, plan evidence-based interventions to modify lifestyle, and improve treatment outcomes. Due to the lack of appropriate instruments, this study was conducted to translate the Effects of Prostate Cancer upon Lifestyle Questionnaire (EPCLQ) into Persian and examine its psychometric properties in a sample of Iranian older adults with prostate cancer.\u0000\u0000\u0000METHODS\u0000This methodological study was carried out between 2021 and 2022. Initially, the EPCLQ, comprising 36 items, was translated into Persian through a meticulous translation and back-translation procedure. Subsequent steps involved the assessment of face validity, qualitative content validity, content validity index, content validity ratio, construct validity via confirmatory factor analysis, and reliability testing of the Persian version of the EPCLQ.\u0000\u0000\u0000RESULTS\u0000The psychometric evaluation led to the exclusion of 4 items from the EPCLQ. The refined model demonstrated satisfactory fit indices (PCFI = 0.732, PNFI = 0.696, CMIN/DF = 2.29, RMSEA = 0.072, IFI = 0.920, CFI = 0.919, and GFI = 0.971), indicating an appropriate fit of the final model. The internal consistency, as measured by Cronbach's alpha, was 0.67, and the intraclass correlation coefficient for the questionnaire was 0.938, reflecting high reliability.\u0000\u0000\u0000CONCLUSIONS\u0000The Persian version of the EPCLQ, now consisting of 32 items, has been validated and is reliable for assessing the impact of prostate cancer on lifestyle among older adults. Its simplicity and the clarity of the items make it suitable for use in clinical settings or during home visits for follow-up assessments.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"118 34","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140678093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of PARP inhibitor treatment on the prevalence and progression of clonal hematopoiesis in patients with advanced prostate cancer","authors":"Catherine H. Marshall, Lukasz P. Gondek, Violet Daniels, Changxue Lu, Sergiu Pasca, Jiajun Xie, Mark C. Markowski, Channing J. Paller, Laura A. Sena, Samuel R. Denmeade, Jun Luo, Emmanuel S. Antonarakis","doi":"10.1002/pros.24712","DOIUrl":"https://doi.org/10.1002/pros.24712","url":null,"abstract":"BackgroundPoly ADP‐ribose polymerase (PARP) inhibitors are approved for the treatment of some men with advanced prostate cancer. Rare but serious side effects include myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The impact of PARP inhibitors on clonal hematopoiesis (CH), a potential precursor lesion associated with MDS and AML, is incompletely understood in prostate cancer. We hypothesized that PARP inhibitors would increase CH prevalence and abundance.MethodsWe prospectively enrolled participants with advanced prostate cancer treated with PARP inhibitors. The presence of CH was assessed from leukocytes using an ultra‐deep error‐corrected dual unique molecular identifiers sequencing method targeting 49 genes most commonly mutated in CH and myeloid malignancies. Variant allele frequencies (VAF) of ≥0.5% were considered clinically significant. Blood samples were collected before and after PARP inhibitor treatment.ResultsTen men were enrolled; mean age of 67 years. Six patients had Gleason 7 disease, and four had Gleason ≥8 disease at diagnosis. Nine had localized disease at diagnosis, and eight had prior treatment with radiation. The mean time between pre‐ and post‐treatment blood samples was 11 months (range 2.6–31 months). Six patients (60%) had CH identified prior to PARP inhibitor treatment, three with multiple clones. Of 11 CH clones identified in follow‐up, 5 (45%) appeared or increased after treatment. DNMT3A, TET2, and PPM1D were the most common CH alterations observed. The largest post‐treatment increase involved the PPM1D gene.ConclusionCH alterations are frequently found after treatment with PARP inhibitors in patients with prostate cancer and this may be one mechanism by which PARP inhibitors lead to increased risk of MDS/AML.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140626995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXA1 regulates ribosomal RNA transcription in prostate cancer","authors":"Tianwei Jia, Chenxu Liu, Ping Guo, Yaning Xu, Wenzheng Wang, Xiaoyu Liu, Song Wang, Xianglin Zhang, Haiyang Guo","doi":"10.1002/pros.24714","DOIUrl":"https://doi.org/10.1002/pros.24714","url":null,"abstract":"BackgroundRibosome biogenesis is excessively activated in tumor cells, yet it is little known whether oncogenic transcription factors (TFs) are involved in the ribosomal RNA (rRNA) transactivation.MethodsNucleolar proteomics data and large‐scale immunofluorescence were re‐analyzed to jointly identify the proteins localized at nucleolus. RNA‐Seq data of five prostate cancer (PCa) cohorts were combined and integrated with multi‐dimensional data to define the upregulated nucleolar TFs in PCa tissues. Then, ChIP‐Seq data of PCa cell lines and two PCa clinical cohorts were re‐analyzed to reveal the TF binding patterns at ribosomal DNA (rDNA) repeats. The TF binding at rDNA was validated by ChIP‐qPCR. The effect of the TF on rRNA transcription was determined by rDNA luciferase reporter, nascent RNA synthesis, and global protein translation assays.ResultsIn this study, we reveal the role of oncogenic TF FOXA1 in regulating rRNA transcription within nucleolar organization regions. By analyzing human TFs in prostate cancer clinical datasets and nucleolar proteomics data, we identified that FOXA1 is partially localized in the nucleolus and correlated with global protein translation. Our extensive FOXA1 ChIP‐Seq analysis provides robust evidence of FOXA1 binding across rDNA repeats in prostate cancer cell lines, primary tumors, and castration‐resistant variants. Notably, FOXA1 occupancy at rDNA repeats correlates with histone modifications associated with active transcription, namely H3K27ac and H3K4me3. Reducing FOXA1 expression results in decreased transactivation at rDNA, subsequently diminishing global protein synthesis.ConclusionsOur results suggest FOXA1 regulates aberrant ribosome biogenesis downstream of oncogenic signaling in prostate cancer.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"219 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140626993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes of 10 years of PSA screening for prostate cancer in Norwegian men with Lynch syndrome","authors":"Eli Marie Grindedal, Manuela Zucknick, Astrid Stormorken, Elin Rønne, Nora M. Tandstad, William B. Isaacs, Karol Axcrona, Lovise Mæhle","doi":"10.1002/pros.24711","DOIUrl":"https://doi.org/10.1002/pros.24711","url":null,"abstract":"BackgroundPathogenic germline variants in the mismatch repair (MMR) genes are associated with an increased risk of prostate cancer (PCa). Since 2010 we have recommended MMR carriers annual PSA testing from the age of 40. Prospective studies of the outcome of long‐term PSA screening are lacking. This study aimed to investigate the incidence and characteristics of PCa in Norwegian MMR carriers attending annual PSA screening (PSA threshold &gt;3.0 ng/mL) to evaluate whether our recommendations should be continued.MethodsThis is a prospective observational study of 225 male MMR carriers who were recommended annual PSA screening by the Section of Inherited Cancer, Oslo University Hospital from 2010 and onwards. Incidence and tumor characteristics (age, PSA at diagnosis, Gleason score, TNM score) were described. IHC and MSI‐analyses were done on available tumors. Standardized incidence ratio (SIR) was calculated based on data from the Cancer Registry of Norway.ResultsTwenty‐two of 225 (9.8%) had been diagnosed with PCa, including 10/69 (14.5%) <jats:italic>MSH2</jats:italic> carriers and 8/61 (13.1%) <jats:italic>MSH6</jats:italic> carriers. Ten of 20 (50%) tumors had Gleason score ≥4 + 3 on biopsy and 6/11 (54.5%) had a pathological T3a/b stage. Eight of 17 (47.1%) tumors showed abnormal staining on IHC and 3/13 (23.1%) were MSI‐high. SIR was 9.54 (95% CI 5.98–14.45) for all MMR genes, 13.0 (95% CI 6.23–23.9) for <jats:italic>MSH2</jats:italic> and 13.74 for <jats:italic>MSH6</jats:italic> (95% CI 5.93–27.08).ConclusionsOur results indicate that the MMR genes, and especially <jats:italic>MSH2</jats:italic> and <jats:italic>MSH6</jats:italic>, are associated with a significant risk of PCa, and a high number of tumors show aggressive characteristics. While the impact of screening on patient outcomes remains to be more firmly established, the high SIR values we observe provide support for continued PSA screening of <jats:italic>MSH2</jats:italic> and <jats:italic>MSH6</jats:italic> carriers. Studies are needed to provide optimal recommendations for PSA‐threshold and to evaluate whether <jats:italic>MLH1</jats:italic> and <jats:italic>PMS2</jats:italic> carriers should not be recommended screening.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140617945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki67","authors":"Fengnian Zhao, Jinge Zhao, Xinyuan Wei, Yifu Shi, Nanwei Xu, Sha Zhu, Junru Chen, Guangxi Sun, Jindong Dai, Zhipeng Wang, Xingming Zhang, Jiayu Liang, Xu Hu, Haoyang Liu, Junjie Zhao, Zhenhua Liu, Ling Nie, Pengfei Shen, Ni Chen, Hao Zeng","doi":"10.1002/pros.24710","DOIUrl":"https://doi.org/10.1002/pros.24710","url":null,"abstract":"BackgroundKI67 is a well‐known biomarker reflecting cell proliferation. We aim to elucidate the predictive role of KI67 in the efficacy of abiraterone for patients with advanced prostate cancer (PCa).MethodsClinicopathological data of 152 men with metastatic PCa, who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry using the prostate biopsy specimen. The predictive value of KI67 on the therapeutic efficacy of abiraterone was explored using Kaplan–Meier curve and Cox regression analysis. The endpoints included prostate‐specific antigen (PSA) progression‐free survival (PSA‐PFS), radiographic PFS (rPFS), and overall survival (OS).ResultsIn total, 85/152 (55.9%) and 67/152 (44.1%) cases, respectively, received abiraterone at metastatic hormone‐sensitive (mHSPC) and castration‐resistant PCa (mCRPC) stage. The median KI67 positivity was 20% (interquartile range: 10%–30%). Overall, KI67 rate was not correlated with PSA response. Notably, an elevated KI67‐positive rate strongly correlated with unfavorable abiraterone efficacy, with KI67 ≥ 30% and KI67 ≥ 20% identified as the optimal cutoffs for prognosis differentiation in mHSPC (median PSA‐PFS: 11.43 Mo vs. 26.43 Mo, <jats:italic>p</jats:italic> &lt; 0.001; median rPFS: 16.63 Mo vs. 31.90 Mo, <jats:italic>p</jats:italic> = 0.003; median OS: 21.77 Mo vs. not reach, <jats:italic>p</jats:italic> = 0.005) and mCRPC (median PSA‐PFS: 7.17 Mo vs. 12.20 Mo, <jats:italic>p</jats:italic> = 0.029; median rPFS: 11.67 Mo vs. 16.47 Mo, <jats:italic>p</jats:italic> = 0.012; median OS: 21.67 Mo vs. not reach, <jats:italic>p</jats:italic> = 0.073) patients, respectively. Multivariate analysis supported the independent predictive value of KI67 on abiraterone efficacy. In subgroup analysis, an elevated KI67 expression was consistently associated with unfavorable outcomes in the majority of subgroups. Furthermore, data from another cohort of 79 PCa patients with RNA information showed that those with KI67 RNA levels above the median had a significantly shorter OS than those below the median (17.71 vs. 30.72 Mo, <jats:italic>p</jats:italic> = 0.035).ConclusionsThis study highlights KI67 positivity in prostate biopsy as a strong predictor of abiraterone efficacy in advanced PCa. These insights will assist clinicians in anticipating clinical outcomes and refining treatment decisions for PCa patients.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of structural, biochemical, pharmacokinetic, and pharmacodynamic properties of the LSD1 inhibitor bomedemstat in preclinical models","authors":"Sumer Jasmine, Adel Mandl, Timothy E. G. Krueger, Susan L. Dalrymple, Lizamma Antony, Jennifer Dias, Cassandra A. Celatka, Amy E. Tapper, Maria Kleppe, Mayuko Kanayama, Yuezhou Jing, Valentina Speranzini, Yuzhuo Z. Wang, Jun Luo, Bruce J. Trock, Samuel R. Denmeade, Michael A. Carducci, Andrea Mattevi, Hugh Y. Rienhoff, John T. Isaacs, W. Nathaniel Brennen","doi":"10.1002/pros.24707","DOIUrl":"https://doi.org/10.1002/pros.24707","url":null,"abstract":"Lysine-specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis-targeted therapies. Safe and effective LSD1 inhibitors are necessary to determine antitumor response in prostate cancer models. For this reason, we characterize the LSD1 inhibitor bomedemstat to assess its clinical potential in NEPC as well as other mCRPC pathological subtypes.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140592910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co‐targeting SKP2 and KDM5B inhibits prostate cancer progression by abrogating AKT signaling with induction of senescence and apoptosis","authors":"LaKendria K. Brown, Thanigaivelan Kanagasabai, Guoliang Li, Sherly I. Celada, Jelonia T. Rumph, Samuel E. Adunyah, LaMonica V. Stewart, Zhenbang Chen","doi":"10.1002/pros.24706","DOIUrl":"https://doi.org/10.1002/pros.24706","url":null,"abstract":"BackgroundProstate cancer (PCa) is the second‐leading cause of cancer mortalities in the United States and is the most commonly diagnosed malignancy in men. While androgen deprivation therapy (ADT) is the first‐line treatment option to initial responses, most PCa patients invariably develop castration‐resistant PCa (CRPC). Therefore, novel and effective treatment strategies are needed. The goal of this study was to evaluate the anticancer effects of the combination of two small molecule inhibitors, SZL‐P1‐41 (SKP2 inhibitor) and PBIT (KDM5B inhibitor), on PCa suppression and to delineate the underlying molecular mechanisms.MethodsHuman CRPC cell lines, C4‐2B and PC3 cells, were treated with small molecular inhibitors alone or in combination, to assess effects on cell proliferation, migration, senescence, and apoptosis.ResultsSKP2 and KDM5B showed an inverse regulation at the translational level in PCa cells. Cells deficient in SKP2 showed an increase in KDM5B protein level, compared to that in cells expressing SKP2. By contrast, cells deficient in KDM5B showed an increase in SKP2 protein level, compared to that in cells with KDM5B intact. The stability of SKP2 protein was prolonged in KDM5B depleted cells as measured by cycloheximide chase assay. Cells deficient in KDM5B were more vulnerable to SKP2 inhibition, showing a twofold greater reduction in proliferation compared to cells with KDM5B intact (<jats:italic>p</jats:italic> &lt; 0.05). More importantly, combined inhibition of KDM5B and SKP2 significantly decreased proliferation and migration of PCa cells as compared to untreated controls (<jats:italic>p</jats:italic> &lt; 0.005). Mechanistically, combined inhibition of KDM5B and SKP2 in PCa cells abrogated AKT activation, resulting in an induction of both cellular senescence and apoptosis, which was measured via Western blot analysis and senescence‐associated β‐galactosidase (SA‐β‐Gal) staining.ConclusionsCombined inhibition of KDM5B and SKP2 was more effective at inhibiting proliferation and migration of CRPC cells, and this regimen would be an ideal therapeutic approach of controlling CRPC malignancy.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An orthotopic prostate cancer model for new treatment development using syngeneic or patient‐derived tumors","authors":"Naz Chaudary, E. Wiljer, Warren Foltz, Pratibha Thapa, Richard P. Hill, Michael Milosevic","doi":"10.1002/pros.24701","DOIUrl":"https://doi.org/10.1002/pros.24701","url":null,"abstract":"BackgroundThere are limited preclinical orthotopic prostate cancer models due to the technical complexity of surgical engraftment and tracking the tumor growth in the mouse prostate gland. Orthotopic xenografts recapitulate the tumor microenvironment, tumor stromal interactions, and clinical behavior to a greater extent than xenografts grown at subcutaneous or intramuscular sites.MethodsThis study describes a novel micro‐surgical technique for orthotopically implanting intact tumors pieces from cell line derived (transgenic adenocarcinoma mouse prostate [TRAMP]‐C2) or patient derived (neuroendocrine prostate cancer [NEPC]) tumors in the mouse prostate gland and monitoring tumor growth using magnetic resonance (MR) imaging.ResultsThe TRAMP‐C2 tumors grew rapidly to a predetermined endpoint size of 10 mm within 3 weeks, whereas the NEPC tumors grew at a slower rate over 7 weeks. The tumors were readily detected by MR and confidently identified when they were approximately 2–3 mm in size. The tumors were less well‐defined on CT. The TRAMP‐C2 tumors were characterized by amorphous sheets of poorly differentiated cells similar to a high‐grade prostatic adenocarcinoma and frequent macroscopic peritoneal and lymph node metastases. In contrast, the NEPC's displayed a neuroendocrine morphology with polygonal cells arranged in nests and solid sheets and high count. There was a local invasion of the bladder and other adjacent tissues but no identifiable metastases. The TRAMP‐C2 tumors were more hypoxic than the NEPC tumors.ConclusionsThis novel preclinical orthotopic prostate cancer mouse model is suitable for either syngeneic or patient derived tumors and will be effective in developing and advancing the current selection of treatments for patients with prostate cancer.","PeriodicalId":501684,"journal":{"name":"The Prostate","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}