bims-meproc 2026-01-04 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–01–04
24 papers selected by
Grigor Varuzhanyan, UCLA

Differential Expression of Key Oncogenic and Tumor Suppressor MicroRNAs Induced by Andrographolide in Androgen-Independent PC3 and Androgen-Dependent LNCaP Prostate Cancer Cells.
Circular RNA-based therapy targeting metabolic vulnerability of fatty acid synthesis overcomes castration-resistant prostate cancer.
Targeting Tumor Microenvironment-Derived NRG1-HER2/3 Signaling with Zenocutuzumab Restores Sensitivity to AR Inhibition in PTEN Wild-type Prostate Cancer.
Adiponectin receptor agonist, AdipoRon, reduces the growth of prostate cancer cells and patient-derived organoids.
Exploiting Oxidative Stress as Achilles' Heel: From Redox Homeostasis to Ferroptosis in Prostate Cancer.
Identifying myosin heavy chain 11 as a predictive biomarker of prostate cancer progression and antiandrogen resistance.
Fbxo2 suppresses prostate cancer progression by regulating YTHDF2 ubiquitination and degradation.
FOXA1 Alterations in Prostate Cancer: Expression, Mutation Classes, and Copy Number Changes.
Differentially Expressed miRNA of Prostate Cancer Compared with Benign Prostatic Hyperplasia Tissues: VAMP Associated Protein B Could Be Used for New Targets and Biomarkers of Prostate Cancer.
The Olive Phenolic S-(-)-Oleocanthal as a Novel Intervention for Neuroendocrine Prostate Cancers: Therapeutic and Molecular Insights.
ADAMTS9-AS2 Disrupts Docetaxel-Resistance in Castration-Resistant Prostate Cancer via Stemness Suppression and Ferroptosis Induction.
In Silico Assessment of Silybum marianum Bioactive Compounds in Prostate Cancer Using Network Pharmacology and Molecular Docking.
Dyadic Associations of Physical Activity, Diet Quality, and Body Mass Index in Black Prostate Cancer Survivors and their Spouses: An Actor-Partner Interdependence Model Analysis.
The impact of diet and gut microbiota on development, treatment, and prognosis in prostate cancer.
Trop2 immuno-PET/CT imaging of prostate cancer: a proof-of-concept translational study.
Assessment of miRNA 106a-5p and 375-3p Expression in the Context of the Wnt/β-Catenin Pathway-Comparison of Prostate Adenocarcinoma and Benign Prostatic Hyperplasia Tissues.
Metabolomic Insights into Prostate Cancer Treatment and Relapse.
Significance of EVs in Prostate Cancer Bone Metastases.
Influence of diabetes mellitus and anti-diabetic drugs on pathophysiology and prognosis for primary prostate cancer.
TDP2 drives immune evasion and metastatic progression in prostate cancer.
Decoding the germline genetic architecture of prostate cancer at a single cell resolution.
Exploring the key functions of T cells and the regulation of the immune microenvironment in prostate cancer using single-cell RNA sequencing and bulk RNA sequencing.
Metabolomics of Prostate Cancer and Clinical Profiles Following Radiotherapy: Need for a Precision Phylometabolomics Approach.
Whole-Slide Telepathology Grading of Prostate Cancer in Biopsies Using ISUP Criteria: Inter- and Intra-Observer Concordance and Implications for Active Surveillance.

Genes (Basel). 2025 Dec 17. pii: 1514. [Epub ahead of print]16(12):

Differential Expression of Key Oncogenic and Tumor Suppressor MicroRNAs Induced by Andrographolide in Androgen-Independent PC3 and Androgen-Dependent LNCaP Prostate Cancer Cells.

Padmavati Sahare, Luis Alberto Bravo-Vázquez, Diego Antonio Veloz-Briones, Daniela Bernal-Vázquez, Ignacio Bolaños-Fernández, Brenda Anguiano, Gabriel Luna-Bárcenas, Sujay Paul.

   BACKGROUND: Prostate cancer remains a major contributor to cancer-related morbidity and mortality worldwide, emphasizing the need for safer and more effective therapeutic options. Andrographolide, a diterpenoid lactone derived from Andrographis paniculata, has shown promising anticancer activity, yet its effects on microRNA (miRNA) regulation in prostate cancer remain insufficiently explored.
METHODS: In this study, we evaluated the cytotoxic and molecular effects of andrographolide on two human prostate cancer cell lines, PC3 and LNCaP, along with HEK-293 cells as a noncancerous model.
RESULTS: Cell viability assessment using the MTT assay revealed dose-dependent cytotoxicity, with 24 h IC50 values of 82.31 µM for PC3, 68.79 µM for LNCaP, and 133.9 µM for HEK-293 cells. Subsequent expression analysis of key oncogenic and tumor suppressor miRNAs demonstrated that andrographolide induced the upregulation of miR-16-5p, miR-34a-5p, and miR-200a-5p miRNAs implicated in apoptosis, proliferation control, and androgen receptor signaling. In contrast, the expression of oncomiRs miR-21-5p and miR-221-5p showed minimal or nonsignificant changes, reflecting the complex and context-specific roles of miRNAs in prostate cancer. Gene expression profiling further indicated differential transcriptional responses between the two prostate cancer cell lines, consistent with their distinct molecular backgrounds.
CONCLUSIONS: Although HEK-293 cytotoxicity and previously reported nephrotoxic effects warrant caution, these results support the potential of andrographolide as an adjuvant phytochemical capable of modulating clinically relevant miRNAs in prostate cancer. Future studies investigating optimized delivery systems and validating direct miRNA targets may help advance andrographolide toward safer and more targeted therapeutic applications.

Keywords:  PC3 and LNCaP cells; andrographolide; cytotoxicity; microRNA expression; prostate cancer

DOI:  https://doi.org/10.3390/genes16121514
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2504904123

Circular RNA-based therapy targeting metabolic vulnerability of fatty acid synthesis overcomes castration-resistant prostate cancer.

Yudong Lin, Ruyue Wang, Fan Li, Zeyi Lu, Wenqin Luo, Haohua Lu, Zhehao Xu, Chang Xu, Yi Lu, Ziwei Zhu, Yang Li, Xudong Mao, Liqun Xia, Xiaojing Yu, Wenjing Su, Lifeng Ding, Gonghui Li.

  Androgen receptor (AR) signaling is essential for prostate cancer (PCa) cell growth and remains a key therapeutic target in castration-resistant PCa (CRPC). While circular RNAs (circRNAs) are increasingly recognized as important regulatory molecules, their roles in AR signaling during PCa progression remain poorly understood. This study identified circUTRN, an AR-inhibited circRNA that is upregulated following neoadjuvant hormonal therapy and downregulated in PCa tissues. circUTRN inhibits proliferation in both castration-sensitive and castration-resistant PCa. Mechanistically, circUTRN binds to acetyl-CoA carboxylase 1 (ACC1) and impairs the activity through both phosphorylation-dependent and independent pathways, thereby disturbing de novo fatty acid synthesis. The dynamic relation between circUTRN and ACC1 expression during PCa progression from treatment-naïve to therapeutic-resistant states highlights the metabolic vulnerability of fatty acid synthesis. Notably, we developed nanoparticles to deliver circUTRN in combination with AR signaling inhibitors (ARSIs). This approach effectively suppressed CRPC xenograft tumor growth, even in models resistant to next-generation ARSIs. This study reveals an AR-regulated circRNA involved in PCa progression and suggests a potential therapeutic strategy for treatment-resistant PCa.

Keywords:  acetyl-CoA carboxylase 1; androgen receptor; castration-resistant prostate cancer; circular RNA; fatty acid synthesis

DOI:  https://doi.org/10.1073/pnas.2504904123
Mol Cancer Ther. 2025 Dec 30. OF1-OF10

Targeting Tumor Microenvironment-Derived NRG1-HER2/3 Signaling with Zenocutuzumab Restores Sensitivity to AR Inhibition in PTEN Wild-type Prostate Cancer.

Brian M Shinder, Young Sun Lee, Ninghui Mao, Nazifa Salsabeel, Zeda Zhang, Harmanpreet Kaur, Xiaoping Chen, Qing Chang, Elisa de Stanchina, Anuradha Gopalan, Charles L Sawyers, Brett S Carver.

Investigating the mechanisms of acquired resistance to antiandrogens remains a critical clinical need as patients with prostate cancer inevitably develop resistance to androgen receptor (AR)-targeted therapies. Previously, we demonstrated that neuregulin 1 (NRG1) derived from cancer-associated fibroblasts (CAF) promotes antiandrogen resistance through human epidermal growth factor receptor 3 (HER3)-AKT signaling. In this study, we sought to further dissect the molecular context in which NRG1-induced PI3K signaling activation plays a dominant role in driving resistance and evaluate whether targeting HER2/3 dimerization can influence sensitivity to AR inhibition. IHC analysis of radical prostatectomy specimens from patients with prostate cancer treated with or without neoadjuvant hormonal therapy shows that NRG1 was significantly upregulated following AR inhibition, independent of PTEN status. However, we found that stimulation with recombinant NRG1 or CAF-conditioned media induced resistance to AR inhibition only in PTEN wild-type prostate cancer cells and not in PTEN-deficient cells. Selective inhibition of NRG1 using the clinical-grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), restored sensitivity to AR-targeted therapies in PTEN wild-type tumors, demonstrating its efficacy as a potential therapeutic agent to block the effects of NRG1. In the context of PTEN loss and AR inhibitor resistance, Zeno did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment-derived NRG1 affects responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN wild-type prostate cancers.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0505
Life Sci. 2025 Dec 26. pii: S0024-3205(25)00811-2. [Epub ahead of print]387 124175

Adiponectin receptor agonist, AdipoRon, reduces the growth of prostate cancer cells and patient-derived organoids.

Francielle C Mosele, Ana Luiza Romano Gabriel, Nilton José Dos Santos, Caroline Nascimento Barquilha, Caio Cesar Damasceno Monção, Micheli Canuto de Lima, Mark A Rubin, Sérgio Luis Felisbino, Joanna Triscott.

  Low adiponectin levels in obese men are associated with an incidence of aggressive prostate cancer (PCa). Despite significant advances in PCa treatment, some cases become resistant, making the development of new therapies crucial. An alternative treatment is the use of agonists, such as AdipoRon. Here, we elucidate the antitumor effects of AdipoRon on PCa models and demonstrate reduced cell proliferation, migration, and invasion in vitro. AdipoRon impaired mitochondrial respiration of androgen-dependent and castration-resistant cells. We show that this agonist reduces AR and PSA expression in androgen-dependent prostate cells. Adiponectin receptors (AdipoR1 and AdipoR2) were upregulated in PC3 and DU-145 cells. We hypothesize that the alteration of PPAR alpha could explain the effects of AdipoRon. Additionally, the antigrowth effects of AdipoRon were observed in the patient-derived organoids PM154 and MSK-PCa16. Our findings reveal that AdipoRon has strong in vitro antitumor effects on PCa, supporting its potential as a promising therapeutic candidate. Future studies should focus on in vivo models to validate these effects and explore the underlying mechanisms, which may open new therapies for PCa. STATEMENT OF IMPLICATION: AdipoRon decreases prostate cancer cell growth.

Keywords:  Adiponectin; Glycolysis; Mitochondria; Prostate

DOI:  https://doi.org/10.1016/j.lfs.2025.124175
Antioxidants (Basel). 2025 Dec 18. pii: 1517. [Epub ahead of print]14(12):

Exploiting Oxidative Stress as Achilles' Heel: From Redox Homeostasis to Ferroptosis in Prostate Cancer.

Sanghyeon Yu, Jihyun Baek, Taesoo Choi, Man S Kim.

  Prostate cancer remains a leading cause of cancer-related mortality and castration-resistant prostate cancer (CRPC) is a critical therapeutic challenge. This review establishes a conceptual framework analyzing ferroptosis vulnerability through two principles: "robustness through redundancy" in defense systems and the "evolutionary arms race" between androgen receptor (AR) signaling and oxidative resistance. We traced the evolutionary trajectory of hormone-sensitive diseases, where the AR coordinates ferroptosis defenses via SLC7A11, MBOAT2, and PEX10 regulation through progressive adaptations: AR-V7 splice variants that maintain defense independently of androgens, AR amplification conferring hypersensitivity, and AR-independent JMJD6-ATF4 bypass in SPOP-mutated tumors. This transforms ferroptosis from a static vulnerability to a stage-specific strategy. Novel approaches include menadione-based VPS34 targeting, which induces triaptosis through an oxidative endosomal catastrophe. We categorized the rational combinations mechanistically as vertical inhibition (multi-step targeting of single pathways), horizontal inhibition (synthetic lethality across parallel defenses), and vulnerability induction (creating exploitable dependencies). Ferroptosis-induced immunogenic cell death enables synergy with checkpoint inhibitors, potentially transforming immunologically "cold" prostate tumors. This review establishes ferroptosis targeting as a precision medicine paradigm exploiting the tension between the oxidative requirements of cancer cells and their evolved, yet architecturally vulnerable, defense systems, providing a framework for stage-specific, biomarker-guided interventions.

Keywords:  FSP1; GPX4; MBOAT2; SLC7A11; androgen receptor; castration resistance; ferroptosis; oxidative stress; precision oncology; prostate cancer

DOI:  https://doi.org/10.3390/antiox14121517
Oncol Lett. 2026 Feb;31(2): 77

Identifying myosin heavy chain 11 as a predictive biomarker of prostate cancer progression and antiandrogen resistance.

Cong Chen, Zhi Li, Jianliang Shen, Guilin Xie, Liangming Pan.

  Prostate cancer (PCa) poses a serious threat to the health of older men, with incidence rates steadily increasing worldwide. Antiandrogen drugs can effectively prolong survival in patients with PCa; however, resistance often develops after prolonged treatment and the mechanisms underlying this resistance remain to be elucidated. In the present study, genes that may serve key roles in antiandrogen drug resistance in PCa were investigated. Using the GSE211781 dataset from the Gene Expression Omnibus database, the present study analyzed RNA-sequencing data from lymph node carcinoma of the prostate (LNCaP) cell lines resistant to three antiandrogen drugs: Bicalutamide, enzalutamide and apalutamide. The present study identified 54 differentially expressed genes common to all three resistant lines, of which nine hub genes were confirmed using protein-protein interaction network analysis. Among these, myosin heavy chain 11 (MYH11) emerged as a key gene associated with both PCa progression and patient prognosis. Functional assays in C4-2 and LNCaP cells further indicated that MYH11 modulates sensitivity to bicalutamide and enzalutamide. Collectively, the present study findings suggest that MYH11 may serve as a potential predictive biomarker of PCa development and antiandrogen drug resistance in the future.

Keywords:  antiandrogen drugs; drug resistance; hub gene; myosin heavy chain 11; prostate cancer

DOI:  https://doi.org/10.3892/ol.2025.15430
Cell Death Dis. 2025 Dec 29.

Fbxo2 suppresses prostate cancer progression by regulating YTHDF2 ubiquitination and degradation.

Xinyu Xu, Guangcheng Dai, Chun-Ling Liu, Qiu Yao, Xiaowei Cai, Yang Wang, Zeyu Chen, Kang Liu, Jin Zhu, Jia Ma, Zhiwei Wang, Boxin Xue, Lixia Wang.

Deregulation of E3 ubiquitin ligases is associated with increased proliferation and metastasis in prostate cancer (PCa); however, the underlying mechanisms remain largely unclear. This study aimed to explore the role of Fbxo2, a SKP1-Cullin-F-box (SCF) E3 ubiquitin ligase, in PCa progression. Analysis of prostate tissue samples revealed that Fbxo2 is downregulated in PCa, and higher Fbxo2 expression correlates with better patient prognosis. Functional assays conducted both in vitro and in vivo demonstrated that Fbxo2 reduces cell proliferation and metastasis in PCa. Using co-immunoprecipitation mass spectrometry (co-IP-MS), co-IP, western blotting, and ubiquitin assays, we identified that m6A reader YTHDF2, an oncoprotein that is upregulated in PCa, was a substrate of Fbxo2-mediated degradation. Notably, Fbxo2 mutants lacking the C-terminal region were less effective in promoting YTHDF2 ubiquitination and destruction. Furthermore, lysine 286 (K286) of YTHDF2 was identified as the key ubiquitination site. A series of rescue experiments revealed that silencing or overexpressing YTHDF2 modulated the effects of Fbxo2 knockdown or overexpression, confirming their functional interplay. Mechanistically, YTHDF2 enhanced the PCa progression and metastasis by modulating the m6A methylation of CDKN1C mRNA. Together, these findings suggest that Fbxo2 axis may serve as a potential prognostic marker and therapeutic target in PCa.

DOI: https://doi.org/10.1038/s41419-025-08396-0
In Vivo. 2026 Jan-Feb;40(1):40(1): 341-348

FOXA1 Alterations in Prostate Cancer: Expression, Mutation Classes, and Copy Number Changes.

Steven Lehrer, Peter Rheinstein.

   BACKGROUND/AIM: Prostate cancer features profound transcriptional dysregulation within the androgen receptor (AR) signaling axis. The pioneer factor FOXA1, which facilitates AR binding to chromatin, is recurrently altered in 10-40% of tumors. Recent studies classify FOXA1 mutations as Class 1 Wing 2 mutations, which enhance AR-dependent tumorigenesis, and Class 2 C-terminal truncations, which promote lineage plasticity and therapy resistance. The interplay of FOXA1 alterations with TMPRSS2-ERG fusions and PROX1 remains incompletely understood.
MATERIALS AND METHODS: Data from The Cancer Genome Atlas (TCGA) Prostate Adenocarcinoma (PRAD) cohort (n=492) were analyzed via UCSC Xena and cBioPortal. FOXA1 mutations were categorized following Eyunni et al. Copy number was assessed by log2(tumor/normal) ratios. Mutual exclusivity and co-occurrence were evaluated using Fisher's exact test with false-discovery-rate correction. Associations between FOXA1 status and genomic instability were assessed using the fraction genome altered (FGA) metric.
RESULTS: FOXA1 was broadly expressed, with subsets showing elevation. Class 1 mutations localized to the Wing 2 region, while Class 2 truncations clustered in the C-terminal domain. Copy number changes were infrequent, indicating mutation-driven reprogramming as the main oncogenic mechanism. TMPRSS2 and ERG strongly co-occurred (log2 OR >3, q<0.001), whereas FOXA1 was mutually exclusive with both TMPRSS2 and ERG (q<0.001). Although FOXA1 alterations showed no significant Pearson correlation with FGA (r=-0.01, p=0.76), a moderate Spearman correlation (ρ=0.52, p<0.001) suggested enrichment in genomically unstable tumors.
CONCLUSION: FOXA1 defines a major oncogenic axis in prostate cancer, distinct from TMPRSS2-ERG fusion and PROX1 induction. Class 1 and 2 FOXA1 mutations drive alternative transcriptional programs leading to therapy resistance, highlighting FOXA1 as a critical biomarker and target for chromatin-directed interventions.

Keywords:  FOXA1; PROX1; TMPRSS2-ERG fusion; lineage plasticity; prostate cancer

DOI:  https://doi.org/10.21873/invivo.14197
Biomedicines. 2025 Nov 28. pii: 2922. [Epub ahead of print]13(12):

Differentially Expressed miRNA of Prostate Cancer Compared with Benign Prostatic Hyperplasia Tissues: VAMP Associated Protein B Could Be Used for New Targets and Biomarkers of Prostate Cancer.

Jae Heon Kim, Ahrim Moon, Miho Song, Kwang Woo Lee, Su Min Seo, Hui Ji Kim, Luis Alfonso Pefianco, Kevin Andrean, Seongho Ryu, Yun-Seob Song.

  Background/Objectives: This NGS-based study sought to identify novel molecular markers for prostate cancer by comparing miRNA expression in cancer and benign prostatic hyperplasia (BPH) tissues. Methods: Using high-throughput sequencing and stringent statistical criteria, the study identified eleven significantly dysregulated miRNAs (five downregulated, six upregulated) that differentiate the two conditions. Enrichment analyses linked these miRNAs to several key cancer-associated pathways, including PI3K-Akt and ErbB signaling. Results: Crucially, the protein vesicle-associated membrane protein-associated protein B (VAPB) was pinpointed as a central hub, regulated by three downregulated miRNAs (miR-143-3p, miR-221-3p, and miR-222-3p). Since VAPB has not been widely studied in prostate cancer, it represents a promising, novel candidate for both diagnosis and therapeutic targeting. Conclusions: Our NGS-based analysis revealed a distinct miRNA expression signature that differentiates prostate cancer from BPH. The downregulation of several tumor-suppressive miRNAs (with concomitant upregulation of oncogenic miRNAs) in prostate cancer may contribute to malignancy-including the de-repression of novel targets like VAPB, which we identify as a promising new biomarker and therapeutic target.

Keywords:  Micro RNA; benign prostate hyperplasia; prostate cancer; the protein vesicle-associated membrane protein-associated protein B

DOI:  https://doi.org/10.3390/biomedicines13122922
Nutrients. 2025 Dec 17. pii: 3947. [Epub ahead of print]17(24):

The Olive Phenolic S-(-)-Oleocanthal as a Novel Intervention for Neuroendocrine Prostate Cancers: Therapeutic and Molecular Insights.

Md Towhidul Islam Tarun, Hassan Y Ebrahim, Dalal Dawud, Zakaria Y Abd Elmageed, Eva Corey, Khalid A El Sayed.

  Background/Objectives. Prostate cancer (PCa) is among the leading causes of death from cancer in men. Frequent use of androgen receptor inhibitors induces PCa transdifferentiation, leading to poorly differentiated neuroendocrine PCa (NEPC). ROR2 is critical for NEPC pathogenesis by activating ASCL1, promoting lineage plasticity. Protein lysine methylation mediated by N-lysine methyltransferases SMYD2 and its downstream effector EZH2 upregulates the NEPC marker ASCL1 and enhances c-MET signaling, promoting PCa aggression. Epidemiological studies suggest a lower incidence of certain malignancies in Mediterranean populations due to their intake of an olive-phenolics-rich diet. Methods. Cell viability, gene knockdown, and immunoblotting were used for in vitro analyses. A nude mouse NEPC xenograft model evaluated the anti-tumor efficacy of purified and crude oleocanthal. Xenograft tumors were subjected to RNA-seq, qPCR, and Western blot analyses, with clinical validation performed using tissue microarrays. Results. A tissue microarray analysis showed that SMYD2 expression was significantly elevated in PCa tissues with higher IHS versus normal prostate tissue cores. The olive phenolic S-(-)-oleocanthal (OC) suppressed the de novo NEPC NCI-H660 cells proliferation. Male athymic nude mice xenografted with the NCI-H660-Luc cells were used to assess OC effects on de novo NEPC progression and recurrence. Male NSG mice transplanted with LuCaP 93 PDX tumor tissues generated a heterogeneous in vivo model used to assess OC effects against t-NEPC progression. Daily oral 10 mg/kg OC administration significantly suppressed the NCI-H660-Luc tumor progression and locoregional recurrence after primary tumor surgical excision. OC treatments effectively suppressed the progression of LuCaP 93 PDX tumors. OC-treated tumors revealed downregulation of ROR2, ASCL1, SMYD2, and EZH2, as well as activated c-MET levels versus the placebo control. RNA sequencing of the collected treated NEPC tumors showed that OC disrupted NEPC splicing, translation, growth factor signaling, and neuronal differentiation. Conclusions. This study's findings validate OC as a novel lead entity for NEPC management by targeting the ROR2-ASCL1-SMYD2-EZH2-c-MET axis.

Keywords:  LuCaP 93 Patient-Derived Xenograft; RNA sequencing; ROR2-ASCL1-SMYD2-EZH2-c-MET axis; S–(–)–oleocanthal; de novo and treatment-induced neuroendocrine prostate cancer; recurrence

DOI:  https://doi.org/10.3390/nu17243947
Adv Sci (Weinh). 2025 Dec 29. e20838

ADAMTS9-AS2 Disrupts Docetaxel-Resistance in Castration-Resistant Prostate Cancer via Stemness Suppression and Ferroptosis Induction.

Ji Liu, Yan Gao, Yadong Guo, Junfeng Zhang, Wentao Zhang, Zhuoran Gu, Haotian Chen, Chengqi Jin, Peng Luo, Shiyu Mao, Yajuan Hao, Shuo Shi, Xudong Yao.

  Castration-resistant prostate cancer (CRPC) chemotherapy resistance remained a significant clinical challenge. Prostate tumor stem cells (PCSCs) played a crucial role in chemotherapy resistance, but the underlying mechanisms were not fully understood. This study investigated how ADAMTS9-AS2 reduced chemotherapy resistance in CRPC through a dual mechanism and explored the potential of polymeric materials targeting PCSCs and enhancing chemotherapy sensitivity. Key regulatory molecules of PCSCs were identified through mRNAsi-based multi-center patient cohorts. The effect of ADAMTS9-AS2 on reducing docetaxel resistance in CRPC was assessed, and its mechanisms were further explored using in vitro and in vivo experiments. Finally, polymeric materials containing TGF-β inhibitor, ferroptosis inducer, and miR-182-5p inhibitor were used to target PCSCs to improve chemotherapy sensitivity. ADAMTS9-AS2 reduced CRPC chemotherapy resistance through dual mechanisms: (1) regulating FOXF2/TGF-β2 axis to suppress PCSCs stemness; (2) encoding a short peptide that competitively retained more SLC7A11 in the cytoplasm than on the cytomembrane, thus promoting ferroptosis. Furthermore, polymeric materials targeting PCSCs significantly enhanced docetaxel sensitivity and inhibited tumor progression. ADAMTS9-AS2 delayed docetaxel resistance by suppressing CRPC stemness and inducing ferroptosis. The use of polymeric materials targeting PCSCs offered a novel strategy to overcome CRPC chemotherapy resistance.

Keywords:  cancer stem cells; docetaxel resistance; ferroptosis; nanomaterial; prostate cancer

DOI:  https://doi.org/10.1002/advs.202520838
J Pharmacopuncture. 2025 Dec 31. 28(4): 351-366

In Silico Assessment of Silybum marianum Bioactive Compounds in Prostate Cancer Using Network Pharmacology and Molecular Docking.

Lisa Dal Pozzo, Secondo Scarsella, Maria Abad Arranz, Md Forhad Shamim, Julie Stephanie Howatson, Kaium Abdul, Israt Jahan Poly.

   Objectives: Prostate cancer is a globally prevalent malignancy with rising resistance to conventional therapies. Although awareness and early diagnosis have improved through screening campaigns, there remains a need for alternative strategies. Silybum marianum L. (SM), or milk thistle, has emerged as a promising natural compound with reported anti-cancer potential. This study aimed to explore the mechanistic basis of SM's activity against prostate cancer using a combination of network pharmacology and molecular docking.
Methods: Core targets related to both SM and prostate cancer were identified through a network pharmacology approach. Protein-protein interaction networks, Gene Ontology (GO), and KEGG enrichment analyses were performed to interpret biological relevance. Molecular docking was used to evaluate the binding affinity of SM's bioactive components with selected targets.
Results: Key proteins identified included SRC, PIK3CD, CDK1, CCNA2, PTPN11, PTK2, RXRA, CYP2C9, and PTGS2, showing significant relevance to SM and prostate cancer. GO analysis emphasized "response to organic cyclic compounds" as a significant term. KEGG and GO enrichment analyses indicated that synaptic and neuronal pathways are central in the disease's progression. Docking simulations revealed strong interactions between core targets and SM constituents, notably (+)-silymonin and silandrin.
Conclusion: This integrated approach highlighted critical molecular targets and pathways modulated by SM, providing a basis for future experimental studies. SM shows potential as a complementary agent in prostate cancer therapy.

Keywords:  Silybummarianum; docking; molecular; network pharmacology; prostatic neoplasms; systems biology

DOI:  https://doi.org/10.3831/KPI.2025.28.4.351
J Racial Ethn Health Disparities. 2025 Dec 27.

Dyadic Associations of Physical Activity, Diet Quality, and Body Mass Index in Black Prostate Cancer Survivors and their Spouses: An Actor-Partner Interdependence Model Analysis.

Haejeong An, Seokhun Kim, Lorna H McNeill, Curtis A Pettaway, Dalnim Cho.

   BACKGROUND: Although prostate cancer (PCa) survivors' health is closely interrelated with that of their spouses/significant others (hereafter spouses), little is known about this interdependence among Black PCa survivors. This study examined the concordance of health behaviors (physical activity (PA), diet quality) and body mass index (BMI) within survivor-spouse dyads, and how each individual's PA and diet quality relate to the other's BMI.
METHODS: Ninety-three Black PCa survivor-spouse dyads completed a survey on PA and diet quality. Height and weight were also self-reported and used to calculate BMI. We assessed PA, diet quality, and BMI concordance using intraclass correlation coefficients (ICCs). Actor and partner effects of PA and diet quality on BMI were tested via actor-partner interdependence models.
RESULTS: The mean BMI of PCa survivors and spouses was 31.10 kg/m2 and 30.52 kg/m2, respectively. ICCs were 0.000 for PA (negligible), 0.453 for diet quality (high), and 0.093 for BMI (small-to-medium). A significant actor effect showed that higher PA among PCa survivors was associated with lower BMI (β = -0.236, p = 0.012). Meanwhile, no significant partner effects were observed.
CONCLUSIONS: The high concordance in diet quality suggests that engaging spouses may be a promising strategy to improve Black PCa survivors' dietary behaviors. Enhancing Black survivors' PA remains critical for effective weight management. Future research should identify modifiable factors that affect spouses' BMI to inform the development of dyadic, weight-management interventions for Black PCa survivors and their spouses. Such efforts may help reduce the disproportionate survivorship burden among Black men.

Keywords:  Dyadic data; Family caregiver; Health behavior; Health inequities; Interdependence; Prostate cancer

DOI:  https://doi.org/10.1007/s40615-025-02802-1
Front Nutr. 2025 ;12 1621389

The impact of diet and gut microbiota on development, treatment, and prognosis in prostate cancer.

Guanmo Liu, Fan Yang, Wei Song, Rui Hou.

  Prostate cancer (PCa) progression is driven by a complex interplay of factors, including genetics, lifestyle, and environmental influences. Diet and gut microbiota have emerged as pivotal cancer development and treatment response modulators. This review delves into the intricate relationship between dietary modifications and gut microbiota, and their combined impact on PCa progression. Diets abundant in plant-based foods, fiber, and prebiotics promote beneficial gut microbiota profiles that support anti-inflammatory and anti-carcinogenic processes. In contrast, the Western dietary pattern, characterized by high levels of saturated fats and processed foods, may lead to dysbiosis, fostering pro-inflammatory conditions and the production of metabolites that enhance tumorigenesis. The gut microbiota influences the behavior of PCa through immune modulation, metabolic by-products, and interactions with systemic therapies. Emerging evidence, primarily derived from preclinical models or studies in non-PCa contexts, suggests that diet and gut microbiota may influence the development and progression of PCa. However, further PCa-specific clinical research is needed to validate these associations. Future research should prioritize the development of precise dietary recommendations and microbiota-targeted therapies that can be seamlessly incorporated into clinical practice for more personalized and effective cancer care.

Keywords:  diet; diet-microbiota axis; gut microbiota; nutrients; prostate cancer

DOI:  https://doi.org/10.3389/fnut.2025.1621389
BMC Med. 2025 Dec 31.

Trop2 immuno-PET/CT imaging of prostate cancer: a proof-of-concept translational study.

Xingru Long, Shuxian An, Xuanbingning Nian, Dongsheng Xu, Weijun Wei, Xiaoli Lan, Liang Dong, Dawei Jiang.

   BACKGROUND: Prostate cancer (PCa) is the second leading cause of death in men and is highly prone to metastasis. This study aims to develop the novel immuno-PET/CT tracer targeting trophoblast cell surface antigen 2 (Trop2), a transmembrane protein overexpressed in aggressive prostate malignancies, and to investigate its diagnostic value in preclinical studies as well as its potential utility in detecting metastases in PCa patients.
METHODS: Integrated analysis of TCGA, GEO, and HPA datasets revealed Trop2 overexpression in prostate adenocarcinoma. By labeling two Trop2-targeted nanobodies (His-tagged T4 and His-tag-free RT4) with 68Ga and 18F, we synthesized three radiotracers, [68Ga]Ga-NOTA-T4, [18F]AlF-RESCA-T4, and [18F]AlF-RESCA-RT4. Preclinical validation included cellular assays and xenograft studies for 68Ga/18F-T4 variants, followed by a first-in-human trial evaluating [18F]AlF-RESCA-RT4 in ten treatment-naïve PCa patients.
RESULTS: Bioinformatics analysis demonstrated Trop2 as a promising target for PCa diagnosis and treatment. In preclinical studies, both [68Ga]Ga-NOTA-T4 and [18F]AlF-RESCA-T4 illustrated high affinity to Trop2, specific tumor uptake (4.33 ± 0.38 %ID/g and 5.50 ± 0.69 %ID/g at 60 min, respectively) in Trop2-positive xenograft mouse models with minimal background distribution. In the translational study, [18F]AlF-RESCA-RT4 outperformed standard [18F]-FDG imaging in metastatic prostate cancer patients, detecting 62.4% more lymph node metastases (SUVmax 21.58 ± 13.12 vs. 4.80 ± 1.77) and 69.4% more bone lesions (SUVmax 7.83 ± 4.32 vs. 4.72 ± 1.22). No adverse events were observed.
CONCLUSIONS: This work successfully establishes that Trop2 is a new biomarker for PCa, and Trop2 immuno-PET/CT imaging can detect PCa lymph node and osseous metastases. The superior tumor-to-background contrast and clinical safety of [18F]AlF-RESCA-RT4 support its translational potential to guide Trop2-targeted therapies and enhance personalized treatment strategies.
TRIAL REGISTRATION: NCT06851663. Retrospectively registered 02/24/2025.

Keywords:  Immuno-PET/CT; Nanobody; Nuclear medicine; Prostate cancer; Trop2

DOI:  https://doi.org/10.1186/s12916-025-04589-8
Int J Mol Sci. 2025 Dec 15. pii: 12073. [Epub ahead of print]26(24):

Assessment of miRNA 106a-5p and 375-3p Expression in the Context of the Wnt/β-Catenin Pathway-Comparison of Prostate Adenocarcinoma and Benign Prostatic Hyperplasia Tissues.

Magdalena Smereczańska, Natalia Domian, Grzegorz Młynarczyk, Irena Kasacka.

  Prostate adenocarcinoma is mainly diagnosed based on serum PSA levels, but elevated PSA levels can also be caused by BPH, which weakens its specificity. Recent scientific studies have demonstrated that specific microRNAs regulate cancer cell proliferation by modulating the Wnt/β-catenin pathway. To date, no published literature has provided a comprehensive assessment of the interactions between miR-106a-5p and miR-375-3p and components of the Wnt/β-catenin pathway in prostate cancer. Therefore, the aim of the present study was to perform a pilot evaluation of the expression of miRNAs 106a-5p and 375-3p, as well as β-catenin, Fzd8, Wnt5a, and cyclin D1 in prostate adenocarcinoma compared with BPH. The study material consisted of samples collected from 30 patients with prostate cancer and 30 with BPH. Protein expression was analyzed using IHC and qRT-PCR methods, while miRNA levels were quantified by dPCR. Our study results revealed lower immunoreactivity and expression of genes encoding β-catenin, Fzd8, Wnt5a, and cyclin D1 and significantly higher fluorescence intensity of miRNA 106a-5p and 375-3p with prostate adenocarcinoma compared to BPH. These parallel alterations in miRNA expression and Wnt/β-catenin-related components reflect disease-specific expression patterns and warrant further investigation in larger cohorts to determine their potential utility as diagnostic biomarkers in prostate diseases.

Keywords:  Fzd8; Wnt5a; cyclin D1; miRNAs; prostate adenocarcinoma; β-catenin

DOI:  https://doi.org/10.3390/ijms262412073
Cancers (Basel). 2025 Dec 15. pii: 3993. [Epub ahead of print]17(24):

Metabolomic Insights into Prostate Cancer Treatment and Relapse.

Kristina Lundquist, Henrik Antti, Camilla Thellenberg Karlsson.

  Background: High-risk prostate cancer is often treated with combined androgen deprivation therapy (ADT) and radiotherapy (RT). Blood biomarkers may enable treatments to be tailored to individual patients. Metabolomics, the study of small-molecule alterations in blood, is promising, and lipids are emerging as potential markers of poor prognosis. This study aims to investigate metabolic changes during prostate cancer treatment and their correlation to disease outcome. Methods: This study included 136 blood plasma samples from 35 patients with high-risk prostate cancer treated with RT and ADT, recruited from the Uppsala/Umeå Comprehensive Cancer Consortium (U-CAN) project. Blood samples were collected before, during, and after treatment and analyzed at Metabolon Inc. (Durham, NC, USA). To study differences in metabolic levels during treatment, three different sampling time points were considered: before ADT, in-between ADT and RT, and after RT. Both multivariate (orthogonal projections to latent structures, OPLS) and univariate analyses were performed, where statistical significance in combination with a large fold change was considered indicative of a substantial change. Results: Significant changes in metabolite levels were observed. Many of the significant metabolites for the whole course of treatment were also significant during ADT but not during RT, indicating that changes during ADT dominated the overall treatment. Changes were found to be especially common in steroids and fatty acids. Multivariate analysis revealed significant differences in metabolites between relapsing and non-relapsing patients. Among the significant metabolites were cholesterol and epiandrosterone. Conclusions: Metabolomics can identify biomarkers for prostate cancer treatment response and relapse. Further studies are needed to identify patterns and individual metabolites to personalize treatment strategies for prostate cancer.

Keywords:  chemometrics; cholesterol; hormone therapy; metabolomics; prostate cancer; radiotherapy

DOI:  https://doi.org/10.3390/cancers17243993
Int J Mol Sci. 2025 Dec 18. pii: 12160. [Epub ahead of print]26(24):

Significance of EVs in Prostate Cancer Bone Metastases.

Kagenori Ito, Takaaki Tamura, Fumihiko Urabe, Shinichi Sakamoto, Takahiro Kimura, Shin Egawa, Takahiro Ochiya.

  Prostate cancer (PCa) exhibits a unique propensity to metastasize to bone, where it predominantly generates osteoblastic lesions. The formation of these lesions is a complex and dynamic process driven by reciprocal interactions between tumor cells and the bone microenvironment. Emerging evidence indicates that extracellular vesicles (EVs) play pivotal roles in the establishment of metastatic colonies and disease progression, as well as in local tumor-bone interactions. Through their diverse cargos, including proteins, lipids, and non-coding RNAs, EVs mediate bidirectional communication that regulates osteoclastogenesis, osteoblast activation, and osteocyte function, ultimately reshaping the bone niche to favor tumor growth. Importantly, EVs exhibit dual and context-dependent functions, acting either as promoters or suppressors of malignancy depending on the cellular source and microenvironmental context. These insights highlight EVs not only as mechanistic drivers of PCa bone metastases but also as promising therapeutic targets. Approaches aimed at modulating EV biogenesis, eliminating deleterious EVs, or harnessing EVs as drug delivery vehicles hold significant potential for advancing treatment strategies against PCa bone metastases.

Keywords:  bone metastasis; extracellular vesicles; osteoblast; osteoclast; prostate cancer

DOI:  https://doi.org/10.3390/ijms262412160
Int Urol Nephrol. 2026 Jan 02.

Influence of diabetes mellitus and anti-diabetic drugs on pathophysiology and prognosis for primary prostate cancer.

Mikhail Kazachok, Aleksander Ślusarczyk, Łukasz Zapała, Tomasz Piecha, Piotr Radziszewski, Piotr Zapała.

   PURPOSE: Cancer diseases and type II diabetes mellitus (DM2) are today among the major health problems, particularly in developed countries. DM2 has been historically suggested to protect against the development of prostate cancer (PCa). This study aimed to explore the mechanisms of this relation and assess its impact on treatment and prognosis for patients with PCa.
METHODS: The consecutive literature search was performed using PubMed, Cochrane, and Google Scholar for papers published between 2015 and 2025.
RESULTS: DM2 might reduce the risk of primary PCa development with a size effect depending on the duration of DM2. Patients with type 2 diabetes often exhibit low levels of testosterone and SHBG, which has been speculated to constitute a protective effect against PCa development. On the other hand, peripheral insulin resistance might be a protective factor, given its proliferation-promoting properties. What remains, however, the backbone element of the DM-PCa prevalence relation is metformin, which has been described to modulate PCa development through activation of AMPK kinase, reducing the c-MYC oncogene and disrupting the action of androgen receptors. Finally, DM constitutes a well-known predictor of worse surgical outcomes as well as radiotherapy toxicity.
CONCLUSION: DM is associated with a modestly lower incidence of prostate cancer, likely mediated by hormonal cross-talk and metabolic changes. Metformin may confer additional protection in a wide range of molecular mechanisms. Nevertheless, diabetes worsens treatment course-raising surgical morbidity and radiotherapy toxicity-necessitating tight metabolic control and thoughtful anti-diabetic drug selection.

Keywords:  Antidiabetic drugs; Diabetes mellitus; Prostate cancer

DOI:  https://doi.org/10.1007/s11255-025-04974-5
PLoS One. 2026 ;21(1): e0339607

TDP2 drives immune evasion and metastatic progression in prostate cancer.

Huan Cao, Anyin Pan, Yuetao Chen, Fei Zheng.

Immune evasion and epithelial-mesenchymal transition (EMT) are critical mechanisms driving tumor progression and therapy resistance in prostate cancer. In this study, we explored the role of TDP2 in modulating the tumor microenvironment (TME) through single-cell RNA sequencing and pathway enrichment analysis. Our results revealed that epithelial cells with high TDP2 expression extensively interact with myeloid cells, macrophages, and fibroblasts, thereby shaping immune responses and facilitating tumor progression. Specifically, TDP2 overexpression suppressed M1 macrophage polarization and dendritic cell (DC) maturation, leading to reduced CD8 + T cell activation and enhanced immune evasion. Additionally, TDP2-high expression was associated with enriched signaling pathways involved in EMT, including COLLAGEN, GALECTIN, MIDKINE (MK), and ONCOSTATIN M (OSM), which promoted tumor cell migration, invasion, and immune evasion. Survival analyses further demonstrated that high TDP2 expression correlated with poor clinical outcomes in prostate cancer patients. Overall, our findings identify TDP2 as a key regulator within the TME and suggest its potential utility as both a prognostic biomarker and therapeutic target in prostate cancer.

DOI: https://doi.org/10.1371/journal.pone.0339607
PLoS Genet. 2025 Dec;21(12): e1011975

Decoding the germline genetic architecture of prostate cancer at a single cell resolution.

Cheng Wang, Tianqi Tang, Yuejun Wang, Jingjing Li.

Prostate cancer exhibits a strong familial association, and its heritability indicates a significant contribution from germline variants. While genome-wide association studies (GWAS) have identified common germline variants associated with prostate cancer risk, translating these statistical associations into functional mechanisms has remained a long-standing challenge. Consequently, most of our understanding of the genetic basis of prostate cancer stems from extensive studies of somatic mutations, leaving the germline genetic architecture largely unresolved. Because most germline variants lie in the noncoding genome and complex human diseases are predominantly driven by regulatory mutations, we herein asked which prostate cell types mediate the functional effects of germline variants, and thus represent the most genetically vulnerable populations. We generated paired epigenomic and transcriptomic profiles from reference human prostate tissues. Integrating these single-cell data with large-scale GWAS data identified a terminally differentiated luminal epithelial subtype that mediates the strongest germline risk in prostate cancer. We subsequently developed a deep learning model to score ~17 million GWAS variants based on their predicted impact on altering local chromatin accessibility in this vulnerable luminal epithelial subtype, and identified high-confidence candidate loci where high-risk germline variants likely alter promoter accessibility in prostate cancer. The implicated genes were involved in several pathways in tumorigenesis, displayed strong dosage sensitivity, and converged on the androgen receptor (AR)-mediated regulon, a mechanism also observed for somatic mutations. Overall, by unveiling cell types and candidate loci that mediate germline risk, our study defines the cell-type-specific germline architecture in prostate cancer and provides a comprehensive framework for understanding cancer heritability.

DOI: https://doi.org/10.1371/journal.pgen.1011975
Autoimmunity. 2026 Dec 31. 59(1): 2596700

Exploring the key functions of T cells and the regulation of the immune microenvironment in prostate cancer using single-cell RNA sequencing and bulk RNA sequencing.

Zhidu Wang, Yan Xing, Dongmei Shang, Xuefei Jin.

  The incidence of prostate cancer continues to increase, making it the second most common malignant tumor among men worldwide. Immunotherapy has emerged as a key therapeutic strategy for treating tumors. Numerous studies have established that the efficacy of tumor immunotherapy is closely associated with the tumor microenvironment and T cell subsets. However, the specific functions of certain T cell subsets in prostate cancer remain incompletely characterized. Therefore, this study aimed to systematically investigate the distribution patterns of T cell subsets within the tumor microenvironment of prostate cancer patients and their correlations with clinicopathological parameters. Therefore, we investigated the impact of T cells on the tumor microenvironment of prostate cancer at the single-cell level. We employed a variety of analytical methods to reveal the functions of T cells, including cell interaction analysis, time-series analysis, enrichment analysis, immune infiltration analysis, and other analytical approaches. By integrating bulk RNA-seq data, we constructed and validated a prognostic risk model based on T cell marker genes. Finally, we utilized the ssGSEA and ESTIMATE algorithms to explore the relationship between the prognostic risk model and immunotherapy. After quality control, 16,999 cells from the single-cell data were retained for downstream analysis. Our study focused on T cells, revealing the communication between various cell types and T cells. Pseudotime analysis showed that different T cell marker genes exhibited differential expression at various time points, corresponding to distinct biological processes. Enrichment analysis indicated that T cell marker genes were enriched in several immune-related pathways. From our analysis, BCAS2, EIF2S2, RIOK3, and ATP6V1E1 were ultimately identified as prognostic markers. Immune infiltration analysis revealed that high-risk patients had lower immune scores, stromal scores, and ESTIMATE scores and greater tumor purity compared to low-risk patients. We analyzed the mechanisms involving T cells in prostate cancer from multiple perspectives, constructed a prognostic model, and conducted immune infiltration analysis. Our findings contribute to the understanding of prostate cancer and its prognosis, providing valuable insights for future research and prognostic assessments in prostate cancer.

Keywords:  T cells; bulk RNA sequencing; immune microenvironment; prostate cancer; single-cell RNA sequencing

DOI:  https://doi.org/10.1080/08916934.2025.2596700
Diagnostics (Basel). 2025 Dec 18. pii: 3242. [Epub ahead of print]15(24):

Metabolomics of Prostate Cancer and Clinical Profiles Following Radiotherapy: Need for a Precision Phylometabolomics Approach.

Hakima Amri, Charles Sturgeon, David Posawatz, Mones Abu-Asab, Ryan R Collins, Simeng Suy, Sean P Collins.

  Introduction: Metabolomics-based phylogenetic profiling of prostate cancer (PCa) patients before and after stereotactic body radiation therapy (SBRT) can provide insight into the way in which treatment outcomes relate to the underlying physiology and physiological responses of individual patients. It also offers the potential for helping identify precision biomarkers. Methods: In this study, we used integrated mass spectrometry to obtain untargeted serum metabolomics data from PCa patients (n = 55), which we then analyzed using a parsimony phylogenetic systems biology approach before correlating the results with the patients' clinical parameters before and after treatment. Results: Radiotherapy (RT) generated five phylogenetic subgroups with distinct metabolomic profiles that did not correspond to hormonal treatment, risk assessment, metastasis, or PSA levels. PSA was neither a factor influencing clade membership nor an indicator of risk assessment or metastasis. Moreover, the hormone-treated patients did not form their own clade but were rather spread among the five clades. The same absence of correlation applied to risk assessment and metastasis. The 88 significantly altered pre-RT and 29 post-RT features showed aberrations in the metabolic pathways of purines, porphyrin, glycerophospholipids, and 2-methylglutaric acid, among others. Discussion: Significantly altered metabolites in a majority of patients who developed metastasis included D-tryptophan, carbamate, 5'-Benzoylphosphoadenosine, Phosphatidylcholine (PC), bilirubin, and hypoxanthine. In general, the cladogram offers a new perspective on evaluating the clinical variables that represent significant indicators of PCa progression, metastasis, and treatment response in individuals. Conclusions: Metabolic profiles and associated clinical phenotypes provided by this precision phylometabolomics approach may offer a deeper understanding of the metabolic factors and pathways implicated in cancer progression and metastasis and should contribute to the development of targeted treatments and more precise monitoring of cancer and cancer therapies.

Keywords:  Clinical Correlation; diagnostic biomarkers; parsimony phylogenetics; precision medicine; treatment response

DOI:  https://doi.org/10.3390/diagnostics15243242
J Urol. 2025 Dec 29. 101097JU0000000000004919

Whole-Slide Telepathology Grading of Prostate Cancer in Biopsies Using ISUP Criteria: Inter- and Intra-Observer Concordance and Implications for Active Surveillance.

M Scott Lucia, Sam Callis, Catherine Tangen, Fawaz Almutairi, Anastasios Chatzitolios, Oleksandr Kravtsov, Sarah Lenon, Varsha Manuchua, Jeffry P Simko, Cornelia M Szecsei, Yunshin Albert Yeh, Lian Zhang, Kenneth A Iczkowski.

   INTRODUCTION: Subjectivity of prostate cancer (PCa) grading impacts biomarker investigations, assessments of imaging, and treatment decisions, especially for active surveillance. We conducted the first telepathology concordance study of PCa needle biopsy grading using contemporary International Society of Urologic Pathology guidelines.
METHODS: Whole slide images (n=120) of PCa biopsy cases across grade groups (GG), were examined by 11 urologic pathologists. Forty cases were blindly regraded, over-sampling cases with lower agreement on first review. Pathologists provided GG, percentage and type of pattern Gleason 4, and tumor length. Consensus for a case was defined as GG agreement by ≥7 pathologists. GG agreement among and within pathologists was measured using model-based weighted Kappa statistics (κw).
RESULTS: Consensus was achieved on 86/120 (72%) cases. Of 34 cases not achieving consensus, most were GG2 vs GG1 (41%) or GG2 vs GG3 (38%). The inter-rater κw was 0.34 (95% CI 0.28, 0.39) indicating fair agreement. Forty regraded cases had an intra-rater κw of 0.49 (95% CI 0.46, 0.53; moderate agreement). Sixty-four percent of the repeated grades agreed. Of the repeated ratings that did not agree, 39% involved GG1 vs GG2. Of the GG1 vs GG2 paired repeated ratings, 77% reported 1-10% pattern 4, and indicated common observation was "poorly-formed glands."
DISCUSSION: Inter- and intra-rater variability in GG is significant, particularly discerning GG1 from GG2 with ≤10% grade 4. These observations have profound implications for treatment decisions (surveillance vs definitive therapy) and studies of new biomarkers and imaging of prostate cancer.

Keywords:  Prostate cancer; grading; telepathology

DOI:  https://doi.org/10.1097/JU.0000000000004919