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Oncogene Jul 2023Therapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To...
Therapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To understand the metabolic alterations involved in enzalutamide resistance, we performed metabolomic, transcriptomic, and cistromic analyses of enzalutamide-sensitive and -resistant PCa cells, xenografts, patient-derived organoids, patient-derived explants, and tumors. We noted dramatically higher basal and inducible levels of reactive oxygen species (ROS) in enzalutamide-resistant PCa and castration-resistant PCa (CRPC), in comparison to enzalutamide-sensitive PCa cells or primary therapy-naive tumors respectively. Unbiased metabolomic evaluation identified that glutamine metabolism was consistently upregulated in enzalutamide-resistant PCa cells and CRPC tumors. Stable isotope tracing studies suggest that this enhanced glutamine metabolism drives an antioxidant program that allows these cells to tolerate higher basal levels of ROS. Inhibition of glutamine metabolism with either a small-molecule glutaminase inhibitor or genetic knockout of glutaminase enhanced ROS levels, and blocked the growth of enzalutamide-resistant PCa. The critical role of compensatory antioxidant pathways in maintaining enzalutamide-resistant PCa cells was validated by targeting another antioxidant program driver, ferredoxin 1. Taken together, our data identify a metabolic need to maintain antioxidant programs and a potentially targetable metabolic vulnerability in enzalutamide-resistant PCa.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Antioxidants; Glutaminase; Glutamine; Reactive Oxygen Species; Drug Resistance, Neoplasm; Nitriles; Androgen Receptor Antagonists; Cell Line, Tumor
PubMed: 37355762
DOI: 10.1038/s41388-023-02756-w -
Science Advances Oct 2023The clinical potential of miRNA-based liquid biopsy has been largely limited by the heterogeneous sources in plasma and tedious assay processes. Here, we develop a...
The clinical potential of miRNA-based liquid biopsy has been largely limited by the heterogeneous sources in plasma and tedious assay processes. Here, we develop a precise and robust one-pot assay called dual-surface-protein-guided orthogonal recognition of tumor-derived exosomes and in situ profiling of microRNAs (SORTER) to detect tumor-derived exosomal miRNAs and enhance the diagnostic accuracy of prostate cancer (PCa). The SORTER uses two allosteric aptamers against exosomal marker CD63 and tumor marker EpCAM to create an orthogonal labeling barcode and achieve selective sorting of tumor-specific exosome subtypes. Furthermore, the labeled barcode on tumor-derived exosomes initiated targeted membrane fusion with liposome probes to import miRNA detection reagents, enabling in situ sensitive profiling of tumor-derived exosomal miRNAs. With a signature of six miRNAs, SORTER differentiated PCa and benign prostatic hyperplasia with an accuracy of 100%. Notably, the diagnostic accuracy reached 90.6% in the classification of metastatic and nonmetastatic PCa. We envision that the SORTER will promote the clinical adaptability of miRNA-based liquid biopsy.
Topics: Male; Humans; Exosomes; Membrane Proteins; MicroRNAs; Prostatic Neoplasms; Biomarkers, Tumor
PubMed: 37792944
DOI: 10.1126/sciadv.adi1556 -
European Journal of Nuclear Medicine... Oct 2023For the implementation of suitable radiation safety measures in [Lu]Lu-PSMA-617 therapy, additional insight into excretion kinetics is important. This study evaluates...
INTRODUCTION
For the implementation of suitable radiation safety measures in [Lu]Lu-PSMA-617 therapy, additional insight into excretion kinetics is important. This study evaluates this kinetics in prostate cancer patients via direct urine measurements.
METHODS
Both the short-term (up to 24 h, n = 28 cycles) and long-term kinetics (up to 7 weeks, n = 35 samples) were evaluated by collection of urine samples. Samples were measured on a scintillation counter to determine excretion kinetics.
RESULTS
The mean excretion half-time during the first 20 h was 4.9 h. Kinetics was significantly different for patients with kidney function below or above eGFR 65 ml/min. Calculated skin equivalent dose in case of urinary contamination was between 50 and 145 mSv when it was caused between 0 and 8 h p.i.. Measurable amounts of Lu were found in urine samples up to 18 days p.i..
CONCLUSION
Excretion kinetics of [Lu]Lu-PSMA-617 is especially relevant during the first 24 h, when accurate radiation safety measures are important to prevent skin contamination. Measures for accurate waste management are relevant up to 18 days.
Topics: Male; Humans; Radiopharmaceuticals; Prostate-Specific Antigen; Prostatic Neoplasms; Dipeptides; Heterocyclic Compounds, 1-Ring; Prostatic Neoplasms, Castration-Resistant; Lutetium
PubMed: 37421427
DOI: 10.1007/s00259-023-06328-8 -
The Journal of Clinical Investigation Dec 2023Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA...
Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.
Topics: Male; Humans; Prostate; Dehydroepiandrosterone; Prostatic Neoplasms
PubMed: 38099500
DOI: 10.1172/JCI171199 -
International Journal of Biological... 2023Numerous studies have substantiated the association between aging and the progression of malignant tumors in humans, notably prostate cancer (PCa). Nevertheless, to the...
Numerous studies have substantiated the association between aging and the progression of malignant tumors in humans, notably prostate cancer (PCa). Nevertheless, to the best of our knowledge, no studies have comprehensively elucidated the intricate characteristics of the aging microenvironment (AME) in PCa. AME regulatory patterns were determined using the NMF algorithm. Then an ageing microenvironment index (AMI) was constructed, with excellent prognostic and immunotherapy prediction ability, and its' clinical relevance was surveyed through spatial transcriptomics. Further, the drug response was analysed using the Genomics of Drug Sensitivity in Cancer (GDSC), the Connectivity Map (CMap) and CellMiner database for patients with PCa. Finally, the AME was studied using in vitro and vivo experiments. Three different AME regulatory patterns were identified across 813 PCa patients, associated with distinct clinical prognosis and physiological pathways. Based on the AMI, patients with PCa were divided into the high-score and low-score subsets. Higher AMI score was significantly infiltrated with more immune cells, higher rate of biochemical recurrence (BCR) and worse response to immunotherapy, antiandrogen therapy and chemotherapy in PCa. In addition, we found that the combination of bicalutamide and embelin was capable of suppressing tumor growth of PCa. Besides, as the main components of AMI, and act as oncogenes and were verified via in vivo and in vitro experiments. AME regulation is significantly associated with the diversity and complexity of TME. Quantitative evaluation of the AME regulatory patterns may provide promising novel molecular markers for individualised therapy in PCa.
Topics: Male; Humans; Multiomics; Prostatic Neoplasms; Immunotherapy; Oncogenes; Aging; Tumor Microenvironment
PubMed: 37564213
DOI: 10.7150/ijbs.85209 -
Medicine Aug 2023Cancer-associated fibroblasts (CAFs), the central players in the tumor microenvironment (TME), can promote tumor progression and metastasis via various functions....
Cancer-associated fibroblasts (CAFs), the central players in the tumor microenvironment (TME), can promote tumor progression and metastasis via various functions. However, the properties of CAFs in prostate cancer (PCa) have not been fully assessed. Therefore, we aimed to examine the CAF characteristics in PCa and construct a CAF-derived signature to predict PCa prognosis. CAFs were identified using single-cell RNA sequencing (scRNA-seq) data from 3 studies. We performed the FindAllMarkers function to extract CAF marker genes and constructed a signature to predict the biochemical relapse-free survival (bRFS) of PCa in the Cancer Genome Atlas (TCGA) cohort. Subsequently, different algorithms were applied to reveal the differences of the TME, immune infiltration, treatment responses in the high- and low-risk groups. Additionally, the CAF heterogeneity was assessed in PCa, which were confirmed by the functional enrichment analysis, gene set enrichment analysis (GSEA), and AUCell method. The scRNA-seq analysis identified a CAF cluster with 783 cells and determined 183 CAF marker genes. Cell-cell communication revealed extensive interactions between fibroblasts and immune cells. A CAF-related prognostic model, containing 7 genes (ASPN, AEBP1, ALDH1A1, BGN, COL1A1, PAGE4 and RASD1), was developed to predict bRFS and validated by 4 independent bulk RNA-seq cohorts. Moreover, the high-risk group of the signature score connected with an immunosuppressive TME, such as a higher level of M2 macrophages and lower levels of plasma cells and CD8+ T cells, and a reduced reaction rate for immunotherapy compared with low-risk group. After re-clustering CAFs via unsupervised clustering, we revealed 3 biologically distinct CAF subsets, namely myofibroblast-like CAFs (myCAFs), immune and inflammatory CAFs (iCAFs) and antigen-presenting CAFs (apCAFs). In conclusion, the CAF-derived signature, the first of its kind, can effectively predict PCa prognosis and serve as an indicator for immunotherapy. Furthermore, our study identified 3 CAF subpopulations with distinct functions in PCa.
Topics: Male; Humans; Cancer-Associated Fibroblasts; Prognosis; Neoplasm Recurrence, Local; Prostatic Neoplasms; RNA-Seq; Tumor Microenvironment; Antigens, Neoplasm; ras Proteins; Carboxypeptidases; Repressor Proteins
PubMed: 37565899
DOI: 10.1097/MD.0000000000034611 -
Archivos Espanoles de Urologia Nov 2023Prostate cancer remains a significant global health challenge. Traditionally anchored by the Gleason score/Grade Group (GS/GG), the landscape of prostate cancer... (Review)
Review
Prostate cancer remains a significant global health challenge. Traditionally anchored by the Gleason score/Grade Group (GS/GG), the landscape of prostate cancer diagnosis is undergoing transformative steps, particularly in the domain of biopsy procedures. GS/GG continues to be pivotal in malignancy grading, but recent technological strides have augmented the diagnostic relevance of biopsies. Integral to this progression is the adoption of advanced imaging techniques, especially magnetic resonance imaging, which has refined biopsy accuracy and efficiency. A deep understanding of prostate cancer pathology reveals a cribriform pattern and intraductal carcinoma of the prostate as independent forms of malignancy, suggesting a potentially aggressive disease course. Furthermore, the distinct behaviour of ductal adenocarcinoma and small cell carcinoma of the prostate, compared with acinar adenocarcinoma, necessitates their accurate differentiation during biopsy. The genomic era ushers in a renewed emphasis on tissue samples obtained from prostate biopsies, especially as mutations in genes, such as /, and paves the way for precision medicine. This review encapsulates the evolving dynamics of prostate biopsy, from technological advancements to the profound implications on prostate cancer management and therapy.
Topics: Male; Humans; Prostate; BRCA1 Protein; BRCA2 Protein; Prostatic Neoplasms; Biopsy; Carcinoma, Intraductal, Noninfiltrating; Neoplasm Grading
PubMed: 38053418
DOI: 10.56434/j.arch.esp.urol.20237609.78 -
La Clinica Terapeutica 2023In the last decade, Prostate Cancer (PCa) has emerged as the second most prevalent and serious medical condition, and is considered one of the leading factors... (Review)
Review
In the last decade, Prostate Cancer (PCa) has emerged as the second most prevalent and serious medical condition, and is considered one of the leading factors contributing to global mortality rates. Several factors (genetic as well as environmental) contribute to its development and seriousness. Since the disease is usually asymptomatic at early stages, it is typically misdiagnosed or over-diagnosed by the diagnostic procedures currently in use, leading to improper treatment. Effective biomarkers and diagnostic techniques are desperately needed in clinical settings for better management of PCa patients. Studies integrating omics sciences have shown that the accuracy and dependability of diagnostic and prognostic evaluations have increased because of the use of omics data; also, the treatment plans using omics can be facilitated by personalized medicine. The present review emphasizes innovative multi-omics methodologies, encompassing proteomics, genomics, microbiomics, metabolomics, and transcriptomics, with the aim of comprehending the molecular alterations that trigger and contribute to PCa. The review shows how early genomic and transcriptomic research has made it possible to identify PCa-related genes that are controlled by tumor-relevant signaling pathways. Proteomic and metabolomic analyses have recently been integrated, advancing our understanding of the complex mechanisms at play, the multiple levels of regulation, and how they interact. By applying the omics approach, new vulnerabilities may be discovered, and customized treatments with improved efficacy will soon be accessible.
Topics: Humans; Male; Proteomics; Precision Medicine; Genomics; Prostatic Neoplasms; Biomarkers
PubMed: 37994753
DOI: 10.7417/CT.2023.2476 -
Nature Structural & Molecular Biology Dec 2023Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of...
Transcription factors are among the most attractive therapeutic targets but are considered largely 'undruggable' in part due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration-resistant prostate cancer, is key for its activity as transcription factor, allowing it to translocate to the nucleus and partition into transcriptional condensates upon activation by androgens. On the basis of our understanding of the interactions stabilizing such condensates and of the structure that the domain adopts upon condensation, we optimized the structure of a small-molecule inhibitor previously identified by phenotypic screening. The optimized compounds had more affinity for their target, inhibited androgen-receptor-dependent transcriptional programs, and had an antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results suggest that it is possible to rationally optimize, and potentially even to design, small molecules that target the activation domains of oncogenic transcription factors.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Androgens; Prostatic Neoplasms; Protein Domains; Transcription Factors; Cell Line, Tumor
PubMed: 38049566
DOI: 10.1038/s41594-023-01159-5 -
The Journal of Clinical Investigation Apr 2024Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the...
Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ERα expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ERα levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient-derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ERα-dependent manner. Overall, our study revealed that, when expressed, ERα functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.
Topics: Humans; Prostatic Neoplasms; Male; Estrogen Receptor alpha; Estrogens; Cell Proliferation; Signal Transduction; Disease Progression; Animals; Mice; Cell Line, Tumor; Neoplasm Proteins
PubMed: 38625747
DOI: 10.1172/JCI170809