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Clinical Cancer Research : An Official... Aug 2023Circulating tumor DNA (ctDNA) is measurable in the majority of metastatic castration-resistant prostate cancer patients. Data indicate that ctDNA present at baseline can...
Circulating tumor DNA (ctDNA) is measurable in the majority of metastatic castration-resistant prostate cancer patients. Data indicate that ctDNA present at baseline can serve as a prognostic biomarker and changes in the ctDNA posttreatment can rapidly predict both time to progression and survival. See related article by Tolmeijer et al., p. 2835.
Topics: Male; Humans; Circulating Tumor DNA; Prostatic Neoplasms, Castration-Resistant; Biomarkers, Tumor
PubMed: 37265409
DOI: 10.1158/1078-0432.CCR-23-1043 -
Cancer Research Dec 2023Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells...
UNLABELLED
Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2-Skp2-p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression.
SIGNIFICANCE
The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008.
Topics: Humans; Male; Cell Line, Tumor; Cell Proliferation; Prostate; Prostatic Neoplasms; Protein Kinases; Signal Transduction
PubMed: 37801613
DOI: 10.1158/0008-5472.CAN-23-0883 -
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 -
Molecular Cancer Oct 2023Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling...
Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.
Topics: Male; Humans; Prostate; Transcriptome; Biopsy; Prostatic Neoplasms; Genomics
PubMed: 37789377
DOI: 10.1186/s12943-023-01863-2 -
Nutrients Mar 2024Cancer has become a serious problem worldwide, as it represents the main cause of death, and its incidence has increased over the years. A potential strategy to counter... (Review)
Review
Cancer has become a serious problem worldwide, as it represents the main cause of death, and its incidence has increased over the years. A potential strategy to counter the growing spread of various forms of cancer is the adoption of prevention strategies, in particular, the use of healthy lifestyles, such as maintaining a healthy weight, following a healthy diet; being physically active; avoiding smoking, alcohol consumption, and sun exposure; and vitamin D supplementation. These modifiable risk factors are associated with this disease, contributing to its development, progression, and severity. This review evaluates the relationship between potentially modifiable risk factors and overall cancer development, specifically breast, colorectal, and prostate cancer, and highlights updated recommendations on cancer prevention. The results of numerous clinical and epidemiological studies clearly show the influence of lifestyles on the development and prevention of cancer. An incorrect diet, composed mainly of saturated fats and processed products, resulting in increased body weight, combined with physical inactivity, alcohol consumption, and smoking, has induced an increase in the incidence of all three types of cancer under study. Given the importance of adopting correct and healthy lifestyles to prevent cancer, global institutions should develop strategies and environments that encourage individuals to adopt healthy and regular behaviors.
Topics: Male; Humans; Risk Factors; Diet; Healthy Lifestyle; Alcohol Drinking; Life Style; Prostatic Neoplasms
PubMed: 38542712
DOI: 10.3390/nu16060800 -
The Malaysian Journal of Pathology Aug 2023Prostate cancer is the second-most frequently diagnosed cancer in men worldwide. Serum prostatespecific antigen is currently used for the early detection of prostate... (Review)
Review
Prostate cancer is the second-most frequently diagnosed cancer in men worldwide. Serum prostatespecific antigen is currently used for the early detection of prostate cancer. However, new biomarkers are needed to decrease over diagnosis and over treatment of prostate cancer due to limitations of prostate-specific antigen. Recently, molecular biomarkers have shown promising results for diagnosis and prognosis of prostate cancer. Molecular biomarkers have improved the sensitivity and specificity of prostate-specific antigen and studies are ongoing to identify molecular biomarkers as a replacement for prostate-specific antigen. This review aims to give an overview of emerging molecular biomarkers for diagnosis and prognosis of prostate cancer.
Topics: Male; Humans; Prostate-Specific Antigen; Prognosis; Prostatic Neoplasms; Mutation; Neoplasms, Second Primary
PubMed: 37658525
DOI: No ID Found -
BMC Cancer Jul 2023A majority of prostate cancer cells are in a non-proliferating, G (quiescent) phase of the cell cycle and may lie dormant for years before activation into a...
BACKGROUND
A majority of prostate cancer cells are in a non-proliferating, G (quiescent) phase of the cell cycle and may lie dormant for years before activation into a proliferative, rapidly progressing, disease phase. Many mechanisms which influence proliferation and quiescence choices remain to be elucidated, including the role of non-coding RNAs. In this study, we investigated the role of a long non-coding RNA (lncRNA), SNHG1, on cell proliferation, quiescence, and sensitivity to docetaxel as a potential factor important in prostate cancer biology.
METHODS
Publically available, anonymous, clinical data was obtained from cBioPortal for analysis. RNAi and prostate cancer cell lines were utilized to investigate SNHG1 in vitro. We measured G cells, DNA synthesis, and cell cycle distribution by flow cytometry. Western blotting was used to assess G arrest and apoptosis. These parameters were also investigated following docetaxel treatment.
RESULTS
We discovered that in prostate cancer patients from The Cancer Genome Atlas (TCGA) data set, high SNHG1 expression in localized tumors correlated with reduced progression-free survival, and in a data set of both primary and metastatic tumors, high SNHG1 expression was associated with metastatic tumors. In vitro analysis of prostate cancer cell lines showed SNHG1 expression correlated with a quiescent versus proliferative phenotype. Knockdown of SNHG1 by RNAi in PC3 and C4-2B cells resulted in an accumulation of cells in the G phase. After knockdown, 60.0% of PC3 cells were in G, while control cultures had 13.2% G. There were reciprocal decreases in G phase, but little impact on the proportion of cells in S and G/M phases, depending on cell line. DNA synthesis and proliferation were largely halted- decreasing by 75% and 81% in C4-2B and PC3 cells, respectively. When cells were treated with docetaxel, SNHG1-depleted C4-2B and PC3 cells were resistant to G arrest, and displayed reduced apoptosis, as indicated by reduced cyclin B1 and cleaved caspase 3, suggesting SNHG1 levels may modulate drug response.
CONCLUSIONS
Overall, these results indicate SNHG1 has complex roles in prostate cancer, as it stimulates cell cycle entry and disease progression, but sensitizes cells to docetaxel treatment.
Topics: Humans; Male; Docetaxel; Cell Division; Cell Proliferation; Prostatic Neoplasms; Apoptosis; Cell Line, Tumor; DNA; RNA, Long Noncoding
PubMed: 37464317
DOI: 10.1186/s12885-023-11006-x -
Current Oncology Reports Feb 2024Prostate cancer is the most frequently diagnosed non-cutaneous malignancy of men in the USA; notably, the incidence is higher among men of African, followed by European... (Review)
Review
PURPOSE OF REVIEW
Prostate cancer is the most frequently diagnosed non-cutaneous malignancy of men in the USA; notably, the incidence is higher among men of African, followed by European and Asian ancestry. Germline mutations and, in particular, mutations in DNA damage repair genes (DDRGs) have been implicated in the pathogenesis of prostate cancer. This review intends to discuss the implication of ancestry on prostate cancer, specifically in regard to lack of diversity in genomic and genetic databases and the ability of providers to properly counsel patients on the significance of cancer genetic results.
RECENT FINDINGS
Ancestral differences in prostate cancer-associated DDRG germline mutations are increasingly recognized. Guidelines for treatment by the National Comprehensive Cancer Network® (NCCN®) support germline testing in certain patients, and a myriad of genetic testing panels for DDRG mutations are now available in clinical practice. However, the consensus among providers on what genes and mutations to include in the genetic tests has evolved from experience from men of European ancestry (EA). Gaps in ancestry-informed clinical practice exist in genetic risk assessment, implementation of screening, counseling, guiding recommendations, treatment, and clinical trial enrollment. The lack of diversity in tumor genomic and genetic databases may hinder ancestry-specific disease-predisposing alterations from being discovered and targeted in prostate cancer and, therefore, impede the ability of providers to accurately counsel patients on the significance of cancer genetic test results.
Topics: Male; Humans; Germ-Line Mutation; Prostatic Neoplasms; Mutation; Genetic Testing; Genetic Predisposition to Disease
PubMed: 38265515
DOI: 10.1007/s11912-024-01493-x -
Journal of Translational Medicine Oct 2023Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict...
PURPOSE
Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk.
METHODS
Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC).
RESULTS
In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS.
CONCLUSION
This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.
Topics: Humans; Male; Biopsy; Neoplasm Grading; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Early Detection of Cancer; Urinalysis; Metabolome; Urine
PubMed: 37821919
DOI: 10.1186/s12967-023-04424-9