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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 -
Swiss Medical Weekly Aug 2023The management of prostate cancer is undergoing rapid changes in all disease settings. Novel imaging tools for diagnosis have been introduced, and the treatment of...
The management of prostate cancer is undergoing rapid changes in all disease settings. Novel imaging tools for diagnosis have been introduced, and the treatment of high-risk localized, locally advanced and metastatic disease has changed considerably in recent years. From clinical and health-economic perspectives, a rational and optimal use of the available options is of the utmost importance. While international guidelines list relevant pivotal trials and give recommendations for a variety of clinical scenarios, there is much room for interpretation, and several important questions remain highly debated. The goal of developing a national consensus on the use of these novel diagnostic and therapeutic strategies in order to improve disease management and eventually patient outcomes has prompted a Swiss consensus meeting. Experts from several specialties, including urology, medical oncology, radiation oncology, pathology and nuclear medicine, discussed and voted on questions of the current most important areas of uncertainty, including the staging and treatment of high-risk localized disease, treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and use of new options to treat metastatic castration-resistant prostate cancer (mCRPC).
Topics: Male; Humans; Consensus; Switzerland; Prostatic Neoplasms; Interdisciplinary Studies; Medical Oncology
PubMed: 37598311
DOI: 10.57187/smw.2023.40108 -
Nature Communications Nov 2023Neuroendocrine prostate cancer is a rapidly progressive and lethal disease characterized by early visceral metastasis, poor prognosis, and limited treatment options....
Neuroendocrine prostate cancer is a rapidly progressive and lethal disease characterized by early visceral metastasis, poor prognosis, and limited treatment options. Uncovering the oncogenic mechanisms could lead to the discovery of potential therapeutic avenues. Here, we demonstrate that the RNA-binding protein ELAVL3 is specifically upregulated in neuroendocrine prostate cancer and that overexpression of ELAVL3 alone is sufficient to induce the neuroendocrine phenotype in prostate adenocarcinoma. Mechanistically, ELAVL3 is transcriptionally regulated by MYCN and subsequently binds to and stabilizes MYCN and RICTOR mRNA. Moreover, ELAVL3 is shown to be released in extracellular vesicles and induce neuroendocrine differentiation of adenocarcinoma cells via an intercellular mechanism. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppresses tumor growth, reduces metastatic risk, and improves survival in neuroendocrine prostate cancer mouse models. Our results identify ELAVL3 as a critical regulator of neuroendocrine differentiation in prostate cancer and propose a drug repurposing strategy for targeted therapies.
Topics: Humans; Male; Animals; Mice; N-Myc Proto-Oncogene Protein; Feedback; Prostatic Neoplasms; Phenotype; Adenocarcinoma; Cell Line, Tumor; ELAV-Like Protein 3
PubMed: 38016952
DOI: 10.1038/s41467-023-43676-3 -
JAMA Oncology Jun 2024Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent...
IMPORTANCE
Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater).
OBJECTIVE
To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers.
DESIGN, SETTING, AND PARTICIPANTS
RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023.
EXPOSURE
Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy.
MAIN OUTCOMES AND MEASURES
Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily.
RESULTS
Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater.
CONCLUSIONS AND RELEVANCE
In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.
Topics: Male; Humans; Prostatic Neoplasms; Aged; Biomarkers, Tumor; Middle Aged; Neoplasm Grading; Prostate-Specific Antigen; Early Detection of Cancer
PubMed: 38635241
DOI: 10.1001/jamaoncol.2024.0455 -
International Journal of Molecular... Sep 2023SUMOylation is an important part of post-translational protein modifications and regulates thousands of proteins in a dynamic manner. The dysregulation of SUMOylation is...
SUMOylation is an important part of post-translational protein modifications and regulates thousands of proteins in a dynamic manner. The dysregulation of SUMOylation is detected in many cancers. However, the comprehensive role of SUMOylation in prostate cancer (PCa) remains unclear. Using 174 SUMOylation-related genes (SRGs) from the MigDSB database and the transcript data of PCa from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we constructed a SUMOylation-related risk score and correlated it with prognosis, tumor mutation burden (TMB), tumor microenvironment (TME) infiltration, and response to chemotherapy and immunotherapy. Moreover, we validated two vital SRGs by RT-qPCR, western blotting, and immunohistochemistry. Two vital SRGs (DNMT3B and NUP210) were finally selected. The risk score based on these genes exhibited excellent predictive efficacy in predicting the biochemical recurrence (BCR) of PCa. A nomogram involving the risk score and T stage was established to further explore the clinical value of the risk score. We found the high-score group was correlated with worse prognosis, higher TMB, a more suppressive immune microenvironment, and a better response to Docetaxel but worse to PD-1/CTLA-4 blockade. Meanwhile, we validated the significantly higher expression level of NUP210 in PCa at mRNA and protein levels. This study elucidated the comprehensive role of SUMOylation-related genes in PCa. Importantly, we highlighted the role of an important SRG, NUP210, in PCa, which might be a promising target in PCa treatment. A better understanding of SUMOylation and utilizing the SUMOylation risk score could aid in precision medicine and improve the prognosis of PCa.
Topics: Male; Humans; Sumoylation; Prostatic Neoplasms; Prostate; Immunotherapy; Precision Medicine; Tumor Microenvironment
PubMed: 37686409
DOI: 10.3390/ijms241713603 -
Current Oncology (Toronto, Ont.) Aug 2023Theranostics (therapy + diagnosis) targeting prostate-specific membrane antigen (PSMA) is an emerging therapeutic modality that could alter treatment strategies for... (Review)
Review
Theranostics (therapy + diagnosis) targeting prostate-specific membrane antigen (PSMA) is an emerging therapeutic modality that could alter treatment strategies for prostate cancer. Although PSMA-targeted radioligand therapy (PSMA-RLT) has a highly therapeutic effect on PSMA-positive tumor tissue, the efficacy of PSMA-RLT depends on PSMA expression. Moreover, predictors of treatment response other than PSMA expression are under investigation. Therefore, the optimal patient population for PSMA-RLT remains unclear. This review provides an overview of the current status of theranostics for prostate cancer, focusing on PSMA ligands. In addition, we summarize various findings regarding the efficacy and problems of PSMA-RLT and discuss the optimal patient for PSMA-RLT.
Topics: Humans; Male; Molecular Imaging; Prostatic Neoplasms
PubMed: 37623010
DOI: 10.3390/curroncol30080529 -
Journal of Geriatric Oncology Sep 2023Sarcopenia is a common skeletal muscle disorder in older people. Here we explore the prevalence of sarcopenia and its impact on men with prostate cancer. (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Sarcopenia is a common skeletal muscle disorder in older people. Here we explore the prevalence of sarcopenia and its impact on men with prostate cancer.
MATERIALS AND METHODS
We searched PubMed, Embase, and Web of Science databases for relevant studies with an explicit definition of sarcopenia in men with prostate cancer which were published between years 2000 and 2022. Prevalence of sarcopenia and its association with time to biochemical recurrence (BCR), progression-free survival (PFS), non-cancer mortality, overall survival (OS), and treatment-related complications in men with prostate cancer were explored. The summary prevalence, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated.
RESULTS
A total of 24 studies comprising 3,616 patients with early and advanced prostate cancer were included. The prevalence of sarcopenia and sarcopenic obesity was 43.8% (95% CI 19.2%-68.5%) and 24.0% (95% CI 5.0%-43.1%), respectively. Sarcopenia was not associated with a shorter time to BCR (HR 0.89, 95% CI 0.64-1.23, p = 0.48), a shorter PFS (HR 1.20, 95% CI 0.73-1.97, p = 0.48), or a shorter OS (HR 1.29, 95% CI 0.90-1.85, p = 0.16). In contrast, sarcopenia was significantly associated with a higher non-cancer mortality (HR 1.85, 95% CI 1.23-2.80, p = 0.003). In four out of five studies eligible for assessment, sarcopenia was not associated with an increased risk of treatment-related complications.
DISCUSSION
Sarcopenia increases the risk of death from other causes in men with prostate cancer. Patients with prostate cancer should be assessed and managed for sarcopenia in everyday clinical practice.
Topics: Male; Humans; Aged; Sarcopenia; Prostatic Neoplasms; Obesity; Proportional Hazards Models; Prognosis
PubMed: 37482497
DOI: 10.1016/j.jgo.2023.101594 -
Oncogene May 2024Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. CaP mortality results from diverse molecular mechanisms that mediate resistance... (Review)
Review
Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. CaP mortality results from diverse molecular mechanisms that mediate resistance to the standard of care treatments for metastatic disease. Recently, alternative splicing has been recognized as a hallmark of CaP aggressiveness. Alternative splicing events cause treatment resistance and aggressive CaP behavior and are determinants of the emergence of the two major types of late-stage treatment-resistant CaP, namely castration-resistant CaP (CRPC) and neuroendocrine CaP (NEPC). Here, we review recent multi-omics data that are uncovering the complicated landscape of alternative splicing events during CaP progression and the impact that different gene transcript isoforms can have on CaP cell biology and behavior. We discuss renewed insights in the molecular machinery by which alternative splicing occurs and contributes to the failure of systemic CaP therapies. The potential for alternative splicing events to serve as diagnostic markers and/or therapeutic targets is explored. We conclude by considering current challenges and promises associated with splicing-modulating therapies, and their potential for clinical translation into CaP patient care.
Topics: Humans; Alternative Splicing; Male; Drug Resistance, Neoplasm; Disease Progression; Prostatic Neoplasms, Castration-Resistant; Prostatic Neoplasms; Gene Expression Regulation, Neoplastic; Animals
PubMed: 38658776
DOI: 10.1038/s41388-024-03036-x -
The Canadian Journal of Urology Apr 2024
Topics: Male; Humans; Prostatic Neoplasms; Gallium Isotopes; Positron-Emission Tomography; Neoplasm Staging
PubMed: 38642457
DOI: No ID Found -
BMC Health Services Research Aug 2023Hospitals account for approximately 6% of United States' gross domestic product. We examined the association between hospital competition and outcomes in elderly with...
BACKGROUND
Hospitals account for approximately 6% of United States' gross domestic product. We examined the association between hospital competition and outcomes in elderly with localized prostate cancer (PCa). We also assessed if race moderated this association.
METHODS
Retrospective study using Surveillance, Epidemiology, and End Results (SEER) - Medicare database. Cohort included fee-for-service, African American and white men aged ≥ 66, diagnosed with localized PCa between 1998 and 2011 and their claims between 1997 and 2016. We used Hirschman-Herfindahl index (HHI) to measure of hospital competition. Outcomes were emergency room (ER) visits, hospitalizations, Medicare expenditure and mortality assessed in acute survivorship phase (two years post-PCa diagnosis), and long-term mortality. We used Generalized Linear Models for analyzing expenditure, Poisson models for ER visits and hospitalizations, and Cox models for mortality. We used propensity score to minimize bias.
RESULTS
Among 253,176 patients, percent change in incident rate of ER visit was 17% higher for one unit increase in HHI (IRR: 1.17, 95% CI: 1.15-1.19). Incident rate of ER was 24% higher for whites and 48% higher for African Americans. For one unit increase in HHI, hazard of short-term all-cause mortality was 7% higher for whites and 11% lower for African Americans. The hazard of long-term all-cause mortality was 10% higher for whites and 13% higher for African Americans.
CONCLUSIONS
Lower hospital competition was associated with impaired outcomes of localized PCa care. Magnitude of impairment was higher for African Americans, compared to whites. Future research will explore process through which competition affects outcomes and racial disparity.
Topics: Aged; Humans; Male; Black or African American; Hospitals; Medicare; Prostatic Neoplasms; Retrospective Studies; United States; White; Quality of Health Care
PubMed: 37543580
DOI: 10.1186/s12913-023-09851-4