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International Journal of Molecular... May 2024To create a radiogenomics map and evaluate the correlation between molecular and imaging phenotypes in localized prostate cancer (PCa), using radical prostatectomy...
To create a radiogenomics map and evaluate the correlation between molecular and imaging phenotypes in localized prostate cancer (PCa), using radical prostatectomy histopathology as a reference standard. Radiomic features were extracted from T2-weighted (T2WI) and Apparent Diffusion Coefficient (ADC) images of clinically localized PCa patients (n = 15) across different Gleason score-based risk categories. DNA extraction was performed on formalin-fixed, paraffin-embedded (FFPE) samples. Gene expression analysis of androgen receptor expression, apoptosis, and hypoxia was conducted using the Chromosome Analysis Suite (ChAS) application and OSCHIP files. The relationship between gene expression alterations and textural features was assessed using Pearson's correlation analysis. Receiver operating characteristic (ROC) analysis was utilized to evaluate the predictive accuracy of the model. A significant correlation was observed between radiomic texture features and copy number variation (CNV) of genes associated with apoptosis, hypoxia, and androgen receptor (-value ≤ 0.05). The identified radiomic features, including Sum Entropy ADC, Inverse Difference ADC, Sum Variance T2WI, Entropy T2WI, Difference Variance T2WI, and Angular Secondary Moment T2WI, exhibited potential for predicting cancer grade and biological processes such as apoptosis and hypoxia. Incorporating radiomics and genomics into a prediction model significantly improved the prediction of prostate cancer grade (clinically significant prostate cancer), yielding an AUC of 0.95. Radiomic texture features significantly correlate with genotypes for apoptosis, hypoxia, and androgen receptor expression in localised prostate cancer. Integration of these into the prediction model improved prediction accuracy of clinically significant prostate cancer.
Topics: Male; Humans; Prostatic Neoplasms; Middle Aged; Aged; Receptors, Androgen; Neoplasm Grading; Magnetic Resonance Imaging; Biopsy; Phenotype; ROC Curve; DNA Copy Number Variations
PubMed: 38791417
DOI: 10.3390/ijms25105379 -
Biomedicines Apr 2024Androgen receptor (AR) is a transcription factor expressed in various normal tissues and is a therapeutic target for prostate and possibly other cancers. A TMA...
Androgen receptor (AR) is a transcription factor expressed in various normal tissues and is a therapeutic target for prostate and possibly other cancers. A TMA containing 18,234 samples from 141 different tumor types/subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. AR positivity was found in 116 tumor types including 66 tumor types (46.8%) with ≥1 strongly positive tumor. Moderate/strong AR positivity was detected in testicular sex cord-stromal tumors (93.3-100%) and neoplasms of the prostate (79.3-98.7%), breast (25.0-75.5%), other gynecological tumors (0.9-100%), kidney (5.0-44.1%), and urinary bladder (5.4-24.2%). Low AR staining was associated with advanced tumor stage (pTa versus pT2-4; < 0.0001) in urothelial carcinoma; advanced pT ( < 0.0001), high tumor grade ( < 0.0001), nodal metastasis ( < 0.0001), and reduced survival ( = 0.0024) in invasive breast carcinoma; high pT ( < 0.0001) and grade ( < 0.0001) in clear cell renal cell carcinoma (RCC); and high pT ( = 0.0055) as well as high grade ( < 0.05) in papillary RCC. AR staining was unrelated to histopathological/clinical features in 157 endometrial carcinomas and in 221 ovarian carcinomas. Our data suggest a limited role of AR immunohistochemistry for tumor distinction and a prognostic role in breast and clear cell RCC and highlight tumor entities that might benefit from AR-targeted therapy.
PubMed: 38790919
DOI: 10.3390/biomedicines12050957 -
Investigating GABA Neuron-Specific Androgen Receptor Knockout in two Hyperandrogenic Models of PCOS.Endocrinology May 2024Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links...
Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links developmental or chronic exposure to hyperandrogenism with programming and evoking the reproductive and metabolic traits of PCOS. While critical androgen targets remain to be determined, central GABAergic neurons are postulated to be involved. Here, we tested the hypothesis that androgen signaling in GABAergic neurons is critical in PCOS pathogenesis in 2 well-characterized hyperandrogenic mouse models of PCOS. Using cre-lox transgenics, GABA-specific androgen receptor knockout (GABARKO) mice were generated and exposed to either acute prenatal androgen excess (PNA) or chronic peripubertal androgen excess (PPA). Females were phenotyped for reproductive and metabolic features associated with each model and brains of PNA mice were assessed for elevated GABAergic input to gonadotropin-releasing hormone (GnRH) neurons. Reproductive and metabolic dysfunction induced by PPA, including acyclicity, absence of corpora lutea, obesity, adipocyte hypertrophy, and impaired glucose homeostasis, was not different between GABARKO and wild-type (WT) mice. In PNA mice, acyclicity remained in GABARKO mice while ovarian morphology and luteinizing hormone secretion was not significantly impacted by PNA or genotype. However, PNA predictably increased the density of putative GABAergic synapses to GnRH neurons in adult WT mice, and this PNA-induced plasticity was absent in GABARKO mice. Together, these findings suggest that while direct androgen signaling in GABA neurons is largely not required for the development of PCOS-like traits in androgenized models of PCOS, developmental programming of GnRH neuron innervation is dependent upon androgen signaling in GABA neurons.
Topics: Animals; Polycystic Ovary Syndrome; Female; Receptors, Androgen; Mice, Knockout; Mice; Disease Models, Animal; GABAergic Neurons; Hyperandrogenism; Ovary; Androgens; Pregnancy; Gonadotropin-Releasing Hormone; Prenatal Exposure Delayed Effects
PubMed: 38788194
DOI: 10.1210/endocr/bqae060 -
Cells May 2024Spermatogenesis is a highly regulated process dependent on androgen receptor (AR) signaling in Sertoli cells. However, the pathogenic mechanisms of spermatogenic...
Spermatogenesis is a highly regulated process dependent on androgen receptor (AR) signaling in Sertoli cells. However, the pathogenic mechanisms of spermatogenic failure, by which loss of AR impairs downstream target genes to affect Sertoli cell function, remain incompletely understood. By using microarray analysis, we identified several AR-regulated genes involved in the maturation of spermatogenesis, including chromodomain Y-like protein (CDYL) and transition proteins 1 (TNP-1), that were significantly decreased in ARKO mouse testes. AR and CDYL were found to co-localize and interact in Sertoli cells. The AR-CDYL complex bound to the promoter regions of TNP1 and modulated their transcriptional activity. CDYL acts as a co-regulator of AR transactivation, and its expression is decreased in the Sertoli cells of human testes from patients with azoospermia. The androgen receptor-chromodomain Y-like protein axis plays a crucial role in regulating a network of genes essential for spermatogenesis in Sertoli cells. Disruption of this AR-CDYL regulatory axis may contribute to spermatogenic failure. These findings provide insights into novel molecular mechanisms targeting the AR-CDYL signaling pathway, which may have implications for developing new therapeutic strategies for male infertility.
Topics: Male; Sertoli Cells; Receptors, Androgen; Spermatogenesis; Animals; Signal Transduction; Humans; Mice; Mice, Knockout; Azoospermia; Mice, Inbred C57BL; Transcription Factors; Homeodomain Proteins
PubMed: 38786072
DOI: 10.3390/cells13100851 -
Current Oncology (Toronto, Ont.) Apr 2024This report aims to shed light on the intricate challenges encountered during the diagnosis and treatment of an uncommon variant of prostate cancer-mixed adenosquamous...
This report aims to shed light on the intricate challenges encountered during the diagnosis and treatment of an uncommon variant of prostate cancer-mixed adenosquamous cell carcinoma of the prostate. Prostate cancers of this nature pose distinctive diagnostic and therapeutic dilemmas due to their rarity and complex histological composition. We present a case of a 63-year-old man with metastatic prostate cancer, featuring adenocarcinoma with squamous cell differentiation, who underwent a multimodal treatment approach. The patient responded to first-line carboplatin, docetaxel, and androgen deprivation therapy, followed by androgen receptor pathway inhibitor (ARPI) maintenance. However, disease progression led to radiation therapy and a subsequent switch to Lutetium (177Lu) vipivotide tetraxetan after chemotherapy challenges. Comprehensive genetic profiling revealed shared mutations in the prostate and liver lesions, emphasizing the role of targeted therapies. Prostate-specific membrane antigen (PSMA)-targeted therapy resulted in a notable PSA decline. This case highlights the evolving treatment landscape for rare prostate cancers, integrating genetic insights for tailored interventions. In conclusion, squamous cell carcinoma (SCC) of the prostate is rare, emphasizing the imperative for enhanced comprehension in diagnosis and management. Our case suggests the potential efficacy of ARPI and PSMA-targeted therapies. Our findings advocate for a more nuanced approach to the management of this rare prostate cancer variant, leveraging genomic insights for personalized treatment strategies. This exploration serves as a foundation for further research and clinical considerations in addressing the challenges posed by mixed adenosquamous cell carcinoma of the prostate.
Topics: Humans; Male; Liver Neoplasms; Middle Aged; Prostatic Neoplasms; Carcinoma, Adenosquamous
PubMed: 38785459
DOI: 10.3390/curroncol31050178 -
Urology Case Reports May 2024The development of potent novel androgen receptor inhibitors (ARi) such as apalutamide have improved the life expectancy in men with castration-resistant prostate cancer...
The development of potent novel androgen receptor inhibitors (ARi) such as apalutamide have improved the life expectancy in men with castration-resistant prostate cancer (CRPCa). However, some serious toxicity can occur limiting the choice of treatment in CRPCa. In our case, the patient experienced severe toxicity after initiation of apalutamide. Diagnostic PSMA-PET/CT confirmed the recurrence and tailored the treatment with Lu-PSMA-617 (RLT), a beta emitter radionuclide. RLT resulted in prolonged progression-free survival, thus postponing the commonly seen additional toxicity of chemotherapy. The case highlights the possibility of early RLT in PSMA avid tumors, a treatment with minimal side-effects.
PubMed: 38779691
DOI: 10.1016/j.eucr.2024.102752 -
Frontiers in Oncology 2024The landscape of treating metastatic prostate cancer has evolved with the addition of Androgen Receptor pathway inhibitor (ARPI) to Androgen Deprivation Therapy (ADT),...
The landscape of treating metastatic prostate cancer has evolved with the addition of Androgen Receptor pathway inhibitor (ARPI) to Androgen Deprivation Therapy (ADT), significantly improving survival rates. However, prolonged use of these therapies introduces notable side effects, prompting a need to revisit intermittent treatment duration. The EORTC 2238 De-Escalate trial is a pragmatic trial seeking to reassess the role of intermittent therapy in patients undergoing maximal androgen blockade (MAB) for metastatic hormone naïve prostate cancer (mHNPC), i.e., the combination of ADT with an ARPI, with the aims of reducing side effects, enhancing Quality of Life (QoL) and optimizing resource usage, while maintaining oncological benefits.
PubMed: 38779087
DOI: 10.3389/fonc.2024.1391825 -
OncoTargets and Therapy 2024Humans are frequently exposed to N-nitrosamines through various sources, including diet, cigarette smoking, contaminated water, the atmosphere, and endogenous...
BACKGROUND
Humans are frequently exposed to N-nitrosamines through various sources, including diet, cigarette smoking, contaminated water, the atmosphere, and endogenous nitrosation. Exposure to these carcinogens may also contribute to the gender-specific incidence of liver cancer, which is significantly higher in males than in females, possibly due to the influence of endogenous hormones such as testosterone. However, the effect of testosterone on N-nitrosamine-induced liver cancer and its underlying mechanism remains unclear.
PURPOSE
To investigate the effect of testosterone on the development of liver cancer induced by N-nitrosamines exposure.
PATIENTS AND METHODS
Histopathological and immunohistochemical staining techniques were employed to analyze the expression levels and nuclear localizations of key signaling molecules, including androgen receptor (AR), β-catenin, and HMGB1, in both tumor and non-tumor regions of liver samples obtained from human patients and mice.
RESULTS
The findings demonstrated a strong correlation between AR and β-catenin in the nuclear region of tumor areas. AR also showed a significant correlation with HMGB1 in the cytoplasmic region of non-tumor areas in both human and mice samples. The study further analyzed the expression levels and patterns of these three proteins during the progression of liver tumors.
CONCLUSION
This study confirms that AR has the ability to modulate the expression levels and patterns of β-catenin and HMGB1 in vivo, thereby exacerbating the progression of liver cancer induced by environmental N-nitrosamines exposure. Importantly, the effect of testosterone on the formation of liver cancer induced by environmental N-nitrosamine exposure intensifies this progression. These findings have important implications for drug safety in clinical practice and emphasize the significance of reducing N-nitrosamines exposure through conscious choices regarding diet and lifestyle to ensure environmental safety.
PubMed: 38774818
DOI: 10.2147/OTT.S456746 -
JU Open Plus Apr 2024Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have...
Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.
BACKGROUND
Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature.
MATERIALS AND METHODS
The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators.
RESULTS
This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non- mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies.
CONCLUSIONS
The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.
PubMed: 38774467
DOI: 10.1097/ju9.0000000000000138 -
Journal For Immunotherapy of Cancer May 2024Androgen deprivation therapy (ADT) is the primary treatment for recurrent and metastatic prostate cancer. In addition to direct antitumor effects, ADT has...
RATIONALE
Androgen deprivation therapy (ADT) is the primary treatment for recurrent and metastatic prostate cancer. In addition to direct antitumor effects, ADT has immunomodulatory effects such as promoting T-cell infiltration and enhancing antigen processing/presentation. Previous studies in our laboratory have demonstrated that ADT also leads to increased expression of the androgen receptor (AR) and increased recognition of prostate tumor cells by AR-specific CD8+T cells. We have also demonstrated that ADT combined with a DNA vaccine encoding the AR significantly slowed tumor growth and improved the survival of prostate tumor-bearing mice. The current study aimed to investigate the impact of the timing and sequencing of ADT with vaccination on the tumor immune microenvironment in murine prostate cancer models to further increase the antitumor efficacy of vaccines.
METHODS
Male FVB mice implanted with Myc-CaP tumor cells, or male C57BL/6 mice implanted with TRAMP-C1 prostate tumor cells, were treated with a DNA vaccine encoding AR (pTVG-AR) and ADT. The sequence of administration was evaluated for its effect on tumor growth, and tumor-infiltrating immune populations were characterized.
RESULTS
Vaccination prior to ADT (pTVG-AR → ADT) significantly enhanced antitumor responses and survival. This was associated with increased tumor infiltration by CD4+ and CD8+ T cells, including AR-specific CD8+T cells. Depletion of CD8+T cells prior to ADT significantly worsened overall survival. Following ADT treatment, however, Gr1+ myeloid-derived suppressor cells (MDSCs) increased, and this was associated with fewer infiltrating T cells and reduced tumor growth. Inhibiting Gr1+MDSCs recruitment, either by using a CXCR2 antagonist or by cycling androgen deprivation with testosterone replacement, improved antitumor responses and overall survival.
CONCLUSION
Vaccination prior to ADT significantly improved antitumor responses, mediated in part by increased infiltration of CD8+T cells following ADT. Targeting MDSC recruitment following ADT further enhanced antitumor responses. These findings suggest logical directions for future clinical trials to improve the efficacy of prostate cancer vaccines.
Topics: Male; Animals; Mice; Prostatic Neoplasms; Receptors, Androgen; Cancer Vaccines; Vaccines, DNA; Androgen Antagonists; Cell Line, Tumor; Mice, Inbred C57BL; Vaccination; Humans; Tumor Microenvironment; Disease Models, Animal; CD8-Positive T-Lymphocytes
PubMed: 38772685
DOI: 10.1136/jitc-2024-008848