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JACC. Basic To Translational Science Mar 2024Low testosterone (T), common in aging men, associates with cardiovascular disease. We investigated whether follicle-stimulating hormone (FSH), which is affected by T,...
Low testosterone (T), common in aging men, associates with cardiovascular disease. We investigated whether follicle-stimulating hormone (FSH), which is affected by T, modulates the cardiovascular effects associated with low T or castration. FSHβ:low-density lipoprotein receptor (LDLR) mice, untreated or castrated (orchiectomy, gonadotropin-releasing hormone agonist or antagonist), demonstrated significantly less atherogenesis compared with similarly treated LDLR mice, but not following FSH delivery. Smaller plaque burden in LDLR mice receiving gonadotropin-releasing hormone antagonists vs agonists were nullified in FSHβ:LDLR mice. Atherosclerotic and necrotic plaque size and macrophage infiltration correlated with serum FSH/T. In patients with prostate cancer, FSH/T following androgen-deprivation therapy initiation predicted cardiovascular events. FSH facilitates cardiovascular disease when T is low or eliminated.
PubMed: 38559622
DOI: 10.1016/j.jacbts.2023.10.010 -
Proceedings of the National Academy of... Apr 2024Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic...
Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.
Topics: Male; Humans; Rats; Mice; Animals; Adenosine Triphosphatases; Prostatic Neoplasms, Castration-Resistant; Cell Line; Chromatin; Mammals; Androgen Receptor Antagonists; DNA Helicases; Nuclear Proteins; Transcription Factors
PubMed: 38557192
DOI: 10.1073/pnas.2322563121 -
Urologic Oncology Jun 2024The incidence of nonmetastatic castrate resistant prostate cancer (nmCRPC) is not well defined in contemporary practice. The aim of this study is to describe the...
OBJECTIVES
The incidence of nonmetastatic castrate resistant prostate cancer (nmCRPC) is not well defined in contemporary practice. The aim of this study is to describe the incidence and patterns of treatment of nmCRPC over the last 6 years at a single high-volume Australian health institution.
SUBJECTS AND METHODS
All men newly diagnosed with prostate cancer at Western Health, Melbourne from January 2016 to December 2021 were included in the study. Those diagnosed with nonmetastatic prostate cancer and treated with medical or surgical castration for biochemical failure post attempted curative therapy were retrospectively reviewed for signs of castration resistance using prostate specific antigen (PSA) and testosterone biochemical markers up until October 2022.
RESULTS
From January 2016 to December 2021, 822 patients were diagnosed with prostate cancer, 590 had localized disease, 373 underwent definitive locoregional therapy, and 31 went on to have biochemical recurrence and were commenced on androgen deprivation therapy. Twenty-five patients had undetectable PSA levels and were classified as having nonmetastatic castrate sensitive prostate cancer (nmCSPC), whilst the remaining 6 patients experienced a rising PSA and were thus classified as nmCRPC. The incidence rate of nmCRPC was 228 cases per 100,000 person-years. The median age at the time of prostate biopsy was 74 years (interquartile range [IQR] 64-79) in the nmCRPC group and 62 years (IQR 57-69) in the nmCSPC group. The median prebiopsy PSA (ng/ml) in the nmCRPC and nmCSPC groups were 27.5 (IQR 19.9-50.4), and 16.5 (IQR 9.0-26.0), respectively. The median duration from prostate cancer diagnosis to onset of nmCRPC was 24 months (IQR 17-29) and the median PSA doubling time was 3.4 months (IQR 2.2-5.7).
CONCLUSIONS
Thus, nmCRPC is an uncommon disease. Further population-based studies are required to better understand the incidence of nmCRPC.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Aged; Retrospective Studies; Middle Aged; Aged, 80 and over; Incidence; Androgen Antagonists; Prostate-Specific Antigen
PubMed: 38555235
DOI: 10.1016/j.urolonc.2024.03.005 -
Pharmacological Research May 2024In American men, the incidence of prostate cancer (PC) is the highest among all types of cancer, making it the second leading cause of mortality associated with cancer.... (Review)
Review
In American men, the incidence of prostate cancer (PC) is the highest among all types of cancer, making it the second leading cause of mortality associated with cancer. For advanced or metastatic PC, antiandrogen therapies are standard treatment options. The administration of these treatments unfortunately carries the potential risk of inducing neuroendocrine prostate cancer (NEPC). Neuroendocrine differentiation (NED) serves as a crucial indicator of prostate cancer development, encompassing various factors such as phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), Yes-associated protein 1 (YAP1), AMP-activated protein kinase (AMPK), miRNA. The processes of autophagy and ferroptosis (an iron-dependent form of programmed cell death) play pivotal roles in the regulation of various types of cancers. Clinical trials and preclinical investigations have been conducted on many signaling pathways during the development of NEPC, with the deepening of research, autophagy and ferroptosis appear to be the potential target for regulating NEPC. Due to the dual nature of autophagy and ferroptosis in cancer, gaining a deeper understanding of the developmental programs associated with achieving autophagy and ferroptosis may enhance risk stratification and treatment efficacy for patients with NEPC.
Topics: Humans; Ferroptosis; Autophagy; Male; Prostatic Neoplasms; Animals; Signal Transduction; Antineoplastic Agents; Neuroendocrine Tumors
PubMed: 38554788
DOI: 10.1016/j.phrs.2024.107162 -
Nucleic Acids Research Jun 2024The use of androgen receptor (AR) inhibitors in prostate cancer gives rise to increased cellular lineage plasticity resulting in resistance to AR-targeted therapies. In...
The use of androgen receptor (AR) inhibitors in prostate cancer gives rise to increased cellular lineage plasticity resulting in resistance to AR-targeted therapies. In this study, we examined the chromatin landscape of AR-positive prostate cancer cells post-exposure to the AR inhibitor enzalutamide. We identified a novel regulator of cell plasticity, the homeobox transcription factor SIX2, whose motif is enriched in accessible chromatin regions after treatment. Depletion of SIX2 in androgen-independent PC-3 prostate cancer cells induced a switch from a stem-like to an epithelial state, resulting in reduced cancer-related properties such as proliferation, colony formation, and metastasis both in vitro and in vivo. These effects were mediated through the downregulation of the Wnt/β-catenin signalling pathway and subsequent reduction of nuclear β-catenin. Collectively, our findings provide compelling evidence that the depletion of SIX2 may represent a promising strategy for overcoming the cell plasticity mechanisms driving antiandrogen resistance in prostate cancer.
Topics: Animals; Humans; Male; Mice; Benzamides; beta Catenin; Cell Line, Tumor; Cell Plasticity; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Nerve Tissue Proteins; Nitriles; PC-3 Cells; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Wnt Signaling Pathway
PubMed: 38554106
DOI: 10.1093/nar/gkae206 -
The Journal of Clinical Investigation Mar 2024Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are...
Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.
Topics: Male; Humans; Animals; Prostatic Neoplasms, Castration-Resistant; Mice; Cyclin-Dependent Kinases; Cyclin-Dependent Kinase 8; Cell Line, Tumor; Xenograft Model Antitumor Assays; Protein Kinase Inhibitors; Gene Expression Regulation, Neoplastic; Tumor Microenvironment
PubMed: 38546787
DOI: 10.1172/JCI176709 -
International Journal of Molecular... Mar 2024The RE-1 silencing transcription factor (REST) is a repressor factor related to neuroendocrine prostate cancer (PCa) (NEPC), a poor prognostic stage mainly associated...
The RE-1 silencing transcription factor (REST) is a repressor factor related to neuroendocrine prostate cancer (PCa) (NEPC), a poor prognostic stage mainly associated with castration-resistant PCa (CRPC). NEPC is associated with cell transdifferentiation and the epithelial-mesenchymal transition (EMT) in cells undergoing androgen deprivation therapy (ADT) and enzalutamide (ENZ). The effect of REST overexpression in the 22rv1 cell line (xenograft-derived prostate cancer) on EMT, migration, invasion, and the viability for ENZ was evaluated. EMT genes, Twist and Zeb1, and the androgen receptor (AR) were evaluated through an RT-qPCR and Western blot in nuclear and cytosolic fractions of REST-overexpressing 22rv1 cells (22rv1-REST). The migratory and invasive capacities of 22rv1-REST cells were evaluated via Transwell assays with and without Matrigel, respectively, and their viability for enzalutamide via MTT assays. The 22rv1-REST cells showed decreased nuclear levels of Twist, Zeb1, and AR, and a decreased migration and invasion and a lower viability for ENZ compared to the control. Results were expressed as the mean + SD of three independent experiments (Mann-Whitney U test, Kruskal-Wallis, Tukey test). REST behaves like a tumor suppressor, decreasing the aggressiveness of 22rv1 cells, probably through the repression of EMT and the neuroendocrine phenotype. Furthermore, REST could represent a response marker to ENZ in PCa patients.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Transcription Factors; Cell Line, Tumor; Receptors, Androgen; Epithelial-Mesenchymal Transition; Prostatic Neoplasms, Castration-Resistant; Benzamides; Nitriles; Phenylthiohydantoin
PubMed: 38542313
DOI: 10.3390/ijms25063332 -
Journal of Clinical Medicine Mar 2024(1) : Paraphilic disorders, marked by intense sexual fantasies and behaviors, present formidable challenges. This review addresses concerns fueled by scandals and child... (Review)
Review
(1) : Paraphilic disorders, marked by intense sexual fantasies and behaviors, present formidable challenges. This review addresses concerns fueled by scandals and child abuse. Emphasizing paraphilias' complexity, it systematically reviews the pharmacotherapy literature, aiming to enhance understanding and guide future research. (2) : A comprehensive search from 1990 to 2023 across major databases identified 28 relevant English-language studies. Inclusion criteria focused on adult pharmacotherapy for paraphilias, and results were evaluated using the Newcastle-Ottawa Scale. (3) : Synthesizing data from selected studies, diverse treatments such as SSRIs and antiandrogens were analyzed, revealing variable effectiveness and side effect profiles. Poor quality of the current literature has been reported. (4) : Highlighting the pivotal role of the serotonergic system, this review underscores the efficacy of SSRIs and androgen deprivation therapy. GnRH analog-associated side effects and the importance of a combined assessment approach are discussed. Critical insights contribute to understanding and ethical considerations in paraphilic disorders.
PubMed: 38541750
DOI: 10.3390/jcm13061524 -
Cancers Mar 2024Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating,... (Review)
Review
Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0-33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials.
PubMed: 38539539
DOI: 10.3390/cancers16061205 -
Current Oncology (Toronto, Ont.) Mar 2024Neuroendocrine prostate cancer (NEPC) is a rare subtype of prostate cancer (PCa) that usually results in poor clinical outcomes and may be accompanied by paraneoplastic... (Review)
Review
Neuroendocrine prostate cancer (NEPC) is a rare subtype of prostate cancer (PCa) that usually results in poor clinical outcomes and may be accompanied by paraneoplastic syndromes (PNS). NEPC is becoming more frequent. It can initially manifest as PNS, complicating diagnosis. Therefore, we reviewed the literature on the different PNS associated with NEPC. We systematically reviewed English-language articles from January 2017 to September 2023, identifying 17 studies meeting PRISMA guidelines for NEPC and associated PNS. A total of 17 articles were included in the review. Among these, Cushing's Syndrome (CS) due to ectopic Adrenocorticotropic hormone (ACTH) secretion was the most commonly reported PNS. Other PNS included syndrome of inappropriate Anti-Diuretic Hormone secretion (SIADH), Anti-Hu-mediated chronic intestinal pseudo-obstruction (CIPO), limbic encephalitis, Evans Syndrome, hypercalcemia, dermatomyositis, and polycythemia. Many patients had a history of prostate adenocarcinoma treated with androgen deprivation therapy (ADT) before neuroendocrine features developed. The mean age was 65.5 years, with a maximum survival of 9 months post-diagnosis. NEPC is becoming an increasingly more common subtype of PCa that can result in various PNS. This makes the diagnosis and treatment of NEPC challenging. Further research is crucial to understanding these syndromes and developing standardized, targeted treatments to improve patient survival.
Topics: Male; Humans; Aged; Prostatic Neoplasms; Androgen Antagonists; Paraneoplastic Syndromes
PubMed: 38534956
DOI: 10.3390/curroncol31030123