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The American Journal of Pathology Mar 2024Endocrine therapy for prostate cancer is based on the use of drugs that diminish androgen concentration and androgen receptor (AR) signaling inhibitors and is limited by... (Review)
Review
Endocrine therapy for prostate cancer is based on the use of drugs that diminish androgen concentration and androgen receptor (AR) signaling inhibitors and is limited by the functional consequences of AR point mutations and increased expression of constitutively active receptors. Many coactivators (>280) interact with different AR regions. Most studies have determined the expression of coactivators and their effects in the presence of increasing concentrations of androgen or the antiandrogen enzalutamide. The p160 group of coactivators (SRC-1, SRC-2, and SRC-3) is highly expressed in prostate cancer and contributes to ligand-dependent activation of the receptor in models that represent therapy-sensitive and therapy-resistant cell lines. The transcriptional coactivators p300 and CREB-binding protein (CBP) are implicated in the regulation of a large number of cellular events, such as proliferation, apoptosis, migration, and invasion. AR coactivators also may predict biochemical and clinical recurrence. The AR coactivator expression, which is enhanced in enzalutamide resistance, includes growth regulating estrogen receptor binding 1 (GREB1) and GATA-binding protein 2 (GATA2). Several coactivators also activate AR-unrelated signaling pathways, such as those of insulin-like growth factors, which inhibit apoptosis in cancer cells. They are expressed in multiple models of resistance to therapy and can be targeted by various inhibitors in vitro and in vivo. The role of the glucocorticoid receptor in endocrine therapy-resistant prostate cancer has been documented previously. Specific coactivators may interact with the glucocorticoid receptor, thus contributing to therapy failure.
Topics: Male; Humans; Androgens; Receptors, Androgen; Receptors, Glucocorticoid; Histone Acetyltransferases; Prostatic Neoplasms; Cell Line, Tumor; Benzamides; Nitriles; Phenylthiohydantoin
PubMed: 38104650
DOI: 10.1016/j.ajpath.2023.12.003 -
Investigative and Clinical Urology Sep 2023
Topics: Male; Humans; Prostate-Specific Antigen; Early Detection of Cancer; Prostatic Neoplasms
PubMed: 37668197
DOI: 10.4111/icu.20230229 -
Lakartidningen Apr 2024Prostate-specific antigen (PSA) based screening is controversial, even though randomised trials show that screening can reduce prostate cancer mortality. The main reason... (Review)
Review
Prostate-specific antigen (PSA) based screening is controversial, even though randomised trials show that screening can reduce prostate cancer mortality. The main reason is that screening leads to overdiagnosis of indolent cancers that would never have surfaced clinically in the absence of screening. Recently, several large studies have shown that magnetic resonance imaging (MRI) improves prostate cancer diagnostics. With MRI, up to half of all men with elevated PSA values can be spared a biopsy. When a biopsy is needed, the needles can be directed towards the suspicious area in the prostate, which increases the detection of clinically significant tumors. In Sweden, regional programmes with organised prostate cancer testing were introduced in 2020. These programmes aim to make prostate cancer testing more standardized, efficient, and equitable. In the future, biomarkers and AI-based systems will likely be important to further improve prostate cancer diagnostics.
Topics: Humans; Prostatic Neoplasms; Male; Prostate-Specific Antigen; Early Detection of Cancer; Magnetic Resonance Imaging; Sweden; Mass Screening; Biopsy; Biomarkers, Tumor
PubMed: 38647107
DOI: No ID Found -
Oncology Research 2023The androgen receptor (AR) is a critical target in all the clinical stages of prostate cancer. To identify a new AR inhibitor, we constructed a new screening system...
The androgen receptor (AR) is a critical target in all the clinical stages of prostate cancer. To identify a new AR inhibitor, we constructed a new screening system using the androgen-dependent growth of prostate cancer cell lines as a screening indicator. We screened 50,000 culture broths of microorganisms using this screening system and found that the fermentation broth produced by a fungus inhibited androgen-dependent growth of human prostate cancer LNCaP cells without cytotoxicity. Purification of this culture medium was performed, and this resulted in deoxynortryptoquivaline (DNT) being identified as a novel inhibitor of AR function. DNT showed potent inhibition of androgen-dependent growth of human prostate cancer LNCaP cells. The AR competitor assay was performed, and DNT did not act as an AR antagonist. However, DNT inhibited AR-dependent transcriptional activity and AR nuclear translocation, it suggested that the suppression of AR function leads to inhibition activity against androgen-dependent growth.
Topics: Male; Humans; Androgens; Prostatic Neoplasms; Cell Line
PubMed: 37744273
DOI: 10.32604/or.2023.030266 -
Annual Review of Medicine Jan 2024Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or... (Review)
Review
Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or low-molecular-weight radioligands due to its extracellular portion. Successful targeting of PSMA began with the development of humanized J591 antibody. Due to their faster clearance compared to antibodies, small-molecule radioligands for targeted imaging and therapy of PC have been favored in recent development efforts. PSMA positron emission tomography (PET) imaging has higher diagnostic performance than conventional imaging for initial staging of high-risk PC and biochemical recurrence detection/localization. However, it remains to be demonstrated how to integrate PSMA PET imaging for therapy response assessment and as an outcome endpoint measure in clinical trials. With the recent approval of Lu-PSMA-617 by the US Food and Drug Administration for metastatic castration-resistant PC progressing after chemotherapy, the high value of PSMA-targeted therapy was confirmed. Compared to standard of care, PSMA-based radioligand therapy led to a better outcome and a higher quality of life. This review, focusing on the advanced PC setting, provides an overview of different approved and nonapproved PSMA-targeted imaging and therapeutic modalities and discusses the future of PSMA-targeted theranostics, also with an outlook on non-radiopharmaceutical-based PSMA-targeted therapies.
Topics: United States; Male; Humans; Quality of Life; Prostate; Prostatic Neoplasms; Positron-Emission Tomography; Precision Medicine
PubMed: 38285513
DOI: 10.1146/annurev-med-081522-031439 -
European Urology Dec 2023In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel...
Clinical and Genomic Differences Between Advanced Molecular Imaging-detected and Conventional Imaging-detected Metachronous Oligometastatic Castration-sensitive Prostate Cancer.
In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson's χ test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. PATIENT SUMMARY: Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods.
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Molecular Imaging; Genomics; Castration
PubMed: 37173210
DOI: 10.1016/j.eururo.2023.04.025 -
Investigative and Clinical Urology Jul 2023
Topics: Male; Humans; Prostatic Neoplasms; Prostate-Specific Antigen; Early Detection of Cancer; Mass Screening
PubMed: 37417555
DOI: 10.4111/icu.20230178 -
Medicina (Kaunas, Lithuania) Dec 2023Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for... (Review)
Review
Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer's disease. ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs. A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology. The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer's disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Alzheimer Disease; Quality of Life; Cognition
PubMed: 38256338
DOI: 10.3390/medicina60010077 -
Journal of Translational Medicine Nov 2023Prostate cancer (PCA) is the fifth leading cause of cancer-related deaths worldwide, with limited treatment options in the advanced stages. The immunosuppressive tumor...
BACKGROUND
Prostate cancer (PCA) is the fifth leading cause of cancer-related deaths worldwide, with limited treatment options in the advanced stages. The immunosuppressive tumor microenvironment (TME) of PCA results in lower sensitivity to immunotherapy. Although molecular subtyping is expected to offer important clues for precision treatment of PCA, there is currently a shortage of dependable and effective molecular typing methods available for clinical practice. Therefore, we aim to propose a novel stemness-based classification approach to guide personalized clinical treatments, including immunotherapy.
METHODS
An integrative multi-omics analysis of PCA was performed to evaluate stemness-level heterogeneities. Unsupervised hierarchical clustering was used to classify PCAs based on stemness signature genes. To make stemness-based patient classification more clinically applicable, a stemness subtype predictor was jointly developed by using four PCA datasets and 76 machine learning algorithms.
RESULTS
We identified stemness signatures of PCA comprising 18 signaling pathways, by which we classified PCA samples into three stemness subtypes via unsupervised hierarchical clustering: low stemness (LS), medium stemness (MS), and high stemness (HS) subtypes. HS patients are sensitive to androgen deprivation therapy, taxanes, and immunotherapy and have the highest stemness, malignancy, tumor mutation load (TMB) levels, worst prognosis, and immunosuppression. LS patients are sensitive to platinum-based chemotherapy but resistant to immunotherapy and have the lowest stemness, malignancy, and TMB levels, best prognosis, and the highest immune infiltration. MS patients represent an intermediate status of stemness, malignancy, and TMB levels with a moderate prognosis. We further demonstrated that these three stemness subtypes are conserved across pan-tumor. Additionally, the 9-gene stemness subtype predictor we developed has a comparable capability to 18 signaling pathways to make tumor diagnosis and to predict tumor recurrence, metastasis, progression, prognosis, and efficacy of different treatments.
CONCLUSIONS
The three stemness subtypes we identified have the potential to be a powerful tool for clinical tumor molecular classification in PCA and pan-cancer, and to guide the selection of immunotherapy or other sensitive treatments for tumor patients.
Topics: Male; Humans; Prostatic Neoplasms; Prognosis; Androgen Antagonists; Multiomics; Neoplasm Recurrence, Local; Immunotherapy; Tumor Microenvironment
PubMed: 37936202
DOI: 10.1186/s12967-023-04683-6 -
Photodiagnosis and Photodynamic Therapy Jun 2024The global health issue of prostate cancer (PCa) requires better diagnosis and treatment. Photoacoustic imaging (PAI) may change PCa management. This review examines... (Review)
Review
The global health issue of prostate cancer (PCa) requires better diagnosis and treatment. Photoacoustic imaging (PAI) may change PCa management. This review examines PAI's principles, diagnostic role, and therapeutic guidance. PAI uses optical light excitation and ultrasonic detection for high-resolution functional and molecular imaging. PAI uses endogenous and exogenous contrast agents to distinguish cancerous and benign prostate tissues with greater sensitivity and specificity than PSA testing and TRUS-guided biopsy. In addition to diagnosing, PAI can guide and monitor PCa therapy. Its real-time imaging allows precise biopsies and brachytherapy seed placement. Photoacoustic temperature imaging allows non-invasive monitoring of thermal therapies like cryotherapy, improving treatment precision and success. Transurethral illumination probes, innovative contrast agents, integration with other imaging modalities, and machine learning analysis are being developed to overcome depth and data complexity restrictions. PAI could become an essential tool for PCa diagnosis and therapeutic guidance as the field advances.
Topics: Humans; Photoacoustic Techniques; Male; Prostatic Neoplasms
PubMed: 38821240
DOI: 10.1016/j.pdpdt.2024.104225