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Cancer Letters Nov 2023PARP inhibitors (PARPi) are transforming the current treatment landscape of metastatic castration-resistant prostate cancer. By reanalysing published data on olaparib,... (Review)
Review
PARP inhibitors (PARPi) are transforming the current treatment landscape of metastatic castration-resistant prostate cancer. By reanalysing published data on olaparib, talazoparib, rucaparib and niraparib, we provide a concise overview of responses by molecular subgroup. As monotherapy, all PARPi showed comparable efficacy and the same hierarchy in responsiveness: patients with tumours harbouring aberrations in BRCA1 or BRCA2 (BRCAm) evidently demonstrate superior responses when compared to aberrations in other homologous recombination repair (HRR) related genes. Niraparib seems to cause more grade ≥3 adverse events in comparison to other PARPi. PARPi have also been combined with androgen-receptor signalling inhibitors (ARSI) for both patients with tumours harbouring aberrations in HRR genes (HRRm), and molecularly unselected patients. Compared to wildtype, BRCAm patients responded best, followed by HRRm. Olaparib-abiraterone, niraparib-abiraterone, and talazoparib-enzalutamide all prolonged progression-free survival compared to an ARSI alone in HRRm patients. In the non-HRRm subgroup, only olaparib-abiraterone and talazoparib-enzalutamide were effective. Results for the combination of rucaparib with enzalutamide are yet to be reported. The rate of grade ≥3 adverse events for the combination regimens is 10-30% higher when compared to an ARSI alone. Given the limited efficacy in unselected patients, these PARPi-ARSI combinations may be best reserved for selected patients.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Phenylthiohydantoin; Benzamides
PubMed: 37689306
DOI: 10.1016/j.canlet.2023.216367 -
Current Opinion in Pharmacology Aug 2023The clinical characteristics of SBMA, also known as Kennedy's disease (OMIM 313200), were initially documented by Dr. H Kawahara in the 18th century and a hundred years... (Review)
Review
The clinical characteristics of SBMA, also known as Kennedy's disease (OMIM 313200), were initially documented by Dr. H Kawahara in the 18th century and a hundred years later by Dr. W. Kennedy. SBMA is a neuromuscular disease caused by expansions of a CAG microsatellite tandem repeat in exon 1 of the androgen receptor (AR) gene located on the X chromosome. These expansions result in the production of AR with an aberrantly expanded polyglutamine (polyQ) tract. In this review, we explore recent advancements in the significance of gene expression changes in skeletal muscle and discuss how pharmacological interventions targeting this aspect of disease pathogenesis can potentially be translated into therapies for SBMA patients.
Topics: Humans; Bulbo-Spinal Atrophy, X-Linked; Receptors, Androgen; Muscle, Skeletal; Muscular Atrophy
PubMed: 37463556
DOI: 10.1016/j.coph.2023.102394 -
Cancers Oct 2023Prostate cancer (PCa) constitutes a significant cause of mortality, with over 37,000 new deaths each year [...].
Prostate cancer (PCa) constitutes a significant cause of mortality, with over 37,000 new deaths each year [...].
PubMed: 37894337
DOI: 10.3390/cancers15204969 -
International Journal of Molecular... Feb 2024Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular... (Review)
Review
Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular treatment and result in resistant and aggressive disease. These breast cancers usually have fewer treatment options. Targeted therapies for cancer patients may offer fewer adverse side effects because of specificity compared to conventional chemotherapy. Signaling pathways of nuclear receptors, such as the estrogen receptor (ER), have been intensively studied and used as therapeutic targets. Recently, the role of the androgen receptor (AR) in breast cancer is gaining greater attention as a therapeutic target and as a prognostic biomarker. The expression of constitutively active truncated AR splice variants in breast cancer is a possible mechanism contributing to treatment resistance. Therefore, targeting both the full-length AR and AR variants, either through the activation or suppression of AR function, depending on the status of the ER, progesterone receptor, or human epidermal growth factor receptor 2, may provide additional treatment options. Studies targeting AR in combination with other treatment strategies are ongoing in clinical trials. The determination of the status of nuclear receptors to classify and identify patient subgroups will facilitate optimized and targeted combination therapies.
Topics: Humans; Male; Receptors, Androgen; Breast Neoplasms; Androgen Receptor Antagonists; Prostatic Neoplasms, Castration-Resistant
PubMed: 38339092
DOI: 10.3390/ijms25031817 -
British Journal of Cancer Dec 2023Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular...
BACKGROUND
Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular mechanisms associated with NEPC development and invasiveness are still poorly understood. Here we investigated the expression and functional significance of Fascin-1 (FSCN1), a pro-metastasis actin-bundling protein associated with poor prognosis of several cancers, in neuroendocrine differentiation of prostate cancer.
METHODS
Differential expression analyses using Genome Expression Omnibus (GEO) database, clinical samples and cell lines were performed. Androgen or antagonist's cellular treatments and knockdown experiments were used to detect changes in cell morphology, molecular markers, migration properties and in vivo tumour growth. Chromatin immunoprecipitation-sequencing (ChIP-Seq) data and ChIP assays were analysed to decipher androgen receptor (AR) binding.
RESULTS
We demonstrated that FSCN1 is upregulated during neuroendocrine differentiation of prostate cancer in vitro, leading to phenotypic changes and NEPC marker expression. In human prostate cancer samples, FSCN1 expression is restricted to NEPC tumours. We showed that the androgen-activated AR downregulates FSCN1 expression and works as a transcriptional repressor to directly suppress FSCN1 expression. AR antagonists alleviate this repression. In addition, FSCN1 silencing further impairs in vivo tumour growth.
CONCLUSION
Collectively, our findings identify FSCN1 as an AR-repressed gene. Particularly, it is involved in NEPC aggressiveness. Our results provide the rationale for the future clinical development of FSCN1 inhibitors in NEPC patients.
Topics: Humans; Male; Androgen Antagonists; Androgens; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Microfilament Proteins; Prostatic Neoplasms; Receptors, Androgen; Neuroendocrine Tumors
PubMed: 37875732
DOI: 10.1038/s41416-023-02449-x -
Biomolecules & Biomedicine Sep 2023Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African... (Review)
Review
Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations of BRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG) fusion. Most benefits were demonstrated in cyclin dependent-kinase 12 (CDK12) mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targeting p53 and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Androgens; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Antineoplastic Agents
PubMed: 37021836
DOI: 10.17305/bb.2023.8782 -
International Journal of Biological... 2023Lung cancer, as the most commonly diagnosed malignancy, still accounts for the leading cause of cancer-related deaths worldwide. The high rate of mortality and tumor...
Lung cancer, as the most commonly diagnosed malignancy, still accounts for the leading cause of cancer-related deaths worldwide. The high rate of mortality and tumor recurrence has prompted clinicians and scientists to urgently explore new targets for improved treatment. Previous studies have indicated a potential role of the androgen receptor (AR) in the progression of non-small cell lung cancer (NSCLC). However, the precise mechanisms underlying this association, particularly its relation to TPD52-mediated cell invasion and cisplatin (DDP) response, have not been fully elucidated. Therefore, further investigation is necessary to gain a better understanding of these mechanisms and their potential implications for lung cancer treatment. In this study, we discovered that AR can suppress NSCLC cell invasion and increase cisplatin response by downregulating the expression of circular RNA (circRNA), specifically circ-SLCO1B7. This suppression is achieved through the direct binding of AR to the 5' promoter region of the host gene SLCO1B7. The decreased expression of circ-SLCO1B7, mediated by AR, released miR-139-5p back to the RISC (RNA induced silencing complex), where it bonds to the 3' untranslated region (3'UTR) of Tumor Protein D52 (TPD52) messenger RNA, resulting in TPD52 reduction. The data also validated the functional contribution of AR/circ-SLCO1B7/miR-139-5p/TPD52 axis to lung cancer progression. Furthermore, analysis of human NSCLC databases and clinical specimens confirmed the association of the AR/circ-SLCO1B7/miR-139-5p/TPD52 signaling pathway with NSCLC progression. Collectively, the results from our study suggest that AR can suppress lung cancer cell invasion and increase DDP response by modulating the circ-SLCO1B7/miR-139-5p/TPD52 signaling pathway. Targeting this novel signaling pathway may be a new therapeutic strategy to effectively constrain NSCLC development.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Cisplatin; Receptors, Androgen; MicroRNAs; Neoplasm Recurrence, Local; Transcription Factors; Cell Proliferation; Drug Resistance, Neoplasm; Cell Line, Tumor; Neoplasm Proteins
PubMed: 37564195
DOI: 10.7150/ijbs.84577 -
Biology of Sex Differences Sep 2023Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated...
BACKGROUND
Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC and explored a promising combination drug regimen to enhance the efficacy of immunotherapy.
METHODS
Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen-androgen receptor axis in sex differences was explored in vivo and in vitro experiments.
RESULTS
Our analysis of scRNA-seq data from 220,156 cells, as well as MxIF and FCM assays, revealed that CD8 T-cells infiltrated highly in the TME of male RCC, but were mostly in an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8 T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8 T-cells and enhance the efficacy of immunotherapy of RCC in vivo.
CONCLUSIONS
Our study delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen-androgen receptor axis plays an important role in immunosuppression in male RCC. Our findings suggest that androgen receptor inhibitors in combination with immunotherapy may be a promising treatment option for male RCC patients.
Topics: Female; Humans; Male; Carcinoma, Renal Cell; CD8-Positive T-Lymphocytes; Receptors, Androgen; Sex Characteristics; Androgens; Single-Cell Analysis; Kidney Neoplasms; Tumor Microenvironment
PubMed: 37715192
DOI: 10.1186/s13293-023-00540-9 -
Nutrients Jul 2023The androgen receptor (AR) is a member of the family of ligand-activated transcription factors. Selective androgen receptor modulators (SARMs) exert their biological... (Review)
Review
The androgen receptor (AR) is a member of the family of ligand-activated transcription factors. Selective androgen receptor modulators (SARMs) exert their biological function through complex interactions with the AR. It has been speculated that overexertion of AR signaling cascades as a result of SARM abuse can be a risk factor for the development of various cardiovascular diseases. The present literature review explores the implications of the interaction between SARMs and the AR on cardiovascular health by focusing on the AR structure, function, and mechanisms of action, as well as the current clinical literature on various SARMs. It is shown that SARMs may increase the risk of cardiovascular diseases through implications on the renin-angiotensin system, smooth muscle cells, sympathetic nervous system, lipid profile, inflammation, platelet activity, and various other factors. More research on this topic is necessary as SARM abuse is becoming increasingly common. There is a noticeable lack of clinical trials and literature on the relationship between SARMs, cardiovascular diseases, and the AR. Future in vivo and in vitro studies within this field are vital to understand the mechanisms that underpin these complex interactions and risk factors.
Topics: Humans; Receptors, Androgen; Cardiovascular Diseases; Androgens; Androgen Receptor Antagonists; Ligands
PubMed: 37571268
DOI: 10.3390/nu15153330 -
Nature Communications Aug 2023Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary...
Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10 and 6.4 × 10). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.
Topics: Male; Humans; DNA Copy Number Variations; Prostatic Neoplasms; Receptors, Androgen; Genome; Genomics; Clone Cells
PubMed: 37563129
DOI: 10.1038/s41467-023-40315-9