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Clinical and Translational Medicine Sep 2022Prostate cancer (PCa) is a major type of cancer in man worldwide. Androgen deprivation therapy (ADT) and the next-generation androgen receptor (AR) pathway inhibitors...
BACKGROUND
Prostate cancer (PCa) is a major type of cancer in man worldwide. Androgen deprivation therapy (ADT) and the next-generation androgen receptor (AR) pathway inhibitors have acquired great success in treating PCa. However, patients treated with ADT or AR targeted therapy are inevitably developing into castration-resistant prostate cancer (CRPC) or becoming drug resistance. The role of mRNA 5-methylcytosine (m5C) modification in cancers is largely unknown. This study aimed to explore the role of the m5C methyltransferase NSUN2 in Prostate cancer (PCa).
METHODS
The expression of NSUN2 and its clinicopathological impact were evaluated in PCa cohorts. The effect of NSUN2 on the biological characteristics of PCa cells was investigated on the basis of gain-offunction and loss-of-function analyses. Subcutaneous models further uncovered the role of NSUN2 in tumor growth. Epi-transcriptome assays with RNA bisulfite sequencing (RNA-BisSeq) analysis and in vitro enzyme reaction assays were performed to validate the targeted effect of NSUN2 on AR. AR-binding sites in the NSUN2 promoter were investigated by ChIP and luciferase assays to uncover the interplay between NSUN2 and AR signaling. RIP-qPCR and EMSA methods were performed to confirm that YBX1 binds to AR m C sites.
RESULTS
NSUN2 is highly expressed in PCa and predicts poor outcome. NSUN2 plays roles as a PCa oncogene both in vitro and in vivo. Depletion of NSUN2 results in decreased expression and activities of AR, including AR-V7. Mechanistically, NSUN2 posttranscriptionally stabilized AR by cluster m C modification in a m5CYBX1-dependent manner. Strikingly, treatment with enzalutamide, an effective AR inhibitor, reduces NSUN2 expression and decreases the m5C modification level in prostate cancer cells. Finally, we found that AR transcriptionally regulates NSUN2.
CONCLUSION
NSUN2 stabilizes AR mRNA through cluster 5-methylcytosine modification and activates a positive feedback loop to promote prostate cancer.
Topics: 5-Methylcytosine; Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Epigenesis, Genetic; Humans; Male; Methyltransferases; Prostatic Neoplasms, Castration-Resistant; RNA, Messenger; Receptors, Androgen
PubMed: 36169095
DOI: 10.1002/ctm2.1028 -
Urologie (Heidelberg, Germany) Dec 2023In advanced prostate cancer, disease progression during ongoing androgen deprivation therapy (ADT) is referred to as castration-resistant prostate cancer (CRPC). Various... (Review)
Review
BACKGROUND
In advanced prostate cancer, disease progression during ongoing androgen deprivation therapy (ADT) is referred to as castration-resistant prostate cancer (CRPC). Various therapeutic modalities are available for its treatment, including endocrine therapy, chemotherapy, poly (ADP-ribose) polymerase [PARP] inhibition, radionuclide therapy, and radioligand therapy.
OBJECTIVES
This review outlines practical aspects and considerations regarding treatment sequencing in mCRPC.
MATERIALS AND METHODS
The findings are based on existing prospective phase 3 studies that have demonstrated clinically relevant and statistically significant benefits in radiographically progression-free and/or overall survival.
RESULTS
Sequential therapy, aside from numerous patient-specific factors, depends on the treatment patients received in the hormone-sensitive prostate cancer (mHSPC) setting. Following pretreatment with ADT alone or ADT plus docetaxel in the mHSPC context, additional endocrine therapy is the standard approach. In the event of progression under combined endocrine therapy initiated in the mHSPC setting, docetaxel currently serves as the standard for the majority of patients. Patients who received triplet therapy as a pretreatment in the mHSPC scenario can be treated with radioligand therapy or second-line chemotherapy.
CONCLUSION
Various active and well-tolerated treatment options are available for patients with metastatic castration-resistant prostate cancer (mCRPC). The choice of therapy is primarily determined by previous treatments, but many other individual factors are also taken into consideration.
Topics: Male; Humans; Docetaxel; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Prospective Studies
PubMed: 37847397
DOI: 10.1007/s00120-023-02212-3 -
Frontiers in Endocrinology 2023Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary... (Review)
Review
Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation anti-androgens and exhibits resistance to endocrine therapy. Loss of , , and expression and and amplification appear to be key drivers for NEPC differentiation. Epigenetic modifications also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of specific gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrine-specific gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenal-permissive 3βHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair- and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Epigenesis, Genetic; Androgen Antagonists; Prostate
PubMed: 37455903
DOI: 10.3389/fendo.2023.1191311 -
Cancer Letters Nov 2015Cancers arising in the male breast are uncommon. Male breast cancer is a hormone-driven disease that often expresses the estrogen receptor, and antiestrogen therapy... (Review)
Review
Cancers arising in the male breast are uncommon. Male breast cancer is a hormone-driven disease that often expresses the estrogen receptor, and antiestrogen therapy represents the mainstay of treatment. Paradoxically, the advent of a wave of antiestrogens eclipsed the therapeutic potential of alternative therapeutic options. At the beginning of the hormonal therapy era the administration of antiandrogens to metastatic male breast cancer patients was proposed. Ever since the use of these compounds has largely been neglected. A therapeutic role for antiandrogens has been envisioned again in recent years. First, molecular characterization efforts pointed to the androgen receptor as a potential therapeutic target. Second, the development of aromatase inhibitors unexpectedly raised the need for neutralizing androgens in order to tackle endocrine feedback mechanisms responsible for acquired resistance. We herein provide an overview of molecular studies where the androgen receptor was investigated at the genomic, transcriptomic or phenotypic level. We then discuss androgens in the context of the endocrine networks nourishing male breast cancer. Finally, clinical evidence on antiandrogens is summarized along with strategies should be implemented to improve the medical management of these patients.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms, Male; Humans; Male; Molecular Targeted Therapy; Neoplasms, Hormone-Dependent; Receptors, Androgen; Signal Transduction; Treatment Outcome
PubMed: 26276719
DOI: 10.1016/j.canlet.2015.07.040 -
Cancer Jan 2017Although androgen-deprivation therapy (ADT) remains the mainstay of castration-sensitive prostate cancer (CSPC) therapy, the disease's heterogeneity and the limited... (Review)
Review
Although androgen-deprivation therapy (ADT) remains the mainstay of castration-sensitive prostate cancer (CSPC) therapy, the disease's heterogeneity and the limited duration of the response have chaperoned the introduction of chemotherapy and the investigation of novel hormonal targeted agents in this setting. Combinations of ADT plus chemotherapy or novel hormonal therapies are being tested at various stages of CSPC with promising results. Furthermore, immunotherapy and experimental drugs are also being actively investigated in this setting. Intriguing multimodality strategies, chiefly deployed for early-stage disease with the aim of maximizing the efficacy and duration of the response, are being explored and may become valid therapeutic options in the future. Ultimately, striking a balance between the clinical gains of these combinations and possibly increased toxicity and reduced quality of life will be necessary. The development of precision medicine and accurate biomarkers is fundamental to progress. Cancer 2017;29-42. © 2016 American Cancer Society.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Quality of Life
PubMed: 27802360
DOI: 10.1002/cncr.30329 -
Frontiers in Immunology 2022Prostate cancer is the second most common cancer in men and represents a significant healthcare burden worldwide. Therapeutic options in the metastatic... (Review)
Review
Prostate cancer is the second most common cancer in men and represents a significant healthcare burden worldwide. Therapeutic options in the metastatic castration-resistant setting remain limited, despite advances in androgen deprivation therapy, precision medicine and targeted therapies. In this review, we summarize the role of immunotherapy in prostate cancer and offer perspectives on opportunities for future development, based on current knowledge of the immunosuppressive tumor microenvironment. Furthermore, we discuss the potential for synergistic therapeutic strategies with modern radiotherapy, through modulation of the tumor microenvironment. Emerging clinical and pre-clinical data suggest that radiation can convert immune desert tumors into an inflamed immunological hub, potentially sensitive to immunotherapy.
Topics: Androgen Antagonists; Humans; Immunotherapy; Male; Precision Medicine; Prostatic Neoplasms; Tumor Microenvironment
PubMed: 35603186
DOI: 10.3389/fimmu.2022.859785 -
PloS One 2023Androgen deprivation therapy (ADT) is the standard of care for high risk and advanced prostate cancer; however, disease progression from androgen-dependent prostate...
Androgen deprivation therapy (ADT) is the standard of care for high risk and advanced prostate cancer; however, disease progression from androgen-dependent prostate cancer (ADPC) to lethal and incurable castration-resistant prostate cancer (CRPC) and (in a substantial minority of cases) neuroendocrine prostate cancer (NEPC) is common. Identifying effective targeted therapies is challenging because of acquired resistance to established treatments and the vast heterogeneity of advanced prostate cancer (PC). To streamline the identification of potentially active prostate cancer therapeutics, we have developed an adaptable semi-automated protocol which optimizes cell growth and leverages automation to enhance robustness, reproducibility, and throughput while integrating live-cell imaging and endpoint viability assays to assess drug efficacy in vitro. In this study, culture conditions for 72-hr drug screens in 96-well plates were established for a large, representative panel of human prostate cell lines including: BPH-1 and RWPE-1 (non-tumorigenic), LNCaP and VCaP (ADPC), C4-2B and 22Rv1 (CRPC), DU 145 and PC3 (androgen receptor-null CRPC), and NCI-H660 (NEPC). The cell growth and 72-hr confluence for each cell line was optimized for real-time imaging and endpoint viability assays prior to screening for novel or repurposed drugs as proof of protocol validity. We demonstrated effectiveness and reliability of this pipeline through validation of the established finding that the first-in-class BET and CBP/p300 dual inhibitor EP-31670 is an effective compound in reducing ADPC and CRPC cell growth. In addition, we found that insulin-like growth factor-1 receptor (IGF-1R) inhibitor linsitinib is a potential pharmacological agent against highly lethal and drug-resistant NEPC NCI-H660 cells. This protocol can be employed across other cancer types and represents an adaptable strategy to optimize assay-specific cell growth conditions and simultaneously assess drug efficacy across multiple cell lines.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Androgens; Reproducibility of Results; Androgen Antagonists; Cell Survival; Cell Line, Tumor; Receptors, Androgen; Automation
PubMed: 37815978
DOI: 10.1371/journal.pone.0287126 -
Medical Sciences (Basel, Switzerland) Apr 2022Prostate cancer therapy for locally advanced and metastatic diseases includes androgen deprivation therapy (ADT). Second-generation antiandrogens have a role in... (Review)
Review
Prostate cancer therapy for locally advanced and metastatic diseases includes androgen deprivation therapy (ADT). Second-generation antiandrogens have a role in castration-resistant prostate cancer. Nevertheless, some patients do not respond to this therapy, and eventually all the patients became resistant. This is due to modifications to intracellular signaling pathways, genomic alteration, cytokines production, metabolic switches, constitutional receptor activation, overexpression of some proteins, and regulation of gene expression. The aim of this review is to define the most important mechanisms that drive this resistance and the newest discoveries in this field, specifically for enzalutamide and abiraterone, with potential implications for future therapeutic targets. Furthermore, apalutamide and darolutamide share some resistance mechanisms with abiraterone and enzalutamide and could be useful in some resistance settings.
Topics: Androgen Antagonists; Disease Progression; Humans; Male; Prostatic Neoplasms, Castration-Resistant
PubMed: 35645241
DOI: 10.3390/medsci10020025 -
Prostate Cancer and Prostatic Diseases Mar 2023Evolving data suggest that men with high-risk localized prostate cancer may benefit from more potent androgen receptor inhibition in the context of curative intent... (Review)
Review
BACKGROUND
Evolving data suggest that men with high-risk localized prostate cancer may benefit from more potent androgen receptor inhibition in the context of curative intent radiotherapy. Recently updated American Society for Clinical Oncology (ASCO) evidence-based guidelines and the National Comprehensive Cancer Network (NCCN) Guidelines have updated recommendations for the consideration of adding second generation anti-androgens to androgen deprivation therapy (ADT) in men receiving radiation therapy (RT) for noncastrate locally advanced high and very high risk nonmetastatic or node positive prostate cancer.
METHODS AND RESULTS
We conducted a comprehensive review of existing published and abstract presented evidence behind RT with ADT for the definitive management of high-risk prostate cancer, particularly focused on the current phase II and III trial evidence for the addition of second generation anti-androgens to ADT in definitive RT treatment of high-risk prostate cancer and specifically focused on the recent STAMPEDE trial results with abiraterone acetate. We review the biological mechanisms in which second generation anti-androgens may help mitigate ADT resistance and provide radiosensitization through inhibition of DNA repair. Finally, we discuss ongoing clinical trials of potent androgen receptor (AR) inhibitors with ADT in this non-metastatic high-risk radiotherapy setting that may inform on future treatment guidelines.
CONCLUSIONS
Recent data suggest an overall survival benefit as well as increased probabilities of disease free and metastasis free survival in men with high and very high-risk localized, node positive, and oligometastatic hormone sensitive prostate cancer with abiraterone acetate and prednisone and support the use of potent AR inhibitors in this setting after informed decision making.
Topics: Male; Humans; Androgen Antagonists; Abiraterone Acetate; Prostatic Neoplasms; Receptors, Androgen; Prednisone; Androgen Receptor Antagonists
PubMed: 36203051
DOI: 10.1038/s41391-022-00598-3 -
European Journal of Pharmacology Jan 2020The development of targeted therapies has been a consistent goal for hormone-related diseases treatment. As a result of increased knowledge of the role of androgens in... (Review)
Review
The development of targeted therapies has been a consistent goal for hormone-related diseases treatment. As a result of increased knowledge of the role of androgens in different diseases, anti-androgen treatment is becoming increasingly important in targeted therapy. Androgens play an important role in different disorders, therefore, androgen receptor signalling is a crucial factor in pathological conditions. The androgen receptor is a transcription factor activated by the testosterone metabolite 5α-dihydrotestosterone and regulates the expression of genes related to sexual differentiation, growth and survival of prostate cells, and to a certain extent, cancer progression. Herein, we review anti-androgen therapies in cancer and other selected diseases and provide examples where anti-androgen drugs can be used as both main and supportive treatments in the multimodal therapeutic scheme. Even in diseases with low serum levels of testosterone or DHT, anti-androgen therapy plays an important role in new treatments. Therefore, the use of anti-androgens is an appealing strategy in which to overcome resistance to primary treatment by assuring better therapy results. In this review, we take into account both older generation hormonal drugs and the new drug classes. Additionally, we review recent studies that suggest new anti-androgen agents have not entirely replaced some of the old standards.
Topics: Androgen Antagonists; Androgens; Animals; Hormone Replacement Therapy; Humans; Neoplasms
PubMed: 31712062
DOI: 10.1016/j.ejphar.2019.172783