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Cells Dec 2020Around 80-90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum... (Review)
Review
Around 80-90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient's response to androgen ablation therapy is variable, and 20-30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.
Topics: Androgen Receptor Antagonists; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction
PubMed: 33321757
DOI: 10.3390/cells9122653 -
Molecular and Cellular Endocrinology Apr 2018The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which... (Review)
Review
The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.
Topics: Androgens; Animals; Humans; Models, Biological; Organ Specificity; Receptors, Androgen
PubMed: 28624515
DOI: 10.1016/j.mce.2017.06.013 -
Androgen receptor-mediated CD8 T cell stemness programs drive sex differences in antitumor immunity.Immunity Jul 2022The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying...
The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying sexual differences in cancers remains elusive. Here, we demonstrated that sex-related differences in tumor burden depended on adaptive immunity. Male CD8 T cells exhibited impaired effector and stem cell-like properties compared with female CD8 T cells. Mechanistically, androgen receptor inhibited the activity and stemness of male tumor-infiltrating CD8 T cells by regulating epigenetic and transcriptional differentiation programs. Castration combined with anti-PD-L1 treatment synergistically restricted tumor growth in male mice. In humans, fewer male CD8 T cells maintained a stem cell-like memory state compared with female counterparts. Moreover, AR expression correlated with tumor-infiltrating CD8 T cell exhaustion in cancer patients. Our findings reveal sex-biased CD8 T cell stemness programs in cancer progression and in the responses to cancer immunotherapy, providing insights into the development of sex-based immunotherapeutic strategies for cancer treatment.
Topics: Animals; CD8-Positive T-Lymphocytes; Female; Humans; Immunotherapy; Male; Mice; Neoplasms; Receptors, Androgen; Sex Characteristics; Tumor Microenvironment
PubMed: 35700739
DOI: 10.1016/j.immuni.2022.05.012 -
Acta Pharmacologica Sinica Jan 2015Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and... (Review)
Review
Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2-3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.
Topics: Androgens; Animals; Drug Discovery; Humans; Male; Prostatic Neoplasms; Receptors, Androgen
PubMed: 24909511
DOI: 10.1038/aps.2014.18 -
Cells Mar 2022Androgen receptor (AR)-mediated transcription is critical in almost all stages of prostate cancer (PCa) growth and differentiation. This process involves a complex... (Review)
Review
Androgen receptor (AR)-mediated transcription is critical in almost all stages of prostate cancer (PCa) growth and differentiation. This process involves a complex interplay of coregulatory proteins, chromatin remodeling complexes, and other transcription factors that work with AR at -regulatory enhancer regions to induce the spatiotemporal transcription of target genes. This enhancer-driven mechanism is remarkably dynamic and undergoes significant alterations during PCa progression. In this review, we discuss the AR mechanism of action in PCa with a focus on how -regulatory elements modulate gene expression. We explore emerging evidence of genetic variants that can impact AR regulatory regions and alter gene transcription in PCa. Finally, we highlight several outstanding questions and discuss potential mechanisms of this critical transcription factor.
Topics: Cell Line, Tumor; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Transcription, Genetic
PubMed: 35269520
DOI: 10.3390/cells11050898 -
Molecules (Basel, Switzerland) Jan 2020The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy among females worldwide. The... (Review)
Review
The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy among females worldwide. The concordance of more than 70% of AR expression in primary and metastatic breast tumors implies that AR may be a new marker and a potential therapeutic target among AR-positive breast cancer patients. Biological insight into AR-positive breast cancer reveals that AR may cross-talk with several vital signaling pathways, including key molecules and receptors. AR exhibits different behavior depending on the breast cancer subtype. Preliminary clinical research using AR-targeted drugs, which have already been FDA-approved for prostate cancer (PC), has given promising results for AR-positive breast cancer patients. However, since the prognostic and predictive value of AR positivity remains uncertain, it is difficult to identify and stratify patients that would benefit from AR-targeted therapies. Herein, through a review of preclinical studies, clinical studies, and clinical trials, we summarize the biology of AR, its prognostic and predictive value, as well as its therapeutic implications by breast cancer molecular subtype.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation, Preclinical; Female; Humans; Molecular Targeted Therapy; Receptors, Androgen; Signal Transduction
PubMed: 31952272
DOI: 10.3390/molecules25020358 -
International Journal of Molecular... Nov 2022Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and a leading cause of cancer-related death globally. It is also a sexually dimorphic disease with... (Review)
Review
Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and a leading cause of cancer-related death globally. It is also a sexually dimorphic disease with a male predominance both in HCC and in its precursors, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of the androgen receptor (AR) in HCC has been well documented; however, AR-targeted therapies have failed to demonstrate efficacy in HCC. Building upon understandings of AR in prostate cancer (PCa), this review examines the role of AR in HCC, non-androgen-mediated mechanisms of induced AR expression, the existence of AR splice variants (AR-SV) in HCC and concludes by surveying current AR-targeted therapeutic approaches in PCa that show potential for efficacy in HCC in light of AR-SV expression.
Topics: Male; Humans; Female; Carcinoma, Hepatocellular; Liver Neoplasms; Receptors, Androgen; Non-alcoholic Fatty Liver Disease
PubMed: 36430245
DOI: 10.3390/ijms232213768 -
Annals of Surgical Oncology Oct 2017A growing body of literature supports the conclusion that the androgen receptor (AR) plays an important role in breast cancer pathogenesis and may prove to be a relevant... (Review)
Review
A growing body of literature supports the conclusion that the androgen receptor (AR) plays an important role in breast cancer pathogenesis and may prove to be a relevant therapeutic target for patients with AR-driven breast cancer. This has been most apparent in the subset of patients with triple-negative breast cancer (TNBC), in whom approximately 50% of tumors may have androgen dependence. Recent phase 2 clinical trials of agents that antagonize AR or reduce androgen production have shown clinical benefit and efficacy to varying degrees. This review highlights three of these recent trials of AR TNBC and acknowledge ongoing research in this exciting area.
Topics: Androgen Receptor Antagonists; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Prognosis; Receptors, Androgen
PubMed: 28766215
DOI: 10.1245/s10434-017-5961-9 -
Expert Opinion on Therapeutic Patents Jun 2019Androgen receptor (AR) is one of the most promising targets of drug discovery because of its importance in male reproductive systems and homeostasis of bone and muscle.... (Review)
Review
INTRODUCTION
Androgen receptor (AR) is one of the most promising targets of drug discovery because of its importance in male reproductive systems and homeostasis of bone and muscle. Various AR-modulating agents have been developed and used clinically to treat androgen-dependent disorders, including prostate cancer, and some new-generation antiandrogens have recently been approved. Intensive studies are underway to develop various AR-modulating compounds, including conventional antagonists, tissue-specific AR modulators (SARMs), degraders, and nonconventional AR-modulating compounds that target sites other than the ligand-binding domain (LBD), such as the N-terminal domain (NTD) or the DNA-binding domain (DBD).
AREAS COVERED
The authors provide an overview of AR-modulating agents from 2012 to 2018.
EXPERT OPINION
The LBD has been the primary target for AR modulation, and important AR-modulating agents, including SARMs and recently approved antiandrogens such as enzalutamide and apalutamide, have been developed as conventional LBD antagonists. Development of LBD-targeting antiandrogens to treat prostate cancer is a kind of cat-and-mouse game between clinical agents and AR mutations, and therefore next-generation antiandrogens are still required. Development of nonconventional AR-modulating agents targeting NTD and DBD, is likely to be a promising approach to develop multiple and synergistic strategies able to overcome any kind of androgen-dependent condition.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Animals; Drug Development; Drug Discovery; Humans; Male; Molecular Targeted Therapy; Patents as Topic; Prostatic Neoplasms; Receptors, Androgen
PubMed: 31092069
DOI: 10.1080/13543776.2019.1618831 -
Steroids Dec 2020Anabolic androgenic steroids (AAS) are testosterone and testosterone-derivative compounds sporadically employed by athletes and increasingly used recreationally to... (Review)
Review
Considerations, possible contraindications, and potential mechanisms for deleterious effect in recreational and athletic use of selective androgen receptor modulators (SARMs) in lieu of anabolic androgenic steroids: A narrative review.
Anabolic androgenic steroids (AAS) are testosterone and testosterone-derivative compounds sporadically employed by athletes and increasingly used recreationally to acquire a competitive edge or improve body composition. Nevertheless, users are subject to undesired side effects majorly associated with tissue-specific androgen receptor (AR) binding-mediated actions. More recently, selective AR modulators (SARMs) have gained popularity towards delivering androgen-associated anabolic actions with hopes of minimal androgenic effects. While several SARMs are in preclinical and clinical phases intended for demographics subject to hypogonadism, muscle wasting, and osteoporosis, several athletic organizations and drug testing affiliates have realized the increasingly widespread use of SARMs amongst competitors and have subsequently banned their use. Furthermore, recreational users are haphazardly acquiring these compounds from the internet and consuming doses several times greater than empirically reported. Unfortunately, online sources are rife with potential contamination, despite a prevailing public opinion suggesting SARMs are innocuous AAS alternatives. Considering each agent has a broad range of supporting evidence in both human and non-human models, it is important to comprehensively evaluate the current literature on commercially available SARMs to gain better understanding of their efficacy and if they can truly be considered a safer AAS alternative. Therefore, the purpose of this review is to discuss the current evidence regarding AAS and SARM mechanisms of action, demonstrate the efficacy of several prominent SARMs in a variety of scientific trials, and theorize on the wide-ranging contraindications and potential deleterious effects, as well as potential future directions regarding acute and chronic SARM use across a broad range of demographics.
Topics: Anabolic Agents; Androgen Antagonists; Animals; Humans; Male; Receptors, Androgen
PubMed: 33148520
DOI: 10.1016/j.steroids.2020.108753