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International Journal of Molecular... Dec 2022Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting in inverse body regions. In a systematic review, the role of hormones in HS will be presented... (Review)
Review
Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting in inverse body regions. In a systematic review, the role of hormones in HS will be presented to better understand the pathomechanisms of HS. The review is based on the PRISMA criteria. Systematic research was carried out using keywords. Subsequently, the data were analyzed based on the clinical response and other relevant information. The main focus of our systematic review was on HS manifestation, exacerbation, sex hormones, antiandrogen therapy, thyroid function, polycystic ovary syndrome, insulin resistance, and adipokines. In HS, there appears to be a dysregulated adipokine release that is shifted towards pro-inflammatory adipokines. Insulin resistance is significantly more common in HS than in healthy patients regardless of BMI, age, and gender. Insulin resistance in HS patients leads to further cardiovascular disease. The mechanism of insulin resistance and role of adipokines should be investigated in future studies to better provide the pathomechanisms of HS. The role of androgens seems to be important in a certain subgroup of female patients. Anti-androgenic therapy can be useful and helpful in some patients. However, further studies are needed to better understand the hormonal relationship in HS.
Topics: Humans; Female; Insulin Resistance; Hidradenitis Suppurativa; Androgens; Gonadal Steroid Hormones; Androgen Antagonists
PubMed: 36499573
DOI: 10.3390/ijms232315250 -
International Journal of Molecular... Jul 2023Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis... (Review)
Review
Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Receptors, Androgen; Signal Transduction; Orchiectomy; Protein Serine-Threonine Kinases
PubMed: 37446279
DOI: 10.3390/ijms241311100 -
Current Opinion in Urology May 2024To summarize the recent findings on the subject of metastasis-directed therapy (MDT) in the treatment of oligometastatic prostate cancer (omPCa). (Review)
Review Meta-Analysis
PURPOSE OF REVIEW
To summarize the recent findings on the subject of metastasis-directed therapy (MDT) in the treatment of oligometastatic prostate cancer (omPCa).
RECENT FINDINGS
Evidence from two randomized clinical trials (RCTs) and a meta-analysis show favorable toxicity profiles, and the potential to delay androgen-deprivation therapy (ADT) for up to two years in nearly half of patients with metachronous hormone-sensitive omPCa. Another RCT showed promising results of MDT as treatment-escalation method combined with androgen receptor signaling inhibitors (ARSI) in first-line treatment for castration-resistant omPCa.Surveys by radiation oncologists and consensus guidelines advocate for MDT across various omPCa scenarios. Multiple single-arm trials present encouraging results; however, the evidence for the benefit of MDT is still weak requiring further investigation to assess its impact on pivotal endpoints, such as survival and quality of life.
SUMMARY
MDT is a promising approach in omPCa, and can be used to defer ADT in newly diagnosed metachronous omPCa patients, or to add to ARSI treatment at first diagnosis of castration-resistance. Ongoing prospective trials are needed to guide its optimal utilization in other settings, and patients should be informed about the evolving landscape of systemic therapies with proven survival benefits alongside MDT options.
Topics: Male; Humans; Prostatic Neoplasms; Antineoplastic Agents, Hormonal; Androgen Antagonists
PubMed: 38426229
DOI: 10.1097/MOU.0000000000001169 -
The Prostate May 2022Bipolar androgen therapy (BAT) is a new treatment concept for men whose prostate cancer has become resistant to standard hormone-blocking therapy. Over the past decade,... (Review)
Review
Bipolar androgen therapy (BAT) is a new treatment concept for men whose prostate cancer has become resistant to standard hormone-blocking therapy. Over the past decade, we have performed a series of clinical studies testing BAT in asymptomatic men with castration-resistant prostate cancer. The key findings from these clinical studies are that BAT (a) can be safely administered to asymptomatic patients with metastatic castrate-resistant prostate cancer; (b) does not produce symptomatic disease progression; (c) produces sustained prostate-specific antigen and objective responses in 30%-40% of patients; and (d) can resensitize and prolong response to subsequent antiandrogen therapy. The concept of BAT has generated significant interest from men with prostate cancer, their families, and their physicians. Here we provide a "Patient's Guide" that answers questions about BAT in a form that is accessible to patients, their families, and physicians. Our goal is to provide information to help patients make the most informed decisions they can regarding their prostate cancer treatment.
Topics: Androgen Antagonists; Androgens; Disease Progression; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Testosterone
PubMed: 35357024
DOI: 10.1002/pros.24328 -
Cell Death & Disease Jul 2022Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due... (Review)
Review
Prostate cancer is a hormone-dependent malignancy, whose onset and progression are closely related to the activity of the androgen receptor (AR) signaling pathway. Due to this critical role of AR signaling in driving prostate cancer, therapy targeting the AR pathway has been the mainstay strategy for metastatic prostate cancer treatment. The utility of these agents has expanded with the emergence of second-generation AR antagonists, which began with the approval of enzalutamide in 2012 by the United States Food and Drug Administration (FDA). Together with apalutamide and darolutamide, which were approved in 2018 and 2019, respectively, these agents have improved the survival of patients with prostate cancer, with applications for both androgen-dependent and castration-resistant disease. While patients receiving these drugs receive a benefit in the form of prolonged survival, they are not cured and ultimately progress to lethal neuroendocrine prostate cancer (NEPC). Here we summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 35864113
DOI: 10.1038/s41419-022-05084-1 -
Drugs in R&D 2010Abiraterone acetate (CB 7630; CB7630; JNJ-212082), the 3β-acetate prodrug of abiraterone, is structurally related to ketoconazole and is being developed by Cougar... (Review)
Review
Abiraterone acetate (CB 7630; CB7630; JNJ-212082), the 3β-acetate prodrug of abiraterone, is structurally related to ketoconazole and is being developed by Cougar Biotechnology as a hormonal therapy for advanced prostate and breast cancers. As a selective inhibitor of adrenal androgens, it is thought to be a safer product than existing second-line hormonal therapies. This review discusses the key development milestones and therapeutic trials of this drug.
Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Animals; Antineoplastic Agents, Hormonal; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Neoplasms; Prodrugs
PubMed: 21171672
DOI: 10.2165/11587960-000000000-00000 -
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 -
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 -
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 -
Journal of Nuclear Medicine : Official... Aug 2022A subset (35%) of triple-negative breast cancers (TNBCs) expresses androgen receptor (AR) activity. However, clinical trials with antiandrogen drugs have shown limited...
A subset (35%) of triple-negative breast cancers (TNBCs) expresses androgen receptor (AR) activity. However, clinical trials with antiandrogen drugs have shown limited efficacy, with about a 19% clinical benefit rate. We investigated the therapeutic enhancement of antiandrogens as radiosensitizers in combination with F-FDG in TNBC. We screened 5 candidate drugs to evaluate shared toxicity when combined with either F-FDG, x-rays, or ultraviolet radiation, at doses below their respective half-maximal inhibitory concentrations. Cytotoxic enhancement of antiandrogen in combination with F-FDG was evaluated using cell proliferation and DNA damage assays. Finally, the therapeutic efficacy of the combination treatment was evaluated in mouse tumor models of TNBC and prostate cancer. Bicalutamide, an antiandrogen drug, was found to share similar toxicity in combination with either F-FDG or x-rays, indicating its sensitivity as a radiosensitizer to F-FDG. Cell proliferation assays demonstrated selective toxicity of combination bicalutamide-F-FDG in AR-positive 22RV1 and MDA-MB-231 cells in comparison to AR-negative PC3 cells. Quantitative DNA damage and cell cycle arrest assays further confirmed radiation-induced damage to cells, suggesting the role of bicalutamide as a radiosensitizer to F-FDG-mediated radiation damage. Animal studies in MDA-MB-231, 22RV1, and PC3 mouse tumor models demonstrated significant attenuation of tumor growth through combination of bicalutamide and F-FDG in the AR-positive model in comparison to the AR-negative model. Histopathologic examination corroborated the in vitro and in vivo data and confirmed the absence of off-target toxicity to vital organs. These data provide evidence that F-FDG in conjunction with antiandrogens serving as radiosensitizers has utility as a radiotherapeutic agent in the ablation of AR-positive cancers.
Topics: Androgen Antagonists; Animals; Cell Line, Tumor; Fluorodeoxyglucose F18; Humans; Mice; Nitriles; Radiation-Sensitizing Agents; Receptors, Androgen; Triple Negative Breast Neoplasms; Ultraviolet Rays
PubMed: 34772792
DOI: 10.2967/jnumed.121.262958