Real-world outcomes in patients with metastatic castration-resistant prostate cancer beyond progression after upfront androgen receptor signaling inhibitor.

BACKGROUND: Upfront androgen receptor signaling inhibitor (ARSI) along with androgen deprivation therapy is the current standard of care for metastatic castration-sensitive prostate cancer. However, evidence on second-line therapy after upfront ARSI is scarce. We aimed to evaluate the oncological outcome of ARSI versus docetaxel (DOC) after upfront ARSI therapy in a real-world clinical practice. METHODS: Subjects were metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed within 2 years of upfront ARSI therapy and received ARSI (ARSI group) or DOC (DOC group) as a second-line therapy. Second-line progression-free survival (second-line PFS), and second-line overall survival (second-line OS) were assessed. Propensity score matching (PSM) was used to adjust the clinicopathological features and treatment patterns. RESULTS: A total of 101 mCRPC patients, 68 in the ARSI group, and 33 in the DOC group, were included in this analysis. Median second-line PFS was 6.3 months in the ARSI group and 4.9 months in the DOC group (p = 0.21). Median second-line OS was 25.0 months in the ARSI group and 14.2 months in the DOC group (p = 0.06). Prostate-specific antigen nadir ≤ 0.2 ng/ml during upfront ARSI therapy was significantly associated with improved second-line PFS. After PSM, no significant difference in second-line PFS and second-line OS were observed between the two groups. CONCLUSION: ARSI or DOC has comparable oncologic outcomes in terms of second-line PFS and second-line OS. Further prospective research with longer follow-ups will be needed to identify the optimal treatment after upfront ARSI therapy.

Seasonal heterochrony of reproductive development and gene expression in a polymorphic salamander.

BACKGROUND: Life cycle evolution includes ecological transitions and shifts in the timing of somatic and reproductive development (heterochrony). However, heterochronic changes can be tissue-specific, ultimately leading to the differential diversification of traits. Salamanders exhibit alternative life cycle polymorphisms involving either an aquatic to terrestrial metamorphosis (biphasic) or retention of aquatic larval traits into adulthood (paedomorphic). In this study, we used gene expression and histology to evaluate how life cycle evolution impacts temporal reproductive patterns in males of a polymorphic salamander. RESULTS: We found that heterochrony shifts the distribution of androgen signaling in the integument, which is correlated with significant differences in seasonal reproductive gland development and pheromone gene expression. In the testes, androgen receptor (ar) expression does not significantly vary between morphs or across seasons. We found significant differences in the onset of spermatogenesis, but by peak breeding season the testes were the same with respect to both histology and gene expression. CONCLUSION: This study provides an example of how seasonal heterochronic shifts in tissue-specific ar gene expression can disparately impact seasonal development and expression patterns across tissues, providing a potential mechanism for differential diversification of reproductive traits.

Population Pharmacokinetics Modeling and Simulation of Deutenzalutamide, A Novel Androgen Receptor Antagonist, in Patients With Metastatic Castration-Resistant Prostate Cancer.

Deutenzalutamide is a new molecular entity androgen receptor antagonist. The primary aim of this study was to develop a population pharmacokinetic model of deutenzalutamide and evaluate effects of intrinsic and extrinsic factors on pharmacokinetics. A nonlinear mixed-effects modeling approach was performed to develop the population pharmacokinetic of deutenzalutamide using data from 1 Phase I trial of deutenzalutamide. Goodness-of-fit plots, prediction-corrected visual predictive check, and bootstrap analysis were carried out to evaluate the final model. Simulation for the developed model was used to evaluate the covariate effects on the pharmacokinetics of deutenzalutamide. A 2-compartment model with first-order absorption and elimination from the central compartment was established for deutenzalutamide. The final covariate included body weight on peripheral compartment volume. This is the first research developing the population pharmacokinetic model of deutenzalutamide in patients with metastatic castration-resistant prostate cancer, and it is expected to support the future clinical administration of deutenzalutamide.

Retrospective study assessing the role of the androgen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

BACKGROUND AND PURPOSE: Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. PATIENTS AND METHODS: We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. RESULTS: Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. CONCLUSIONS: AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

The Ser434Phe Androgen Receptor Gene Mutation Does Not Affect Fertility but is Associated with Increased Prolactin.

Introduction: Prolactin is a hormone secreted by the anterior pituitary gland essential for lactation. Non-physiological hyperprolactinemia characterized by serum prolactin levels exceeding 20 ng/mL in men and 25 ng/mL in women, often results from medication use or pituitary gland tumors. In a minority of cases, the cause of hyperprolactinemia remains unknown despite clinical investigations. Familial idiopathic hyperprolactinemia may stem from mutations in genes encoding prolactin (PRL) and its receptor (PRLR). Methods: This study investigated genetic polymorphisms in PRL and PRLR genes using polymerase chain reaction (PCR) and Sanger sequencing in three sisters affected by familial idiopathic hyperprolactinemia. No mutations were found in these genes, prompting whole exome sequencing (WES) of the proband to identify other potentially involved genes. Results: WES revealed a heterozygous missense substitution c.1301C>T (p.Ser434Phe) in the androgen receptor (AR) gene. Next-generation sequencing (NGS) for the AR gene confirmed that the proband and her two affected sisters, along with three asymptomatic sisters, were all heterozygous carriers of the mutation. Their father was hemizygous, while their mother had a normal genotype. Conclusion: The heterozygous missense mutation in the AR gene found in this family with familial idiopathic hyperprolactinemia is not yet explained. Hence, further research is warranted to elucidate the functional implications of this mutation on AR and its role in the pathogenesis of hyperprolactinemia.

N-terminal domain of androgen receptor is a major therapeutic barrier and potential pharmacological target for treating castration resistant prostate cancer: a comprehensive review.

The incidence rate of prostate cancer (PCa) has risen by 3% per year from 2014 through 2019 in the United States. An estimated 34,700 people will die from PCa in 2023, corresponding to 95 deaths per day. Castration resistant prostate cancer (CRPC) is the leading cause of deaths among men with PCa. Androgen receptor (AR) plays a critical role in the development of CRPC. N-terminal domain (NTD) is the essential functional domain for AR transcriptional activation, in which modular activation function-1 (AF-1) is important for gene regulation and protein interactions. Over last 2 decades drug discovery against NTD has attracted interest for CRPC treatment. However, NTD is an intrinsically disordered domain without stable three-dimensional structure, which has so far hampered the development of drugs targeting this highly dynamic structure. Employing high throughput cell-based assays, small-molecule NTD inhibitors exhibit a variety of unexpected properties, ranging from specific binding to NTD, blocking AR transactivation, and suppressing oncogenic proliferation, which prompts its evaluation in clinical trials. Furthermore, molecular dynamics simulations reveal that compounds can induce the formation of collapsed helical states. Nevertheless, our knowledge of NTD structure has been limited to the primary sequence of amino acid chain and a few secondary structure motif, acting as a barrier for computational and pharmaceutical analysis to decipher dynamic conformation and drug-target interaction. In this review, we provide an overview on the sequence-structure-function relationships of NTD, including the polymorphism of mono-amino acid repeats, functional elements for transcription regulation, and modeled tertiary structure of NTD. Moreover, we summarize the activities and therapeutic potential of current NTD-targeting inhibitors and outline different experimental methods contributing to screening novel compounds. Finally, we discuss current directions for structure-based drug design and potential breakthroughs for exploring pharmacological motifs and pockets in NTD, which could contribute to the discovery of new NTD inhibitors.

Development of a comprehensive open access "molecules with androgenic activity resource (MAAR)" to facilitate risk assessment of chemicals.

The increasing prevalence of endocrine-disrupting chemicals (EDCs) and their potential adverse effects on human health underscore the necessity for robust tools to assess and manage associated risks. The androgen receptor (AR) is a critical component of the endocrine system, playing a pivotal role in mediating the biological effects of androgens, which are male sex hormones. Exposure to androgen-disrupting chemicals during critical periods of development, such as fetal development or puberty, may result in adverse effects on reproductive health, including altered sexual differentiation, impaired fertility, and an increased risk of reproductive disorders. Therefore, androgenic activity data is critical for chemical risk assessment. A large amount of androgenic data has been generated using various experimental protocols. Moreover, the data are reported in different formats and in diverse sources. To facilitate utilization of androgenic activity data in chemical risk assessment, the Molecules with Androgenic Activity Resource (MAAR) was developed. MAAR is the first open-access platform designed to streamline and enhance the risk assessment of chemicals with androgenic activity. MAAR's development involved the integration of diverse data sources, including data from public databases and mining literature, to establish a reliable and versatile repository. The platform employs a user-friendly interface, enabling efficient navigation and extraction of pertinent information. MAAR is poised to advance chemical risk assessment by offering unprecedented access to information crucial for evaluating the androgenic potential of a wide array of chemicals. The open-access nature of MAAR promotes transparency and collaboration, fostering a collective effort to address the challenges posed by androgenic EDCs.

Treatment-induced stemness and lineage plasticity in driving prostate cancer therapy resistance.

Most human cancers are heterogeneous consisting of cancer cells at different epigenetic and transcriptional states and with distinct phenotypes, functions, and drug sensitivities. This inherent cancer cell heterogeneity contributes to tumor resistance to clinical treatment, especially the molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) and androgen receptor signaling inhibitors (ARSIs). Therapeutic interventions, in turn, induce lineage plasticity (also called lineage infidelity) in cancer cells that also drives therapy resistance. In this Perspective, we focus our discussions on cancer cell lineage plasticity manifested as treatment-induced switching of epithelial cancer cells to basal/stem-like, mesenchymal, and neural lineages. We employ prostate cancer (PCa) as the prime example to highlight ARSI-induced lineage plasticity during and towards development of castration-resistant PCa (CRPC). We further discuss how the tumor microenvironment (TME) influences therapy-induced lineage plasticity. Finally, we offer an updated summary on the regulators and mechanisms driving cancer cell lineage infidelity, which should be therapeutically targeted to extend the therapeutic window and improve patients' survival.

Examination of the anabolic activity and mechanisms of action of the combination of Diosgenin and Ecdysterone in C2C12 myotubes.

Plant steroids such as ecdysterone (ECDY) or diosgenin (DIO) have been associated with anabolic and performance-enhancing effects for years. However, the molecular mechanisms have not yet been extensively studied in skeletal muscle cells. Consequently, the anabolic activity and associated molecular mechanisms of ECDY and DIO alone and in combination were investigated in C2C12 myotubes. Dose-dependent effects of both compounds on myotube diameter, mRNA expression of IGF-1 and PI3KR1 as well as expression of myosin heavy chain (MHC) proteins were analyzed in differentiated C2C12 cells. In addition, the binding affinities to androgen and estrogen receptors were analyzed. Treatment with ECDY and DIO significantly induced hypertrophy of C2C12 myotubes. Partially additive effects were observed. This is supported by the mRNA expression of IGF-1 and PI3KR1 as well as in the expression of MHC. However, no clear statement can be made regarding which combination has the strongest additive effects. Besides the results suggest that, in contrast to ECDY, DIO has antiandrogenic effects and bind on AR. Consequently, it indicate that two different mechanisms of action are activated in ECDY and DIO combinations. However, this must be confirmed in further cell cultures studies and human interventions concerning anti-doping regulations.

Drug Interactions between Androgen Receptor Axis-Targeted Therapies and Antithrombotic Therapies in Prostate Cancer: Delphi Consensus.

Background/Objectives: Abiraterone acetate, apalutamide, darolutamide, and enzalutamide, which make up the androgen receptor axis-targeted therapies (ARATs) drug class, are commonly used in the management of prostate cancer. Many patients on ARATs also receive oral antithrombotic therapy (i.e., anticoagulants or antiplatelets). The concomitant use of ARATs and antithrombotic therapies creates the potential for clinically relevant drug-drug interactions, but the literature regarding the actual consequences of these interactions, and guidance for co-prescribing, is limited. We assembled a multidisciplinary panel of experts and provided them with clinical information derived from a comprehensive literature review regarding the drug-drug interactions between ARATs and antithrombotic therapies. Methods: A three-stage modified electronic Delphi process was used to gather and consolidate opinions from the panel. Each stage consisted of up to three rounds of voting to achieve consensus on which ARAT/antithrombotic therapy drug pairs warrant attention, the possible clinical consequences of drug-drug interactions, and suggested actions for management. Results: The panel achieved consensus to avoid 11 ARAT/antithrombotic therapy drug pairs and modify therapy for eight pairs. Assessments relied heavily on pharmacokinetic data and extrapolation from drug-drug interaction studies of similarly metabolized drugs. Conclusions: This e-Delphi process highlights the need for further research into the clinical impact of ARAT/antithrombotic drug interactions. Nonetheless, the suggested actions aim to provide clinicians with a practical framework for therapeutic decision making.

Androgen Receptor Promotes Lung Cancer Metastasis by Modifying the miR23a-3p/EPHB2 Pathway.

OBJECTIVE: This study aimed to investigate the reasons behind the lower survival rates in male lung cancer patients than in female lung cancer patients. METHODS: Through various techniques, such as Argonaute immunoprecipitation, luciferase assays, and ChIP, this study confirmed the positive effects of androgen receptor (AR) on lung cancer cell invasion across different in vitro cell lines and in vivo mouse models. RESULTS: The findings suggest that AR enhanced the invasion of lung cancer cells by modifying EPHB2 signals at the protein expression level, which in turn required changes in miRNA-23a-3p. Restoring miRNA-23a-3p could counteract the intensified invasion of lung cancer cells mediated by AR. CONCLUSION: This study revealed that AR may facilitate the lung cancer matastasis by modulating miRNA-23a-3p/EPHB2 signaling and that targeting this signaling pathway could provide new approaches to inhibit lung cancer metastasis.

The Subcutaneous Adipose Microenvironment as a Determinant of Body Fat Development in Polycystic Ovary Syndrome.

Context: Adipose steroid metabolism modifies body fat development in polycystic ovary syndrome (PCOS). Objective: To determine whether subcutaneous (SC) abdominal adipose aldo-keto reductase 1C3 (AKR1C3; a marker of testosterone generation) is increased in normal-weight women with PCOS vs age- and body mass index (BMI)-matched normoandrogenic ovulatory women (controls) and is related to SC abdominal adipose activator protein-1 (AP-1; a marker of adipocyte differentiation) and/or androgen receptor (AR) protein expression in predicting fat accretion. Design: Prospective cohort study. Setting: Academic center. Patients: Eighteen normal-weight PCOS women; 17 age- and BMI-matched controls. Interventions: Circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, SC abdominal fat biopsy, immunohistochemistry. Main Outcome Measures: Clinical characteristics, hormonal concentrations, body fat distribution, SC adipose AKR1C3, AR, and AP-1 protein expression. Results: Women with PCOS had significantly higher serum androgen levels and greater android/gynoid fat mass ratios than controls. SC adipose AKR1C3, AR, and AP-1 protein expressions were comparable between the study groups, but groups differed in correlations. In PCOS women vs controls, SC adipose AKR1C3 protein expression correlated positively with android and gynoid fat masses and negatively with SC adipose AP-1 protein expression. SC adipose AR protein expression correlated negatively with fasting serum free fatty acid and high-density lipoprotein levels. In both study groups, SC adipose AKR1C3 protein expression negatively correlated with serum cortisol levels. Conclusion: In normal-weight PCOS women, SC abdominal adipose AKR1C3 protein expression, in combination with intra-adipose AP-1 and AR-dependent events, predicts fat accretion in the presence of physiological cortisol levels.

NR5A1/SF-1 Collaborates with Inhibin α and the Androgen Receptor.

Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts with numerous partners. Here, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual carrying an ACMG-categorized 'pathogenic' NR5A1/SF-1 variant in comparison to the healthy carrier father. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in NR1H2 and INHA associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the AR and INHA gene promoters were found. Transactivation studies showed that wild-type NR5A1/SF-1 regulates INHA and AR gene expression, while the NR5A1/SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate AR gene transcription; however, the NR1H2 variant showed normal activity. This study expands the NR5A1/SF-1 network of interacting partners, while not solving the exact interplay of different variants that might be involved in revealing the observed DSD phenotype. It also illustrates that understanding complex genetics in DSDs is challenging.

The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice.

Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors.

FOXM1 Transcriptionally Co-Upregulates Centrosome Amplification and Clustering Genes and Is a Biomarker for Poor Prognosis in Androgen Receptor-Low Triple-Negative Breast Cancer.

There are currently no approved targeted treatments for quadruple-negative breast cancer [QNBC; ER-/PR-/HER2-/androgen receptor (AR)-], a subtype of triple-negative breast cancer (TNBC). AR-low TNBC is more proliferative and clinically aggressive than AR-high TNBC. Centrosome amplification (CA), a cancer hallmark, is rampant in TNBC, where it induces spindle multipolarity-mediated cell death unless centrosome clustering pathways are co-upregulated to avert these sequelae. We recently showed that genes that confer CA and centrosome clustering are strongly overexpressed in AR-low TNBCs relative to AR-high TNBCs. However, the molecular mechanisms that index centrosome clustering to the levels of CA are undefined. We argue that FOXM1, a cell cycle-regulated oncogene, links the expression of genes that drive CA to the expression of genes that act at kinetochores and along microtubules to facilitate centrosome clustering. We provide compelling evidence that upregulation of the FOXM1-E2F1-ATAD2 oncogene triad in AR-low TNBC is accompanied by CA and the co-upregulation of centrosome clustering proteins such as KIFC1, AURKB, BIRC5, and CDCA8, conferring profound dysregulation of cell cycle controls. Targeting FOXM1 in AR-low TNBC may render cancer cells incapable of clustering their centrosomes and impair their ability to generate excess centrosomes. Hence, our review illuminates FOXM1 as a potential actionable target for AR-low TNBC.

Novel Treatment Strategies for Low-Risk Metastatic Castration-Sensitive Prostate Cancer.

BACKGROUND: The treatment strategy for metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly in recent years. Based on various guidelines, an upfront androgen receptor signaling inhibitor (ARSI) is the first choice, but in patients of Asian descent, including Japanese patients, there are a certain number of cases in which androgen deprivation therapy (ADT) and CAB are more effective. If patients can be identified who show a marked response to ADT within 12 weeks after the initiation of ADT, which is the inclusion criterion for ARSI clinical trials targeting mCSPC, it would be valuable from an economic standpoint. METHODS: A total of 218 patients with pure prostate adenocarcinoma and treated with ADT at the Kanazawa University Hospital between January 2000 and December 2020 were included in this study. As a risk classification for mCSPC, in addition to the LATITUDE and CHAARTED criteria, we used the castration-sensitive prostate cancer classification proposed by Kanazawa University (Canazawa), developed by the Department of Urology of Kanazawa University. The Canazawa classification was based on three factors: Gleason pattern 5, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) ≥ 300 IU/L. It defined patients with one factor or less as low-risk and patients with two or three factors as high-risk. The overall survival (OS) and time to castration resistance (TTCR) were estimated retrospectively using the Kaplan-Meier method, and factors associated with TTCR were identified using univariate and multivariate analyses. RESULTS: The median follow-up period was 40.4 months, the median OS period was 85.2 months, and the median TTCR period was 16.4 months. The Canazawa risk classification provided the clearest distinction between the OS and TTCR in mCSPC patients. Multivariate analysis revealed a decrease in PSA levels of <95% at 12 weeks after ADT initiation and was a predictor of short TTCR in low-risk, low-volume patients across all risk classifications. CONCLUSION: The Canazawa classification differentiated the prognosis of mCSPC patients more clearly. A PSA reduction rate of <95% at 12 w after starting ADT in low-risk, low-volume patients of all risk classifications was significantly shorter than the TTCR. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs based on the rate of PSA reduction at 12 w.

Dihydrotestosterone Enhances MICA-Mediated Immune Responses to Epstein-Barr Virus-Associated Gastric Carcinoma.

BACKGROUND: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a subset of gastric cancers linked to EBV infection. While the role of male hormones in cancers such as prostate, breast, and ovarian cancers is well-studied, their impact on EBVaGC remains less understood. This study aims to examine the effect of dihydrotestosterone (DHT) on EBVaGC, particularly focusing on its influence on the immune response. METHODS: The study utilized the SNU719 EBVaGC cell line. Cells were treated with DHT to assess androgen receptor (AR) expression and the activation of signaling pathways, including NF-κB. The expression of MHC class I polypeptide-related sequence A (MICA) and its interaction with the NKG2D receptor on NK and T cells was evaluated. Cytotoxicity assays were conducted to determine DHT's effect on NK and T cell-mediated cytotoxicity, and proinflammatory cytokine gene expression was analyzed. RESULTS: DHT significantly increased AR expression in EBVaGC cells and activated the NF-κB pathway, which led to increased transcription of target genes such as MICA and EBNA1. These changes enhanced the interaction with receptors on NK and T cells, thereby boosting their cytotoxicity against EBVaGC cells. Importantly, DHT did not upregulate proinflammatory cytokine genes. CONCLUSION: DHT enhances the immune response against EBVaGC by upregulating MICA and activating NK and T cells. These findings suggest potential therapeutic strategies targeting androgen signaling to improve anti-tumor immunity in EBVaGC.

Molecular Targets of Minor Cannabinoids in Breast Cancer: In Silico and In Vitro Studies.

BACKGROUND: Breast cancer therapy has been facing remarkable changes. Classic treatments are now combined with other therapies to improve efficacy and surpass resistance. Indeed, the emergence of resistance demands the development of novel therapeutic approaches. Due to key estrogen signaling, estrogen receptor-positive (ER+) breast cancer treatment has always been focused on aromatase inhibition and ER modulation. Lately, the effects of phytocannabinoids, mainly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have been evaluated in different cancers, including breast. However, Cannabis sativa contains more than 120 phytocannabinoids less researched and understood. METHODS: Here, we evaluated, both in silico and in vitro, the ability of 129 phytocannabinoids to modulate important molecular targets in ER+ breast cancer: aromatase, ER, and androgen receptor (AR). RESULTS: In silico results suggested that some cannabinoids may inhibit aromatase and act as ERα antagonists. Nine selected cannabinoids showed, in vitro, potential to act either as ER antagonists with inverse agonist properties, or as ER agonists. Moreover, these cannabinoids were considered as weak aromatase inhibitors and AR antagonists with inverse agonist action. CONCLUSIONS: Overall, we present, for the first time, a comprehensive analysis of the actions of the phytocannabinoids in targets of ER+ breast tumors, pointing out their therapeutic potential in cancer and in other diseases.