RESUMEN
Liver metastases (LM) remain a major cause of cancer-related death and are a major clinical challenge. LM and the female sex are predictors of a poorer response to immunotherapy but the underlying mechanisms remain unclear. We previously reported on a sexual dimorphism in the control of the tumor microenvironment (TME) of colorectal carcinoma liver metastases (CRCLM) and identified estrogen as a regulator of an immunosuppressive TME in the liver. Here we aimed to assess the effect of estrogen deprivation on the cytokine/chemokine profile associated with CRCLM, using a multiplex cytokine array and the RNAscope technology, and its effects on the innate and adaptive immune responses in the liver. We also evaluated the benefit of combining the selective estrogen-receptor degrader Fulvestrant with immune checkpoint blockade for the treatment of CRCLM. We show that estrogen depletion altered the cytokine/chemokine repertoire of the liver, decreased macrophage polarization, as reflected in reduced accumulation of tumor infiltrating M2 macrophages and increased the accumulation of CCL5+/CCR5+ CD8+ T and NKT cells in the liver TME. Similar results were obtained in a murine pancreatic ductal adenocarcinoma model. Importantly, treatment with Fulvestrant also increased the accumulation of CD8+CCL5+, CD8+CCR5+ T and NK cells in the liver TME and enhanced the therapeutic benefit of anti-PD1 immunotherapy, resulting in a significant reduction in the outgrowth of LM. Taken together, our results show that estrogen regulates immune cell recruitment to the liver and suggest that inhibition of estrogen action could potentiate the tumor-inhibitory effect of immunotherapy in hormone-independent and immunotherapy-resistant metastatic cancer. SIGNIFICANCE: The immune microenvironment of the liver plays a major role in controlling the expansion of hepatic metastases and is regulated by estrogen. We show that treatment of tumor-bearing mice with an estrogen receptor degrader potentiated an anti-metastatic effect of immunotherapy. Our results provide mechanistic insight into clinical findings and a rationale for evaluating the efficacy of combination anti-estrogen and immunotherapy for prevention and/or treatment of hepatic metastases in female patients.
Asunto(s)
Fulvestrant , Inmunoterapia , Neoplasias Hepáticas , Microambiente Tumoral , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Animales , Ratones , Femenino , Humanos , Inmunoterapia/métodos , Fulvestrant/farmacología , Fulvestrant/uso terapéutico , Antagonistas del Receptor de Estrógeno/farmacología , Antagonistas del Receptor de Estrógeno/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Línea Celular Tumoral , Citocinas/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Masculino , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/inmunología , Ratones Endogámicos C57BLRESUMEN
Glioblastoma (GBM), a malignant brain tumor originating in glial cells, is one of the most common primary brain malignancies, affecting one in 100,000 people, typically in the frontal lobe. Estrogens, like estradiol-17 (E2), significantly influence GBM progression, metastasis, and angiogenesis. Estrogen receptors (ERs) are crucial in signal transduction and physiology, making them potential therapeutic targets. However, their roles in GBM pathogenesis remain unclear. This review explores ERs in GBM, focusing on their involvement in tumor immune evasion, modulation of the tumor microenvironment, and the mechanisms underlying GBM progression. Additionally, therapeutic opportunities targeting ERs for GBM treatment are discussed. Estrogen, synthesized primarily in ovaries and in smaller amounts by adrenal glands and fat tissues, regulates reproductive systems, bone density, skin health, and cardiovascular function. The invasive nature and heterogeneity of GBM complicate therapy development. Preclinical findings suggest that endocrine therapy with hormone receptor agonists or antagonists can extend patient survival and improve post-treatment quality of life. The ERß pathway, in particular, shows tumor-suppressive potential, limiting glioma progression with fewer side effects. ERß agonists could become a novel drug class for GBM treatment. Identifying biomarkers and specific therapeutic targets is crucial for early detection and improved prognosis. Estrogen and its receptors are advantageous for GBM treatment due to their regulation of numerous biological processes, ability to penetrate the blood-brain barrier, and genomic and non-genomic control of transcription, making them promising targets for GBM therapy.
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Neoplasias Encefálicas , Glioblastoma , Receptores de Estrógenos , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/antagonistas & inhibidores , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Antagonistas del Receptor de Estrógeno/uso terapéutico , Antagonistas del Receptor de Estrógeno/farmacología , Antagonistas del Receptor de Estrógeno/química , Microambiente Tumoral/efectos de los fármacosRESUMEN
INTRODUCTION: Breast cancer is the most frequently diagnosed cancer worldwide. With around 70% of breast cancers expressing the estrogen receptor (ER), molecules capable of antagonizing and degrading ER (SERDs) or covalently binding to and antagonizing ER (SERCAs) are at the forefront of efforts to bring better treatments to patients. AREAS COVERED: This review summarizes patent applications that claim estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs) identified using SciFinder between the period July 2021 to December 2023. A total of 91 new patent applications from 32 different applicants are evaluated with stratification into acidic SERDs, basic SERDs, SERCAs and miscellaneous degraders. EXPERT OPINION: The widespread adoption of fulvestrant in the treatment of ER+ breast cancer continues to stimulate research into orally bioavailable SERDs and SERCAs. A number of molecules have entered clinical development and, although some have been discontinued, a cohort of potential new treatments have generated encouraging efficacy and safety data. Notably, the first example of an oral SERD, elacestrant, has now been approved by the FDA and EMA, providing further encouragement for this class of targeted therapies.
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Neoplasias de la Mama , Desarrollo de Medicamentos , Patentes como Asunto , Receptores de Estrógenos , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Animales , Femenino , Receptores de Estrógenos/metabolismo , Antagonistas del Receptor de Estrógeno/farmacología , Terapia Molecular Dirigida , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Antineoplásicos Hormonales/farmacologíaRESUMEN
Breast cancer is one of the most common malignant tumors in women worldwide, with the majority of cases showing expression of estrogen receptors (ERs). Although drugs targeting ER have significantly improved survival rates in ER-positive patients, drug resistance remains an unmet clinical need. Fulvestrant, which overcomes selective estrogen receptor modulator (SERM) and AI (aromatase inhibitor) resistance, is currently the only long-acting selective estrogen receptor degrader (SERD) approved for both first and second-line settings. However, it fails to achieve satisfactory efficacy due to its poor solubility. Therefore, we designed and synthesized a series of novel scaffold (THC) derivatives, identifying their activities as ER antagonists and degraders. G-5b, the optimal compound, exhibited binding, antagonistic, degradation or anti-proliferative activities comparable to fulvestrant in ER+ wild type and mutants breast cancer cells. Notably, G-5b showed considerably improved stability and solubility. Research into the underlying mechanism indicated that G-5b engaged the proteasome pathway to degrade ER, subsequently inhibiting the ER signaling pathway and leading to the induction of apoptosis and cell cycle arrest events. Furthermore, G-5b displayed superior in vivo pharmacokinetics and pharmacodynamics properties, coupled with a favorable safety profile in the MCF-7 tamoxifen-resistant (MCF-7/TR) tumor xenograft model. Collectively, G-5b has emerged as a highly promising lead compound, offering potent antagonistic and degradation activities, positioning it as a novel long-acting SERD worthy of further refinement and optimization.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Antagonistas del Receptor de Estrógeno , Fulvestrant , Antagonistas de Estrógenos/farmacología , Tamoxifeno/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Receptor alfa de Estrógeno/metabolismoRESUMEN
The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.
Asunto(s)
Neoplasias de la Mama , Tetrahidronaftalenos , Animales , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Fulvestrant/farmacología , Fulvestrant/uso terapéutico , Antagonistas del Receptor de Estrógeno/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Tamoxifeno , Estrógenos , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismoRESUMEN
Endocrine therapy (ET) is a well-validated strategy for estrogen receptor α positive (ERα + ) breast cancer therapy. Despite the clinical success of current standard of care (SoC), endocrine-resistance inevitably emerges and remains a significant medical challenge. Herein, we describe the structural optimization and evaluation of a new series of selective estrogen receptor covalent antagonists (SERCAs) based on benzothiophene scaffold. Among them, compounds 15b and 39d were identified as two highly potent covalent antagonists, which exhibits superior antiproliferation activity than positive controls against MCF-7 cells and shows high selectivity over ERα negative (ERα-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERαY537S (PDB ID: 7WNV) and intact mass spectrometry, respectively. Further in vivo studies demonstrated potent antitumor activity in MCF-7 xenograft mouse model and an improved safety profile. Collectively, these compounds could be promising candidates for future development of the next generation SERCAs for endocrine-resistant ERα + breast cancer.
Asunto(s)
Neoplasias de la Mama , Antagonistas del Receptor de Estrógeno , Humanos , Ratones , Animales , Femenino , Receptor alfa de Estrógeno , Receptores de Estrógenos , Cristalografía por Rayos X , Neoplasias de la Mama/tratamiento farmacológico , Células MCF-7 , Antagonistas de EstrógenosRESUMEN
PURPOSE: GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. PATIENTS AND METHODS: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2- metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. RESULTS: Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit. CONCLUSIONS: GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Receptores de Estrógenos/genética , Posmenopausia , Antagonistas del Receptor de Estrógeno , Tomografía de Emisión de PositronesRESUMEN
Menopausal hormone therapy (MHT) was widely used to treat menopause-related symptoms in menopausal women. However, MHT therapies were controversial with the increased risk of breast cancer because of different estrogen and progestogen combinations, and the molecular basis behind this phenomenon is currently not understood. To address this issue, we identified differentially expressed genes (DEGs) between the estrogen plus progestogens treatment (EPT) and estrogen treatment (ET) using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data. As a result, a total of 96 upregulated DEGs were first identified. Seven DEGs related to the cell cycle (CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3) were validated by RT-qPCR. Specifically, these seven DEGs were increased in EPT compared to ET (p < 0.05) and had higher expression levels in breast cancer than adjacent normal tissues (p < 0.05). Next, we found that estrogen receptor (ER)-positive breast cancer patients with a higher CNNE2 expression have a shorter overall survival time (p < 0.05), while this effect was not observed in the other six DEGs (p > 0.05). Interestingly, the molecular docking results showed that CCNE2 might bind to 17ß-estradiol (−6.791 kcal/mol), progesterone (−6.847 kcal/mol), and medroxyprogesterone acetate (−6.314 kcal/mol) with a relatively strong binding affinity, respectively. Importantly, CNNE2 protein level could be upregulated with EPT and attenuated by estrogen receptor antagonist, acolbifene and had interactions with cancer driver genes (AKT1 and KRAS) and high mutation frequency gene (TP53 and PTEN) in breast cancer patients. In conclusion, the current study showed that CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3 might contribute to EPT-related tumorigenesis in breast cancer, with CCNE2 might be a sensitive risk indicator of breast cancer risk in women using MHT.
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Neoplasias de la Mama , Progestinas , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Biología Computacional , Estradiol/efectos adversos , Antagonistas del Receptor de Estrógeno/uso terapéutico , Terapia de Reemplazo de Estrógeno/efectos adversos , Estrógenos/efectos adversos , Femenino , Humanos , Acetato de Medroxiprogesterona/uso terapéutico , Menopausia , Simulación del Acoplamiento Molecular , Progesterona/efectos adversos , Progestinas/efectos adversos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Receptores de Estrógenos/metabolismo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Resveratrol may improve organ dysfunction after experimental hemorrhagic or septic shock, and some of these effects appear to be mediated by estrogen receptors. However, the influence of resveratrol on liver function and hepatic microcirculation after hemorrhagic shock is unknown, and a presumed mediation via estrogen receptors has not been investigated in this context. METHODS: Male Sprague-Dawley rats (200-300g, n = 14/group) underwent hemorrhagic shock for 90 min (MAP 35±5 mmHg) and were resuscitated with shed blood and Ringer's solution. Animals were treated intravenously with vehicle (1% EtOH), resveratrol (0.2 mg/kg), the unselective estrogen receptor antagonist ICI 182,780 (0.05 mg/kg) or resveratrol + ICI 182,780 prior to retransfusion. Sham-operated animals did not undergo hemorrhage but were treated likewise. After 2 hours of reperfusion, liver function was assessed either by plasma disappearance rate of indocyanine green (PDRICG) or evaluation of hepatic perfusion and hepatic integrity by intravital microscopy, serum enzyme as well as cytokine levels. RESULTS: Compared to vehicle controls, administration of resveratrol significantly improved PDRICG, hepatic perfusion index and hepatic integrity after hemorrhagic shock. The co-administration of ICI 182,780 completely abolished the protective effect only with regard to liver function. CONCLUSIONS: This study shows that resveratrol may improve liver function and hepatocellular integrity after hemorrhagic shock in rats; estrogen receptors mediate these effects at least partially.
Asunto(s)
Choque Hemorrágico , Animales , Citocinas/farmacología , Antagonistas del Receptor de Estrógeno/farmacología , Estrógenos/farmacología , Fulvestrant/farmacología , Hemorragia , Verde de Indocianina/farmacología , Hígado , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos , Resucitación , Resveratrol/farmacología , Solución de Ringer/farmacologíaRESUMEN
PURPOSE: Radiation therapy (RT) and hormone receptor (HR) inhibition are used for the treatment of HR-positive breast cancers; however, little is known about the interaction of the androgen receptor (AR) and estrogen receptor (ER) in response to RT in AR-positive, ER-positive (AR+/ER+) breast cancers. Here we assessed radiosensitisation of AR+/ER+ cell lines using pharmacologic or genetic inhibition/degradation of AR and/or ER. METHODS: Radiosensitisation was assessed with AR antagonists (enzalutamide, apalutamide, darolutamide, seviteronel, ARD-61), ER antagonists (tamoxifen, fulvestrant) or using knockout of AR. RESULTS: Treatment with AR antagonists or ER antagonists in combination with RT did not result in radiosensitisation changes (radiation enhancement ratios [rER]: 0.76-1.21). Fulvestrant treatment provided significant radiosensitisation of CAMA-1 and BT-474 cells (rER: 1.06-2.0) but not ZR-75-1 cells (rER: 0.9-1.11). Combining tamoxifen with enzalutamide did not alter radiosensitivity using a 1 h or 1-week pretreatment (rER: 0.95-1.14). Radiosensitivity was unchanged in AR knockout compared to Cas9 cells (rER: 1.07 ± 0.11), and no additional radiosensitisation was achieved with tamoxifen or fulvestrant compared to Cas9 cells (rER: 0.84-1.19). CONCLUSION: While radiosensitising in AR + TNBC, AR inhibition does not modulate radiation sensitivity in AR+/ER+ breast cancer. The efficacy of ER antagonists in combination with RT may also be dependent on AR expression.
Asunto(s)
Neoplasias de la Mama , Tolerancia a Radiación , Receptores Androgénicos , Receptores de Estrógenos , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Andrógenos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/radioterapia , Línea Celular Tumoral , Antagonistas del Receptor de Estrógeno/uso terapéutico , Femenino , Fulvestrant/uso terapéutico , Humanos , Naftalenos , Piperidinas , Pirrolidinas , Tolerancia a Radiación/efectos de los fármacos , Tolerancia a Radiación/genética , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Tiazoles , TriazolesRESUMEN
Estrogens are well-known to regulate development of sexual dimorphism of the brain; however, their role in embryonic brain development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs from early neurogenesis specifically in a type of glia in the olfactory bulb (OB), which we name estrogen-responsive olfactory bulb (EROB) cells. In response to estrogen, EROB cells overlay the outermost layer of the OB and interact tightly with olfactory sensory neurons at the olfactory glomeruli. Inhibiting estrogen activity using an estrogen receptor antagonist, ICI182,780 (ICI), and/or EROB cell ablation impedes olfactory glomerular development, including the topological organisation of olfactory glomeruli and inhibitory synaptogenesis in the OB. Furthermore, activation of estrogen signalling inhibits both intrinsic and olfaction-dependent neuronal activity in the OB, whereas ICI or EROB cell ablation results in the opposite effect on neuronal excitability. Altering the estrogen signalling disrupts olfaction-mediated behaviour in later larval stage. We propose that estrogens act on glia to regulate development of OB circuits, thereby modulating the local excitability in the OB and olfaction-mediated behaviour.
Asunto(s)
Estrógenos/metabolismo , Neurogénesis , Neuroglía/citología , Bulbo Olfatorio/embriología , Animales , Antagonistas del Receptor de Estrógeno/farmacología , Fulvestrant/farmacología , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Bulbo Olfatorio/citología , Bulbo Olfatorio/efectos de los fármacos , Neuronas Receptoras Olfatorias/citología , Neuronas Receptoras Olfatorias/metabolismo , Receptores de Estrógenos/antagonistas & inhibidores , Sinapsis/metabolismo , Sinapsis/fisiología , Pez CebraRESUMEN
Maternal exposure to dibutyl phthalate (DBP) may result in ovarian dysfunction in female offspring. However, the underlying mechanisms remain elusive. Pregnant Sprague-Dawley rats were intraperitoneally injected with different doses of DBP, estradiol, and corn oil from gestational day 7 until the end of lactation. The reproductive characteristics, mRNA, and protein expression of ovaries for the adult female offspring were compared. KGN cells were cultured in vitro with DBP, estrogen receptor antagonist, or ALK-5 inhibitor. Genes, proteins, estradiol, and progesterone expressed by KGN, cell proliferation, and apoptosis were measured respectively. Maternal perinatal exposure to DBP induced prolonged estrous period, increased secondary follicles, significant decreased mRNA, and protein levels of TGF-ß2, TGF-ß3, and TGF-ßRII in ovaries of the adult female offspring, but none difference for serum levels of sex hormones, ovarian TGF-ß1, and estrogen receptor. The mRNA levels of LHR, FSHR, and CYP19a in ovaries were also decreased. DBP might decrease the mRNA of TGF-ß2, TGF-ß3, and TGF-ßR II of KGN. DBP can inhibit the mRNA of CYP19 at 24 h, which might be blocked by the estrogen receptor antagonist, whose effects were attenuated at 48 h. DBP combined with FSH might time-dependently regulate the gene expression of TGF-ßR II, inhibitory at 24 h, but stimulative at 48 h, which could be blocked by the ALK5 inhibitor. However, the protein expressed by KGN was not influenced by DBP. DBP stimulated the proliferation of KGN at 24 h, which could be blocked by estrogen receptor antagonist, but attenuated at 48 h. The progesterone in culture medium secreted by KGN was decreased by DBP at 24 h. Maternal perinatal exposure to DBP induced decreased gene expression of TGF-ß signaling and functional proteins in ovaries of the adult female offspring. Molecular cross-talk between estrogen receptor and TGF-ß signaling pathway may play role in the mechanism of granulosa dysfunction induced by DBP.
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Dibutil Ftalato , Exposición Materna , Ovario , Efectos Tardíos de la Exposición Prenatal , Animales , Dibutil Ftalato/toxicidad , Regulación hacia Abajo , Estradiol , Antagonistas del Receptor de Estrógeno , Femenino , Exposición Materna/efectos adversos , Ovario/fisiopatología , Embarazo , Progesterona , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/metabolismo , Factor de Crecimiento Transformador beta2/genética , Factor de Crecimiento Transformador beta2/metabolismo , Factor de Crecimiento Transformador beta3/genética , Factor de Crecimiento Transformador beta3/metabolismoRESUMEN
Nuclear Estrogen receptors (ER) are cytoplasmic proteins; translocated to the nucleus to induce transcriptional signals after getting bound to the estrogen hormone. ER activation implicated in cancer cell proliferation of female reproductive organs. Thus, the discovery of ER antagonists is a reliable strategy to combat estrogen-dependent breast cancer. Endometrial carcinoma is one of the complications encountered upon long-term therapy by selective estrogen receptor modulators (SERMs) like Tamoxifen (TMX) and methyl piperidinopyrazole (MPP). Thus, the ER-full antagonist is a solution to improve the safety of this class of therapeutics during the treatment of breast cancer. We selected MPP as a lead structure to design conformationally constrained analogs. Structural rigidification is a proven strategy to transform the SERMs into full antagonists. Accordingly, we synthesized 7-methoxy-3-(4-methoxyphenyl)-4,5-dihydro-2H-benzo[g]indazoles (4), (6a-c),(8-12) along with the biphenolic counterparts(13-19)that are the anticipated active metabolites. The 4-nitrophenyl derivative(4)is with the most balanced profile regardingthe in vivoanti-uterotrophic potential (EC50 = 4.160 µM); and the cytotoxicity assay of the corresponding active metabolite(13)against ER+ breast cancer cell lines (MCF-7 IC50 = 7.200 µM, T-47D IC50 = 11.710 µM). The inconsiderable uterotrophic activities of the elaborated ER-antagonists and weak antiproliferative activity of the compound(13)against ovarian cancer (SKOV-3 IC50 = 29.800 µM) highlighted it as a good start point to elaborate potential ER-full antagonists devoid of endometrial carcinoma. Extending the pendant chain that protrudes from the 2-(4-(substituted)-phenyl) ring of the new benzo-indazoles is recommended for enhancing the potency based on the binding mode of compound(13)in the ligand-binding domain (LBD) of ER.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Antagonistas del Receptor de Estrógeno/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Receptores de Estrógenos/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Antagonistas del Receptor de Estrógeno/síntesis química , Antagonistas del Receptor de Estrógeno/química , Femenino , Humanos , Ligandos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Ratas Wistar , Receptores de Estrógenos/metabolismo , Relación Estructura-ActividadRESUMEN
New twelve in silico designed coumarin-based ERα antagonists, namely 3DQ-1a to 3DQ-1е, were synthesized and confirmed as selective ERα antagonists, showing potencies ranging from single-digit nanomolar to picomolar. The hits were confirmed as selective estrogen receptor modulators and validated as antiproliferative agents using MCF-7 breast cancer cell lines exerting from picomolar to low nanomolar potency, at the same time showing no agonistic activity within endometrial cell lines. Their mechanism of action was inspected and revealed to be through the inhibition of the Raf-1/MAPK/ERK signal transduction pathway, preventing hormone-mediated gene expression on either genomic direct or genomic indirect level, and stopping the MCF-7 cells proliferation at G0/G1 phase. In vivo experiments, by means of the per os administration to female Wistar rats with pre-induced breast cancer, distinguished six derivatives, 3DQ-4a, 3DQ-2a, 3DQ-1a, 3DQ-1b, 3DQ-2b, and 3DQ-3b, showing remarkable potency as tumor suppressors endowed with optimal pharmacokinetic profiles and no significant histopathological profiles. The presented data indicate the new compounds as potential candidates to be submitted in clinical trials for breast cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Cumarinas/farmacología , Diseño de Fármacos , Antagonistas del Receptor de Estrógeno/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Cumarinas/síntesis química , Cumarinas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Antagonistas del Receptor de Estrógeno/síntesis química , Antagonistas del Receptor de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. METHODS: In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating. FINDINGS: Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68-0·88), with a median follow-up of 43·7 months (IQR 37·8-47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52-1·07), with a median follow-up of 39·4 months (IQR 37·0-42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9-not estimable) in the CDKI group and was 45·7 months (95% CI 41·7-not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67-0·89), with a median follow-up of 45·1 months (95% CI 39·2-48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs. INTERPRETATION: The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer. FUNDING: None.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Fulvestrant/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ensayos Clínicos Fase III como Asunto , Antagonistas del Receptor de Estrógeno/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Topical 17-beta-estradiol (E2) regulates the hair cycle, hair shaft differentiation, and sebum production. Vitamin A also regulates sebum production. Vitamin A metabolism proteins localized to the pilosebaceous unit (PSU; hair follicle and sebaceous gland); and were regulated by E2 in other tissues. This study tests the hypothesis that E2 also regulates vitamin A metabolism in the PSU. First, aromatase and estrogen receptors localized to similar sites as retinoid metabolism proteins during mid-anagen. Next, female and male wax stripped C57BL/6J mice were topically treated with E2, the estrogen receptor antagonist ICI 182,780 (ICI), letrozole, E2 plus letrozole, or vehicle control (acetone) during mid-anagen. E2 or one of its inhibitors regulated most of the vitamin A metabolism genes and proteins examined in a sex-dependent manner. Most components were higher in females and reduced with ICI in females. ICI reductions occurred in the premedulla, sebaceous gland, and epidermis. Reduced E2 also reduced RA receptors in the sebaceous gland and bulge in females. However, reduced E2 increased the number of retinal dehydrogenase 2 positive hair follicle associated dermal dendritic cells in males. These results suggest that estrogen regulates vitamin A metabolism in the skin. Interactions between E2 and vitamin A have implications in acne treatment, hair loss, and skin immunity.
Asunto(s)
Proteínas Portadoras/metabolismo , Estradiol/metabolismo , Estrógenos/metabolismo , Piel/metabolismo , Tretinoina/metabolismo , Animales , Aromatasa/metabolismo , Células Dendríticas/metabolismo , Epidermis , Antagonistas del Receptor de Estrógeno/farmacología , Femenino , Fulvestrant/farmacología , Cabello , Folículo Piloso/metabolismo , Masculino , Ratones Endogámicos C57BL , Oxidorreductasas/metabolismo , Receptores de Estrógenos/metabolismo , Glándulas Sebáceas/metabolismo , Factores SexualesRESUMEN
Although concerns have been raised about the adverse effects of triphenyl phosphate (TPhP) on female fertility, its risk to ovarian functioning remains unknown. In this study, female C57BL/6 mice at postnatal day 21 were exposed on a daily basis to TPhP dose of 2, 10, and 50 mg/kg for 40 days. A significant delay in pubertal timing was observed in the mice exposed to 50 mg/kg of TPhP. An estrogen-responsive reporter transgenic mice assay demonstrated that TPhP significantly downregulated the estrogen receptor (ER) signaling by 45.1% in the whole body in the 50 mg/kg group, and by 14.7-43.7% in the uterus for all exposure groups compared with the control. This strong antagonistic activity of TPhP toward ER explained the delay in pubertal timing. A significant reduction in the number of follicles in all stages was observed in mice after being exposed to TPhP for 40 days at concentrations of 10 and 50 mg/kg, resulting in a decline of the ovarian reserve. The elevation of the follicle-stimulating hormone concentration may have contributed to this phenomenon, as controlled by the antagonistic activity of TPhP toward ER in the brain. The toxic effects of TPhP on ovarian functioning highlight this chemical as a potential risk factor for female fertility.
Asunto(s)
Antagonistas del Receptor de Estrógeno , Reserva Ovárica , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , OrganofosfatosRESUMEN
BACKGROUND: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes. PATIENTS AND METHODS: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively. RESULTS: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale. CONCLUSION: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated. TRIAL REGISTRATION NUMBER: NCT02028507 (ClinTrials.gov). EUDRACT STUDY NUMBER: 2013-003170-27.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Capecitabina/uso terapéutico , Medición de Resultados Informados por el Paciente , Piperazinas/uso terapéutico , Posmenopausia , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Calidad de Vida , Androstadienos/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Capecitabina/efectos adversos , Progresión de la Enfermedad , Antagonistas del Receptor de Estrógeno/uso terapéutico , Europa (Continente) , Femenino , Fulvestrant/uso terapéutico , Estado de Salud , Humanos , Israel , Metástasis de la Neoplasia , Piperazinas/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/efectos adversos , Factores de TiempoRESUMEN
Estrogens, particularly 17ß-estradiol (estradiol, E2), regulate memory formation. E2 acts through its intracellular receptors, estrogen receptors (ER) ERα and ERß, as well as a recently identified G protein-coupled estrogen receptor (GPER). Although the effects of E2 on memory have been investigated, studies examining the effects of GPER stimulation are scarce. Selective GPER agonism improves memory in ovariectomized female rats, but little information is available regarding the effects of GPER stimulation in male rodents. The aim of the present study was to investigate the effects of the GPER agonist, G1, on consolidation and reconsolidation of inhibitory avoidance (IA) and object recognition (OR) memory in male rats. Animals received vehicle, G1 (15, 75, 150 µg/kg; i.p.), or the GPER antagonist G15 (100 µg/kg; i.p.) immediately after training, or G1 (150 µg/kg; i.p.) 3 or 6 h after training. To investigate reconsolidation, G1 was administered immediately after IA retention Test 1. Results indicated that G1 administered immediately after training at the highest dose enhanced both OR and IA memory consolidation, while GPER blockade immediately after training impaired OR. No effects of GPER stimulation were observed when G1 was given 3 or 6 h after training or after Test 1. The present findings provide evidence that GPER is involved in the early stages of memory consolidation in both neutral and emotional memory tasks in male adult rats.
Asunto(s)
Memoria/fisiología , Receptores Acoplados a Proteínas G/fisiología , Reconocimiento en Psicología/fisiología , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Antagonistas del Receptor de Estrógeno/farmacología , Estrógenos/farmacología , Masculino , Memoria/efectos de los fármacos , Motivación/fisiología , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
There has been intense interest in developing orally bioavailable SERDs, energized by the recent discovery of treatment-resistant ESR1 mutations. Overcoming the two decades long challenge of combining all the desirable activities and properties into one molecule, GDC-9545 (giredestrant) was identified with an exceptional preclinical profile. This Viewpoint seeks to place this molecule in the historical context of previously reported oral SERDs and highlights the exciting clinical potential for a best-in-class oral SERD.