Search results for: Androgen Receptor
#33983833 2021/05/13 To Up
Heart Failure With Targeted Cancer Therapies: Mechanisms and Cardioprotection.Oncology has seen growing use of newly developed targeted therapies. Although this has resulted in dramatic improvements in progression-free and overall survival, challenges in the management of toxicities related to longer-term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and noncancer cells, overlap in signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities are of important concern. In this review, we highlight several targeted therapies commonly used across a variety of cancer types, including HER2 (human epidermal growth factor receptor 2)+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK (mitogen-activated protein kinase kinase)/BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors. We present the oncological indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity, and potential mechanistic rationale for specific cardioprotective strategies.
Virginia S Hahn, Kathleen W Zhang, Lova Sun, Vivek Narayan, Daniel J Lenihan, Bonnie Ky
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#33983588 // To Up
Current Biomarkers for Precision Medicine in Breast Cancer.Breast cancer has become the prototypical solid tumor where targets have been identified within the tumor allowing for personalized approach for systemic therapy. Biomarkers are beginning to play an important role in preparing the way for precision treatment. Mandatory biomarkers for every newly diagnosed case of breast cancer are estrogen receptors and progesterone receptors in selecting patients for endocrine treatment and HER2 for identifying patients likely to benefit from antiHER2 therapy. Although methodological problems exist in the determination of Ki67, because of its clearly established clinical value, wide availability, and low costs relative to the available multianalyte signatures, Ki67 may be used for determining prognosis, especially if values are low or high. Also, the androgen receptor (AR) pathway is emerging as a potential therapeutic target in breast cancer. AR-targeted treatments for breast cancer are in development and have shown promising preliminary results. While, most established biomarkers in breast cancer require tissue samples, serum tumor markers are easily accessible and require a less invasive procedure. Among them, tissue polypeptide-specific antigen (TPS), a specific epitope structure of a peptide in serum associated with human cytokeratin 18, is linked to the proliferative activity of tumors. TPS may be a valuable and independent prognostic biomarker for breast cancer.In order to accelerate progress towards precision treatment for women with breast cancer, we need additional predictive biomarker, especially for enhancing the positive predictive value for endocrine and antiHER2 therapies, as well as biomarkers for predicting response to specific forms of chemotherapy.
Soo Kyung Ahn, So-Youn Jung
#33982774 2021/05/13 To Up
Proliferating cell nuclear antigen directly interacts with androgen receptor and enhances androgen receptor‑mediated signaling.Androgen receptor (AR) and/or its constitutively active splicing variants (AR‑Vs), such as AR‑V7 and ARv567es, is required for prostate cancer cell growth and survival, and cancer progression. Proliferating cell nuclear antigen (PCNA) is preferentially overexpressed in all cancers and executes its functions through interaction with numerous partner proteins. The aim of the present study was to investigate the potential role of PCNA in the regulation of AR activity. An identical consensus sequence of the PCNA‑interacting protein‑box (PIP‑box) was identified at the N‑terminus of human, mouse and rat AR proteins. It was found that PCNA complexes with the full‑length AR (AR‑FL) and AR‑V7, which can be attenuated by the small molecule PIP‑box inhibitor, T2AA. PCNA also complexes with ARv567es and recombinant AR protein. The PCNA inhibitors, PCNA‑I1S and T2AA, inhibited AR transcriptional activity and the expression of AR target genes in LNCaP‑AI and 22Rv1 cells, but not in AR‑negative PC‑3 cells. The knockdown of PCNA expression reduced dihydrotestosterone‑stimulated AR transcriptional activity and abolished the inhibitory effect of PCNA‑I1S on AR activity. The PCNA inhibitor, PCNA‑I1, exerted additive growth inhibitory effects with androgen deprivation and enzalutamide in cells expressing AR‑FL or AR‑FL/AR‑V7, but not in AR‑negative PC‑3 cells. Finally, R9‑AR‑PIP, a small peptide mimicking AR PIP‑box, was found to bind to GFP‑PCNA at K of 2.73 µM and inhibit the expression of AR target genes, AR transcriptional activity and the growth of AR‑expressing cells. On the whole, these data strongly suggest that AR is a PCNA partner protein and interacts with PCNA via the PIP‑box and that targeting the PCNA‑AR interaction may represent an innovative and selective therapeutic strategy against prostate cancer, particularly castration‑resistant prostate cancers overexpressing constitutively active AR‑Vs.
Shan Lu, Zhongyun Dong
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#33982355 2021/05/12 To Up
Androgenetic alopecia in women and men is not related to COVID-19 infection severity: A prospective cohort study of hospitalized COVID-19 patients.The ongoing outbreak of COVID-19 has posed significant threats to international health. The first biologic step of potential infectivity of COVID-19 is the priming of the spike proteins by transmembrane protease, serine 2 (TMPRSS2). TMPRSS2 cleave angiotensin converting enzyme 2 (ACE2) for augmented viral entry and thus is regarded as essential for viral spread and pathogenesis in the infected hosts .
Shatila Torabi, Mahnaz Mozdourian, Roxana Rezazadeh, Abolfazl Payandeh, Shapour Badiee, Emadodin Darchini-Maragheh
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#33981146 2021/05/05 To Up
Treatment Strategies for Metastatic Castration-Sensitive Prostate Cancer: From "All-Comers" to "Personalized" Approach.Standard treatment for metastatic castration-sensitive prostate cancer (mCSPC) was androgen-deprivation therapy (ADT) for >7 decades, and this was termed the "all-comers" approach. A remarkable evolution in the treatment of mCSPC has been noted in the previous several years. High-quality clinical trials have shown that the addition of docetaxel or androgen receptor pathway inhibitors, such as abiraterone acetate, enzalutamide, and apalutamide, to ADT improves the overall survival (OS) as compared to ADT alone. The first 2 trials demonstrated the benefits of docetaxel and abiraterone acetate in terms of OS in high-volume and high-risk cancer subgroups, respectively. The later trials indicated that upfront combination therapies were associated with improved OS in all patients, irrespective of tumor volume and risk category. Upfront combination therapies are becoming a standard of care for all patients with mCSPC. However, meta-analyses have failed to show that all upfront combination therapies provide significant survival benefits in all patient subgroups. In the low-volume subgroup, significance was observed only for treatment with enzalutamide and radiation to the prostate. Men with low-volume low-risk cancer who have favorable response to ADT achieve long-term survival with ADT only, and toxicities induced by combination therapies would exceed the benefit for these patients. Treatments should be tailored to each patient because mCSPC has marked diversity in its biological and clinical features. Recent advances in diagnostic and molecular technologies will provide useful prognostic and predictive biomarkers, and the treatment strategy will shift from the "for all-comers" to the "individualized" approach.
Kenichi Harada, Masaki Shiota, Akinori Minato, Masahiro Matsumoto, Ikko Tomisaki, Masato Fujisawa, Naohiro Fujimoto
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#33980773 2021/05/11 To Up
Maternal exposure of mice to sodium p-perfluorous nonenoxybenzene sulfonate causes endocrine disruption in both dams and offspring.The toxicity of certain novel perfluoroalkyl substances (PFCs) has attracted increasing attention. However, the toxic effects of sodium p-perfluorous nonenoxybenzene sulfonate (OBS) on the endocrine system have not been elucidated. In this study, OBS was added to the drinking water during the pregnancy and lactation of the healthy female mice at dietary levels of 0.0 mg/L (CON), 0.5 mg/L (OBS-L), and 5.0 mg/L (OBS-H). OBS exposure during the pregnancy and lactation resulted in the presence of OBS residues in the placenta and fetus. We also analyzed physiological and biochemical parameters and gene expression levels in mice of the F0 and F1 generations after maternal OBS exposure. The total serum cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly increased in female mice of the F0 generation. The androgen levels in the serum and the ovarian mRNA levels of androgen receptor (AR) also tended to increase after maternal OBS exposure in the F0 generation mice. Moreover, maternal OBS exposure altered the mRNA expression of endocrine-related genes in male mice of F1 generation. Notably, the serum TC and LDL-C levels were significantly increased in 8-weeks-old male mice of the F1 generation, and the serum high-density lipoprotein cholesterol (HDL-C) levels were decreased in 24-week-old male mice of the F1 generation. These results indicated that maternal OBS exposure can interfere with endocrine homeostasis in the F0 and F1 generations. Therefore, exposure to OBS during pregnancy and lactation has the potential toxic effects on the dams and male offspring, which cannot be overlooked.
Caiyun Wang, Cuiyuan Jin, Wenqing Tu, Yuanxiang Jin
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#33980561 2021/05/12 To Up
Dilemmas in management of osteoporosis in patients with complete androgen insensitivity syndrome.Complete androgen insensitivity syndrome (CAIS)-resulting in 46,XY karyotype, but female phenotype-is a disorder of sex development and primary amenorrhea, but its effect on bone mineral density (BMD) is singular and difficult to manage. Androgens are an important modulator of bone remodeling and health, and the androgen receptor (AR) is pivotal for signaling within the bone cells. CAIS results in a severely disrupted AR throughout the body, causing an elevated risk of early osteoporosis. Timing of gonadectomy and hormone replacement therapy protocols are not established, creating a wide variety of treatment plans and BMD profiles. Our objective is to report a patient with CAIS status post prepubertal orchiectomy that developed early osteoporosis and to describe the lack of optimal strategies and consensus available to improve bone health in this population. Additionally, our case illustrates the fact there are no guidelines advocating the use of newer drugs for osteoporosis in this population.
Tanner Slayden, Elizabeth M Bauer, Mohamed Km Shakir, Thanh Duc Hoang
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#33979195 // To Up
Evolution of Disparities in Prostate Cancer Treatment: Is This a New Normal?Despite notable screening, diagnostic, and therapeutic advances, disparities in prostate cancer incidence and outcomes remain prevalent. Although commonly discussed in the context of men of African descent, disparities also exist based on socioeconomic level, education level, and geographic location. The factors in these disparities span systemic access issues affecting availability of care, provider awareness, and personal patient views and mistrust. In this review, we will discuss common themes that patients have noted as impediments to care. We will review how equitable access to care has helped improve outcomes among many different groups of patients, including those with local disease and those with metastatic castration-resistant prostate cancer. Even with more advanced presentation, challenges with recommended screening, and lower rates of genomic testing and trial inclusion, Black populations have benefited greatly from various modalities of therapy, achieving comparable and at times superior outcomes with certain types of immunotherapy, chemotherapy, androgen receptor-based inhibitors, and radiopharmaceuticals in advanced disease. We will also briefly discuss access to genomic testing and differences in patterns of gene expression among Black patients and other groups that are traditionally underrepresented in trials and genomic cohort studies. We propose several strategies on behalf of providers and institutions to help promote more equitable care access environments and continued decreases in prostate cancer disparities across many subgroups.
Frank C Cackowski, Brandon Mahal, Elisabeth I Heath, Bradley Carthon
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#33978290 2021/05/12 To Up
Low amounts of heavy water increase the phase separation propensity of a fragment of the androgen receptor activation domain.The phase equilibria of intrinsically disordered proteins are exquisitely sensitive to changes in solution conditions and this can be used to investigate the driving forces of phase separation in vitro as well as the biological roles of phase transitions in live cells. Here we investigate how using D O as co-solvent in an aqueous buffer changes the phase equilibrium of a fragment of the activation domain of the androgen receptor, a transcription factor that plays a role in the development of the male phenotype and is a therapeutic target for castration resistant prostate cancer. We show how replacing even small fractions of H O with D O increases the propensity of this fragment to undergo liquid-liquid phase separation, likely reflecting a stabilization of the hydrophobic interactions that drive condensation. Our results indicate that it is necessary to take this effect into consideration when studying phase separation phenomena with biophysical methods that require using D O as a co-solvent. In addition they suggest that additions of D O may be used to enhance phase separation phenomena in cells, facilitating their observation. This article is protected by copyright. All rights reserved.
Stasė Bielskutė, Carla Garcia-Cabau, Marta Frigolé-Vivas, Elzbieta Szulc, Eva De Mol, Mireia Pesarrodona, Jesús García, Xavier Salvatella
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#33977248 2021/03/22 To Up
Transcription factor 4 expression in circulating tumor cells from castration-resistant prostate cancer.Neuroendocrine differentiation is partly caused by antiandrogen therapy and exhibits an androgen receptor-independent growth mechanism. We hypothesized that the expression of transcription factor 4, an inducer of neuroendocrine differentiation, in circulating tumor cells is related to drug resistance in castration-resistant prostate cancer.
Naoya Nagaya, Geun Taek Lee, Yan Lu, Takeshi Ashizawa, Masayoshi Nagata, Isaac Yi Kim, Shigeo Horie
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