Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens
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Prnu-BICALUTAMIDE
PRODUCT MONOGRAPH PrNU-BICALUTAMIDE Bicalutamide Tablets, 50 mg Non-Steroidal Antiandrogen NU-PHARM INC. DATE OF PREPARATION: 50 Mural Street, Units 1 & 2 October 16, 2009 Richmond Hill, Ontario L4B 1E4 Control#: 133521 Page 1 of 27 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION....................................................... 3 SUMMARY PRODUCT INFORMATION ............................................................................. 3 INDICATIONS AND CLINICAL USE ................................................................................... 3 CONTRAINDICATIONS ........................................................................................................ 3 WARNINGS AND PRECAUTIONS....................................................................................... 4 ADVERSE REACTIONS......................................................................................................... 5 DRUG INTERACTIONS ......................................................................................................... 9 DOSAGE AND ADMINISTRATION ................................................................................... 10 OVERDOSAGE...................................................................................................................... 10 ACTION AND CLINICAL PHARMACOLOGY.................................................................. 10 STORAGE AND STABILITY............................................................................................... 11 DOSAGE FORMS, COMPOSITION AND PACKAGING -
Expression of Aromatase, Estrogen Receptor and , Androgen
0031-3998/06/6006-0740 PEDIATRIC RESEARCH Vol. 60, No. 6, 2006 Copyright © 2006 International Pediatric Research Foundation, Inc. Printed in U.S.A. Expression of Aromatase, Estrogen Receptor ␣ and , Androgen Receptor, and Cytochrome P-450scc in the Human Early Prepubertal Testis ESPERANZA B. BERENSZTEIN, MARI´A SONIA BAQUEDANO, CANDELA R. GONZALEZ, NORA I. SARACO, JORGE RODRIGUEZ, ROBERTO PONZIO, MARCO A. RIVAROLA, AND ALICIA BELGOROSKY Research Laboratory [E.B.B., M.S.B., C.R.G., N.I.S., J.R., M.A.R., A.B.], Hospital de Pediatria Garrahan, Buenos Aires C124 5AAM, Argentina; Centro de Investigaciones en Reproduccion [R.P.], Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C112 1ABG, Argentina ABSTRACT: The expression of aromatase, estrogen receptor ␣ might affect adult testicular cell mass, as well as testicular (ER␣) and  (ER), androgen receptor (AR), and cytochrome P-450 function (8). side chain cleavage enzyme (cP450scc) was studied in prepubertal In humans (9), there are three growth phases of LCs testis. Samples were divided in three age groups (GRs): GR1, during testicular development. Fetal LCs produce testoster- ϭ newborns (1- to 21-d-old neonates, n 5); GR2, postnatal activation one required for fetal masculinization and Insl-3, necessary ϭ stage (1- to 7-mo-old infants, n 6); GR3, childhood (12- to for testicular descent (10). They regress during the third ϭ ␣ 60-mo-old boys, n 4). Absent or very poor detection of ER by trimester of pregnancy. A second wave of infantile LCs has immunohistochemistry in all cells and by mRNA expression was been described during the postnatal surge of luteinizing observed. -
Context-Specific Efficacy of Apalutamide Therapy in Preclinical
cancers Article Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer Marco A. De Velasco 1,2,* , Yurie Kura 1,2, Naomi Ando 1, Noriko Sako 1, Eri Banno 1, Kazutoshi Fujita 1, Masahiro Nozawa 1, Kazuhiro Yoshimura 1 , Kazuko Sakai 2, Kazuhiro Yoshikawa 3, Kazuto Nishio 2 and Hirotsugu Uemura 1,* 1 Department of Urology Kindai, University Faculty of Medicine, Osaka-Sayama 589-8511, Japan; [email protected] (Y.K.); [email protected] (N.A.); [email protected] (N.S.); [email protected] (E.B.); [email protected] (K.F.); [email protected] (M.N.); [email protected] (K.Y.) 2 Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan; [email protected] (K.S.); [email protected] (K.N.) 3 Research Creation Support Center, Aichi Medical University, Nagakute 480-1195, Japan; [email protected] * Correspondence: [email protected] (M.A.D.V.); [email protected] (H.U.) Simple Summary: Next-generation antiandrogens have transformed the therapeutic landscape for castration-resistant prostate cancer. Their utility in other indications, such as high-risk castration- sensitive cancers and as combination therapy, are being investigated. Our aim was to profile the in vivo antitumor activity of apalutamide in phenotypically distinct mouse models of Pten-deficient castration-naïve and castration-resistant prostate cancer, using both early- and late-stage disease Citation: De Velasco, M.A.; Kura, Y.; models, and to profile the molecular responses. -
Influence of Androgen Receptor on the Prognosis of Breast Cancer
Journal of Clinical Medicine Article Influence of Androgen Receptor on the Prognosis of Breast Cancer 1, , 2, 1 2 3 Ki-Tae Hwang * y , Young A Kim y , Jongjin Kim , Jeong Hwan Park , In Sil Choi , Kyu Ri Hwang 4 , Young Jun Chai 1 and Jin Hyun Park 3 1 Department of Surgery, Seoul Metropolitan Government Seoul National University Boramae Medical Center, 39, Boramae-Gil, Dongjak-gu, Seoul 156-707, Korea; [email protected] (J.K.); [email protected] (Y.J.C.) 2 Department of Pathology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 156-707, Korea; [email protected] (Y.A.K.); [email protected] (J.H.P.) 3 Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 156-707, Korea; [email protected] (I.S.C.); [email protected] (J.H.P.) 4 Department of Obstetrics & Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 156-707, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-2-870-2275; Fax: +82-2-831-2826 These authors contributed equally to this work. y Received: 28 February 2020; Accepted: 8 April 2020; Published: 10 April 2020 Abstract: We investigated the prognostic influence of androgen receptor (AR) on breast cancer. AR status was assessed using immunohistochemistry with tissue microarrays from 395 operable primary breast cancer patients who received curative surgery. The Kaplan–Meier estimator was used to analyze the survival rates and a log-rank test was used to determine the significance of the differences in survival. The Cox proportional hazards model was used to calculate the hazard ratio (HR) and the 95% confidence interval (CI) of survival. -
Immunohistochemical Study of Androgen, Estrogen and Progesterone Receptors in Salivary Gland Tumors
Oral Pathology Oral Pathology Immunohistochemical study of androgen, estrogen and progesterone receptors in salivary gland tumors Fabio Augusto Ito(a) Abstract: The aim of this work was to study the immunohistochemi- (b) Kazuhiro Ito cal expression of androgen receptor, estrogen receptor and progesterone Ricardo Della Coletta(c) Pablo Agustín Vargas(c) receptor in pleomorphic adenomas, Warthin’s tumors, mucoepidermoid Márcio Ajudarte Lopes(c) carcinomas and adenoid cystic carcinomas of salivary glands. A total of 41 pleomorphic adenomas, 30 Warthin’s tumors, 30 mucoepidermoid carcinomas and 30 adenoid cystic carcinomas were analyzed, and the im- (a) DDS, PhD; (b)MD, Professor – Department of Pathology, Londrina State University, munohistochemical expression of these hormone receptors were assessed. Londrina, PR, Brazil. It was observed that all cases were negative for estrogen and progesterone (c) DDS, PhD, Professor, Department of Oral receptors. Androgen receptor was positive in 2 cases each of pleomorphic Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), adenoma, mucoepidermoid carcinoma and adenoid cystic carcinoma. In Piracicaba, SP, Brazil. conclusion, the results do not support a role of estrogen and progesterone in the tumorigenesis of pleomorphic adenomas, Warthin’s tumors, muco- epidermoid carcinomas and adenoid cystic carcinomas. However, andro- gen receptors can play a role in a small set of salivary gland tumors, and this would deserve further studies. Descriptors: Receptors, androgen; Receptors, estrogen; Receptors, progesterone; Salivary gland neoplasms. Corresponding author: Márcio Ajudarte Lopes Semiologia, Faculdade de Odontologia de Piracicaba, UNICAMP Av. Limeira, 901 Caixa Postal: 52 CEP: 13414-903 Piracicaba - SP - Brazil E-mail: [email protected] Received for publication on Oct 01, 2008 Accepted for publication on Sep 22, 2009 Braz Oral Res. -
WO 2018/111890 Al 21 June 2018 (21.06.2018) W !P O PCT
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/111890 Al 21 June 2018 (21.06.2018) W !P O PCT (51) International Patent Classification: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, C07K 16/28 (2006.01) A61K 31/4166 (2006.01) MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 59/595 (2006.01) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (21) International Application Number: PCT/US20 17/065841 Declarations under Rule 4.17: (22) International Filing Date: — as to applicant's entitlement to apply for and be granted a 12 December 2017 (12.12.2017) patent (Rule 4.1 7(H)) — as to the applicant's entitlement to claim the priority of the (25) Filing Language: English earlier application (Rule 4.17(Hi)) (26) Publication Langi English — of inventorship (Rule 4.1 7(iv)) (30) Priority Data: Published: 62/433,158 12 December 2016 (12.12.2016) US — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) (71) Applicant (for all designated States except AL, AT, BE, BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, P T RO, RS, SE, SI, SK, SM, TR): GENENTECH, INC. [US/US]; 1 DNA Way, South San Francisco, CA 94080-4990 (US). -
The Role of the Androgen Receptor Signaling in Breast Malignancies PANAGIOTIS F
ANTICANCER RESEARCH 37 : 6533-6540 (2017) doi:10.21873/anticanres.12109 Review The Role of the Androgen Receptor Signaling in Breast Malignancies PANAGIOTIS F. CHRISTOPOULOS*, NIKOLAOS I. VLACHOGIANNIS*, CHRISTIANA T. VOGKOU and MICHAEL KOUTSILIERIS Department of Experimental Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece Abstract. Breast cancer (BrCa) is the most common decades, BrCa still has a poor prognosis with 5-year survival malignancy among women worldwide, and one of the leading rates of metastatic disease reaching to 26% only. BrCa is the causes of cancer-related deaths in females. Despite the second leading cause of death among female cancers with development of novel therapeutic modalities, triple-negative 40,610 estimated deaths in the U.S. expected in 2017 (1). breast cancer (TNBC) remains an incurable disease. Androgen Breast cancer comprises a heterogeneous group of diseases receptor (AR) is widely expressed in BrCa and its role in the with variable course and outcome. Currently, BrCa is sub- disease may differ depending on the molecular subtype and the classified into distinct molecular subtypes named: normal stage. Interestingly, AR has been suggested as a potential target breast like, luminal A/B, HER-2 related, basal-like and claudin- candidate in TNBC, while sex hormone levels may regulate the low (2, 3). Estrogen receptor (ER), progesterone receptor (PR) role of AR in BrCa subtypes. In the presence of estrogen and HER2 have long been established as useful prognostic and receptor α ( ERa ), AR may antagonize the ER α- induced effects, predictive biomarkers. Hormonal therapy in ER and PR whereas in the absence of estrogens, AR may act as an ER α- positive tumors (4), as well as the use of monoclonal antibodies mimic, promoting tumor. -
Estrogen Receptor Β, a Regulator of Androgen Receptor Signaling in The
Estrogen receptor β, a regulator of androgen receptor PNAS PLUS signaling in the mouse ventral prostate Wan-fu Wua, Laure Maneixa, Jose Insunzab, Ivan Nalvarteb, Per Antonsonb, Juha Kereb, Nancy Yiu-Lin Yub, Virpi Tohonenb, Shintaro Katayamab, Elisabet Einarsdottirb, Kaarel Krjutskovb, Yu-bing Daia, Bo Huanga, Wen Sua,c, Margaret Warnera, and Jan-Åke Gustafssona,b,1 aCenter for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204; bCenter for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 14186 Stockholm, Sweden; and cAstraZeneca-Shenzhen University Joint Institute of Nephrology, Centre for Nephrology & Urology, Shenzhen University Health Science Center, Shenzhen 518060, China Contributed by Jan-Åke Gustafsson, March 31, 2017 (sent for review February 8, 2017; reviewed by Gustavo E. Ayala and David R. Rowley) − − − − As estrogen receptor β / (ERβ / ) mice age, the ventral prostate (13). Several ERβ-selective agonists have been synthesized (14– (VP) develops increased numbers of hyperplastic, fibroplastic le- 20), and they have been found to be antiinflammatory in the brain sions and inflammatory cells. To identify genes involved in these and the gastrointestinal tract (21, 22) and antiproliferative in cell changes, we used RNA sequencing and immunohistochemistry to lines (23–27) and cancer models (23, 28). We have previously − − compare gene expression profiles in the VP of young (2-mo-old) shown that there is an increase in p63-positive cells in ERβ / − − and aging (18-mo-old) ERβ / mice and their WT littermates. We mouse VP but that these cells were not confined to the basal layer also treated young and old WT mice with an ERβ-selective agonist but were interdispersed with the basal and luminal layer (13). -
A Dissertation Entitled the Androgen Receptor
A Dissertation entitled The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit Submitted to the Graduate Faculty as partial fulfillment of the requirements for the PhD Degree in Biomedical science Dr. Manohar Ratnam, Committee Chair Dr. Lirim Shemshedini, Committee Member Dr. Robert Trumbly, Committee Member Dr. Edwin Sanchez, Committee Member Dr. Beata Lecka -Czernik, Committee Member Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo August 2011 Copyright 2011, Mesfin Gonit This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit As partial fulfillment of the requirements for the PhD Degree in Biomedical science The University of Toledo August 2011 Prostate cancer depends on the androgen receptor (AR) for growth and survival even in the absence of androgen. In the classical models of gene activation by AR, ligand activated AR signals through binding to the androgen response elements (AREs) in the target gene promoter/enhancer. In the present study the role of AREs in the androgen- independent transcriptional signaling was investigated using LP50 cells, derived from parental LNCaP cells through extended passage in vitro. LP50 cells reflected the signature gene overexpression profile of advanced clinical prostate tumors. The growth of LP50 cells was profoundly dependent on nuclear localized AR but was independent of androgen. Nevertheless, in these cells AR was unable to bind to AREs in the absence of androgen. -
Phosphorylation-Induced Conformational Dynamics in an Intrinsically Disordered Protein and Potential Role in Phenotypic Heterogeneity
Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity Prakash Kulkarnia,1, Mohit Kumar Jollyb, Dongya Jiab,c, Steven M. Mooneyd, Ajay Bhargavae, Luciane T. Kagoharaf, Yihong Chena, Pengyu Haog, Yanan Hea, Robert W. Veltrif, Alexander Grishaeva, Keith Weningerg, Herbert Levineb,h,i,1, and John Orbana,j,1 aInstitute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850; bCenter for Theoretical Biological Physics, Rice University, Houston, TX 77005; cGraduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX 77005; dDepartment of Biology, University of Waterloo, Waterloo, ON Canada N2L 3G1; eShakti BioResearch, Woodbridge, CT 06525; fDepartment of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287; gDepartment of Physics, North Carolina State University, Raleigh, NC 27695; hDepartment of Physics and Astronomy, Rice University, Houston, TX 77005; iDepartment of Bioengineering, Rice University, Houston, TX 77005; and jDepartment of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742 Contributed by Herbert Levine, February 15, 2017 (sent for review January 3, 2017; reviewed by Takahiro Inoue and Vladimir N. Uversky) Intrinsically disordered proteins (IDPs) that lack a unique 3D and inheritance of biological traits (17), further emphasizing their structure and comprise a large fraction of the human proteome importance in state (or phenotype) switching. Moreover, if overex- play important roles in numerous cellular functions. Prostate- pressed, IDPs have the potential to engage in multiple “promiscuous” Associated Gene 4 (PAGE4) is an IDP that acts as a potentiator of interactions with other proteins, which can lead to changes in phe- the Activator Protein-1 (AP-1) transcription factor. -
Combined Oral Contraceptives Plus Spironolactone Compared With
177:5 M Alpañés, F Álvarez-Blasco Randomized trial of common 177:5 399–408 Clinical Study and others drugs for PCOS Combined oral contraceptives plus spironolactone compared with metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial Macarena Alpañés*, Francisco Álvarez-Blasco*, Elena Fernández-Durán, Manuel Luque-Ramírez and Héctor F Escobar-Morreale Correspondence Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology & Nutrition, Hospital should be addressed Universitario Ramón y Cajal & Universidad de Alcalá & Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS & to H F Escobar-Morreale Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Madrid, Spain Email *(M Alpañés and F Álvarez-Blasco contributed equally to this work) hectorfrancisco.escobar@ salud.madrid.org Abstract Objective: We aimed to compare a combined oral contraceptive (COC) plus the antiandrogen spironolactone with the insulin sensitizer metformin in women with polycystic ovary syndrome (PCOS). Design: We conducted a randomized, parallel, open-label, clinical trial comparing COC (30 μg of ethinylestradiol and 150 μg of desogestrel) plus spironolactone (100 mg/day) with metformin (850 mg b.i.d.) for one year in women with PCOS (EudraCT2008–004531–38). Methods: The composite primary outcome included efficacy (amelioration of hirsutism, androgen excess and menstrual dysfunction) and cardiometabolic safety (changes in the frequencies of disorders of glucose tolerance, dyslipidemia and hypertension). A complete anthropometric, biochemical, hormonal and metabolic evaluation was conducted every three months and data were submitted to intention-to-treat analyses. European Journal European of Endocrinology Results: Twenty-four patients were assigned to COC plus spironolactone and 22 patients to metformin. -
Receptor Af®Nity and Potency of Non-Steroidal Antiandrogens: Translation of Preclinical ®Ndings Into Clinical Activity
Prostate Cancer and Prostatic Diseases (1998) 1, 307±314 ß 1998 Stockton Press All rights reserved 1365±7852/98 $12.00 http://www.stockton-press.co.uk/pcan Review Receptor af®nity and potency of non-steroidal antiandrogens: translation of preclinical ®ndings into clinical activity GJCM Kolvenbag1, BJA Furr2 & GRP Blackledge3 1Medical Affairs, Zeneca Pharmaceuticals, Wilmington, DE, USA; 2Therapeutic Research Department, and 3Medical Research Department, Zeneca Pharmaceuticals, Alderley Park, Maccles®eld, Cheshire, UK The non-steroidal antiandrogens ¯utamide (Eulexin1), nilutamide (Anandron1) and bicalutamide (Casodex1) are widely used in the treatment of advanced prostate cancer, particularly in combination with castration. The naturally occurring ligand 5a-DHT has higher binding af®nity at the androgen receptor than the non-steroidal antiandrogens. Bicalutamide has an af®nity two to four times higher than 2-hydroxy¯utamide, the active metabolite of ¯utamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors. Animal studies have indicated that bicalutamide also exhi- bits greater potency in reducing seminal vesicle and ventral prostate weights and inhibiting prostate tumour growth than ¯utamide. Although preclinical data can give an indication of the likely clinical activity, clinical studies are required to determine effective, well-tolerated dosing regimens. As components of combined androgen blockade (CAB), controlled studies have shown survival bene®ts of ¯utamide plus a luteinising hormone-releasing hormone analogue (LHRH-A) over LHRH-A alone, and for nilutamide plus orchiectomy over orchiectomy alone. Other studies have failed to show such survival bene®ts, including those comparing ¯utamide plus orchiectomy with orchiectomy alone, and nilutamide plus LHRH-A with LHRH-A alone.