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The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands

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The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands biomedicines Review The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy Elisabeth A. Messner 1,2, Thomas M. Steele 1,3, Maria Malvina Tsamouri 1,2 , Nazila Hejazi 4 , Allen C. Gao 1,3, Maria Mudryj 1,5 and Paramita M. Ghosh 1,3,6,* 1 VA Northern California Health Care System, Mather, CA 95655, USA; [email protected] (E.A.M.); [email protected] (T.M.S.); [email protected] (M.M.T.); [email protected] (A.C.G.); [email protected] (M.M.) 2 Graduate Group for Integrative Pathobiology, University of California Davis, Davis, CA 95616, USA 3 Department of Urologic Surgery, University of California Davis, Davis, CA 95718, USA 4 Department of Clinical Science, California Northstate University, Elk Grove, CA 95757, USA; [email protected] 5 Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA 95616, USA 6 Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA 95718, USA * Correspondence: [email protected]; Tel.: +1-916-843-9336 Received: 8 September 2020; Accepted: 13 October 2020; Published: 15 October 2020 Abstract: The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD—and the current state of the available compounds in clinical development. Keywords: castration-resistant prostate cancer; androgen receptor; N-terminal domain; DNA-binding domain; Ligand-binding domain; alternatively spliced variants 1. Introduction The prostate gland, located beneath the bladder, secretes alkaline prostatic fluid that constitutes 30% of the semen [1]. The prostate is composed of three distinct zones: the central zone (CZ), which includes the ductal tube from the seminal vesicle to the descending urethra, the peripheral zone (PZ), which is situated at the posterior of the gland and the transitional zone (TZ), which surrounds the transitional urethra [1]. The normal prostatic acinus consists of an epithelial structure of basal and luminal cells surrounded by fibromuscular stroma (Figure1). Luminal, basal, and neuroendocrine cells constitute the normal prostate epithelia in a roughly 60:40:1 ratio [2]. Prostate cancer (PCa) develops most often in the PZ, less often in the TZ, and rarely in the CZ [3,4]. Upon development of PCa, Biomedicines 2020, 8, 422; doi:10.3390/biomedicines8100422 www.mdpi.com/journal/biomedicines Biomedicines 2020, 8, x FOR PEER REVIEW 2 of 20 Biomedicines 2020, 8, 422 2 of 19 cells constitute the normal prostate epithelia in a roughly 60:40:1 ratio [2]. Prostate cancer (PCa) develops most often in the PZ, less often in the TZ, and rarely in the CZ [3,4]. Upon development of thePCa, ratio the of ratio luminal of luminal to basal to percentages basal percentages are greatly are gr altered,eatly altered, with the with luminal the luminal cells constituting cells constituting>99% of the>99% tumor of the [2] tumor (Figure [2]1). (Figure 1). FigureFigure 1. 1.Disruption Disruption ofof thethe prostaticprostatic epitheliumepithelium duringduring neoplasticneoplastic progression.progression. ( (LeftLeft)) The The normal normal prostaticprostatic acinus acinus consists consists of of an an epithelial epithelial compartmentcompartment consistingconsisting of basal (orange) and and luminal luminal (pink) (pink) cells,cells, as as well well as as a a minor minor population population ofof neuroendocrineneuroendocrine cellscells (darker(darker orange) that serve as as stem stem cells cells in in casecase of of damage damage repair. repair. The The basal basal cells cells line linethe the basementbasement membrane.membrane. (Right) Cancer is characterized byby luminal luminal hyperproliferation hyperproliferation resultingresulting inin thethe formationformation of multiple new glands, loss loss of of basal basal cells, cells, breakdownbreakdown of of basement basement membrane, membrane, prominent prominent nucleolinucleoli (green),(green), andand nuclearnuclear enlargement.enlargement. Among men worldwide and in the United States, PCa is a leading contributor to overall cancer Among men worldwide and in the United States, PCa is a leading contributor to overall cancer incidence [5]. In 2020, 191,930 new cases and 33,330 deaths are predicted for PCa in the United States [5]. incidence [5]. In 2020, 191,930 new cases and 33,330 deaths are predicted for PCa in the United States The[5]. meanThe mean age ofage initial of initial diagnosis diagnosis is 66 is 66 [6]. [6]. According According to to the the Surveillance, Surveillance, Epidemiology,Epidemiology, and and End End ResultsResults (SEER) (SEER) Cancer Cancer Stat Stat Facts: Facts: ProstateProstate CancerCancer SurvivalSurvival Statistics, which which reports reports survival survival by by stage, stage, thethe relative relative 5-year 5-year survival survival rate rate for PCafor PCa initially initially diagnosed diagnosed when when localized localized (within (within the prostate the prostate gland), orgland), regional or (externalregional (external to the prostate to the in prostate adjacent in lymph adjacent nodes lymph and nodes seminal and vesicles), seminal isvesicles), almost 100% is almost [7,8]. However,100% [7,8]. for However, patients with for patients distant metastasiswith distant at initialmetastasis diagnosis, at initial the diagnosis, relative 5-year the relative survival 5-year drops tosurvival 30.2% [ 7drops,8]. Despite to 30.2% diagnostic [7,8]. Despite advancements diagnostic inadvancements the past 30 years, in the only past about30 years, 76% only of diseases about 76% are initiallyof diseases diagnosed are initially when diagnosed they are still when localized they are [9 ].stil Aboutl localized 13% of[9]. the About patients 13% are of the first patients diagnosed are first with regionaldiagnosed disease, with whileregional 6% aredisease, diagnosed while with 6% distantare diagnosed metastasis with (5% distant remain metastasis unstaged) [(5%7,8]. remain unstaged)Serum [7,8]. levels of prostate-specific antigen (PSA), a serine protease produced in the prostate epithelium,Serum can levels be usedof prostate-specific both to diagnose antigen and to track(PSA), PCa. a serine While protease the diagnostic produced capability in the ofprostate PSA is limited,epithelium, it remains can be theused main both biomarker to diagnose of and PCa to progression. track PCa. While The androgenthe diagnostic receptor capability (AR), of the PSA main is promoterlimited, it of remains PCa, regulates the mainPSA biomarkergene transcription, of PCa progression. making serumThe androgen PSA levels receptor a strong (AR), indicator the main of ARpromoter transcriptional of PCa, regulates activity and PSA subsequently gene transcription, of disease making state. serum Specifically, PSA levels PSA a levels strong are indicator positively of associatedAR transcriptional with disease activity stage and and subsequently clinical grade of [10 disease]. PSA takesstate. onSpecifically, a particularly PSA significant levels are rolepositively in PCa toassociated indicate treatment with disease effi cacystage and and relapse clinical [ 10grade]. Thus, [10]. a PSA reduction takes inon PSAa particularly following significant treatment isrole often in interpretedPCa to indicate as the treatment abatement efficacy of disease. and Retentionrelapse [10] in. circulationThus, a reduction following in PS PCaA following treatment indicatestreatment the is continuedoften interpreted presence as of prostate-derivedthe abatement of cancer disease. in theRetention system in [10 circulation]. following PCa treatment indicatesThree the possible continued treatments presence for of localized prostate-derived PCa are expectantcancer in the management, system [10]. surgery, and radiation. ExpectantThree management, possible treatments for low-risk for localized disease, includes PCa are eitherexpectant watchful management, waiting or surgery, active surveillance and radiation. [11]. RadicalExpectant prostatectomy management, and for/or low-risk radiation disease, may includes be performed either inwatchful cases ofwaiting a more or advanced active surveillance localized cancer[11]. Radical [12]. However, prostatectomy 20–40% and/or of patients radiation who may undergo be performed these treatments in cases of will a more experience advanced biochemical localized recurrencecancer
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