A Monge

J Shamash

J Waxman

JS Sack

RA Cox

S Ngan

V Boonyaratanakornkit

WK Kelly

British Journal of Cancer

English

PubMed

Waxman, J

Ngan, S

Spiral - Imperial College Digital Repository

EditorialAndrogen resistance in prostate cancerJ Waxman*,1 and S Ngan11Department of Cancer Medicine, Division of Medicine, Faculty of Medicine, Imperial College London, Room 1014, Garry Weston Centre, HammersmithCampus Du Cane Road, London W12 0NN, UKBritish Journal of Cancer (2008) 98, 1. doi:10.1038/sj.bjc.6604076 www.bjcancer.comPublished online 8 January 2008& 2008 Cancer Research UKThe growth of prostate cancer is regulated by the androgen receptor(AR), which is a transcription factor that binds with steroidhormones, co-activators and co-receptors of AR, and translocatesto the cell nucleus where the AR-complex initiates a number ofandrogen-related gene transcription events. In patients with prostatecancer treated with hormonal therapy, it is thought that with timeand exposure to anti-androgens, AR mutates. This mutation causes achange in the regulation of prostate cancer cell growth, which maybecome independent of treatments aimed to decrease the availabilityof testosterone and dehydrotestosterone to the receptor.There have been hundreds of AR mutations described, but oneof the most commonly observed is at codon 877 (Sack et al, 2001).Mutation at codon 877 allows the tumour to become dependent forits growth upon the drugs used to treat it (Monge et al, 2006). Inthis situation, withdrawal of anti-androgens leads to a transientresponse in 20–40% of patients (Kelly and Scher, 1993).As prostate cancer progresses, it is thought that there is furtherclonal evolution so that selection processes occur, leading to new‘resistance’ to hormonal therapy, but this may not be an absoluteresistance. It is likely that this selection process causes changessuch that an individual’s tumour may respond to further hormonaltreatment; should that hormonal treatment be selective for themutation that has developed. Thus it is likely that patients willrespond to third- and fourth-line therapy with prednisone oroestrogens or dexamethasone or hydrocortisone or other steroidalagents. It is superficially and relatively straightforward to under-stand why these responses should occur. This is because thecellular receptors for these steroids are members of a supergenefamily sharing considerable structural homology (Boonyaratanakornkitand Edwards, 2007).In this context, it is of interest to review the publication byShamash et al reported in this current edition of the British Journalof Cancer. In their report, Shamash et al describe 56 patients withprostate cancer who were treated with sequential hormonaltherapy and then, on progression, with a novel chemotherapyregimen. During the period of treatment with chemotherapy,hormonal therapy was discontinued. At the end of the treatment,43 patients were re-challenged with hormonal therapy. Twenty-twoof these patients were non-castrate at the end of treatment and 21castrate. Sixteen of this group of 43 patients (37%) then went on tohave a further PSA in response to either an LHRH agonist givenwith an anti-androgen or to a combination of diethylstilboestroland dexamethasone. The responses were transient, but what isremarkable is that 12 out of 28 patients, who were treated withhormonal therapy following chemotherapy, went on to haveanother transient PSA response after progression on maximalandrogen blockade (Shamash et al, 2007).It is not clear whether these responses seen were due to inductionof hormonal sensitivity through an unknown mechanism or due toregrowth of hormone-sensitive clones of cells which were previouslysuppressed by the original anti-androgen therapies. Regardless ofmechanism, this paper has given oncologists and their patientsreasons to be grateful for a further option in the treatmentarmamentarium, and this has been confirmed by Cox and Sundar intwo patients in correspondence published in this current edition ofthe British Journal of Cancer (Cox and Sundar, 2007).REFERENCESBoonyaratanakornkit V, Edwards DP (2007) Receptor mechanismsmediating non-genomic actions of sex steroids. Semin Reprod Med25: 139 – 153Cox RA, Sundar S (2007) Re-induction of hormone sensitivity todiethylstilboestrol in androgen refractory prostate cancer patientsfollowing chemotherapy. Br J Cancer 98: 238 – 239Kelly WK, Scher HI (1993) Prostate-specific antigen decline afterantiandrogen withdrawal: the flutamide withdrawal syndrome. J Urol149: 607 – 609Monge A, Jagia M, Lapouge G, Sasorith S, Cruchant M, Wurtz JM, JacqminD, Bergerat JP, Céraline J (2006) Unfaithfulness and promiscuity of amutant androgen receptor in a hormone-refractory prostate cancer. CellMol Life Sci 63: 487 – 497Sack JS, Kish KF, Wang C, Attar RM, Kiefer SE, An Y, Wu GY, Scheffler JE,Salvati ME, Krystek Jr SR, Weinmann R, Einspahr HM (2001) Crystallo-graphic structures of the ligand-binding domains of the androgenreceptor and its T877A mutant complexed with the natural agonistdihydrotestosterone. Proc Natl Acad Sci USA 98: 4904 – 4909Shamash J, Davies A, Ansell W, Wilson P, Oliver T, Powles T (2007) Aphase II study investigating the re-induction of endocrine sensitivityfollowing chemotherapy in androgen independent prostate cancer. BrJ Cancer 98: 22 – 24Published online 8 January 2008*Correspondence: Dr J Waxman; E-mail: j.waxman@imperial.ac.ukBritish Journal of Cancer (2008) 98, 1& 2008 Cancer Research UK All rights reserved 0007 – 0920/08 $30.00www.bjcancer.com

Androgen resistance in prostate cancer

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Receptor mechanisms mediating non-genomic actions of sex steroids. Semin Reprod Med 25: 139–153 Cox RA, Sundar S

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2359684

Androgen resistance in prostate cancer

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