Open AccessJournal Article
Selection for Androgen Receptor Mutations in Prostate Cancers Treated with Androgen Antagonist
Mary-Ellen Taplin,Glenn J. Bubley,Yoo-Joung Ko,Eric J. Small,Melissa P. Upton,Barur R. Rajeshkumar,Steven P. Balk +6 more
TLDR
Findings demonstrate that AR mutations occur in response to strong selective pressure from flutamide treatment, and these mutations responded to subsequent treatment with bicalutamide, an AR antagonist that blocks the mutant ARs.Abstract:
The role of androgen receptor (AR) mutations in androgen-independent prostate cancer (PCa) was determined by examining AR transcripts and genes from a large series of bone marrow metastases. Mutations were found in 5 of 16 patients who received combined androgen blockade with the AR antagonist flutamide, and these mutant ARs were strongly stimulated by flutamide. In contrast, the single mutant AR found among 17 patients treated with androgen ablation monotherapy was not flutamide stimulated. Patients with flutamide-stimulated AR mutations responded to subsequent treatment with bicalutamide, an AR antagonist that blocks the mutant ARs. These findings demonstrate that AR mutations occur in response to strong selective pressure from flutamide treatment.read more
Citations
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Journal ArticleDOI
The development of androgen-independent prostate cancer
Brian J. Feldman,David Feldman +1 more
TL;DR: It is predicted that understanding the pathways that lead to the development of androgen-independent prostate cancer will pave the way to effective therapies for these, at present, untreatable cancers.
Journal ArticleDOI
Molecular determinants of resistance to antiandrogen therapy
Charlie D. Chen,Derek S. Welsbie,Chris Tran,Sung Hee Baek,Randy Chen,Robert L. Vessella,Michael G. Rosenfeld,Charles L. Sawyers +7 more
TL;DR: Using microarray-based profiling of isogenic prostate cancer xenograft models, it is found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy.
Journal ArticleDOI
Androgen Receptor in Prostate Cancer
TL;DR: AR remains important in the development and progression of prostate cancer and the inhibition of AR activity through mechanisms in addition to androgen ablation, such as modulation of signal transduction pathways, may delay prostate cancer progression.
Journal ArticleDOI
Increased Expression of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate Cancer
Michael Stanbrough,Glenn J. Bubley,Kenneth N. Ross,Todd R. Golub,Mark A. Rubin,Trevor M. Penning,Phillip G. Febbo,Steven P. Balk +7 more
TL;DR: Enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets.
Journal ArticleDOI
Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis
TL;DR: Strategies that are focused on the androgen receptor either directly or indirectly, as single agents or in combination, that are in clinical development that are discussed are discussed.
References
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Journal ArticleDOI
In vivo amplification of the androgen receptor gene and progression of human prostate cancer.
Tapio Visakorpi,E. Hyytinen,Pasi A. Koivisto,Minna Tanner,Riitta Keinänen,C. Palmberg,Aarno Palotie,Teuvo L.J. Tammela,Jorma Isola,Olli-P. Kallioniemi +9 more
TL;DR: This work has identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer which involves amplification of the androgen receptor (AR) gene.
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Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer.
Mary-Ellen Taplin,Glenn J. Bubley,Todd D. Shuster,Martha E. Frantz,Amy E. Spooner,George K. Ogata,Harold N. Keer,Steven P. Balk +7 more
TL;DR: Functional studies of two of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen, and may provide a selective growth advantage after androgen ablation.
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A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens
Jos Veldscholte,C. Ris-Stalpers,George G. J. M. Kuiper,Guido Jenster,Cor A. Berrevoets,Eric Claassen,H. C. J. Van Rooij,Jan Trapman,Albert O. Brinkmann,Eppo Mulder +9 more
TL;DR: In the LNCaP androgen receptor a single point mutation is discovered changing the sense of codon 868 (Thr to Ala) in the ligand binding domain, which influences both binding and the induction of gene expression by different steroids and antisteroids.
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Bilateral orchiectomy with or without flutamide for metastatic prostate cancer
Mario A. Eisenberger,Brent A. Blumenstein,E. David Crawford,Gary J. Miller,David G. McLeod,Patrick J. Loehrer,George Wilding,Kathy Sears,Daniel J. Culkin,Ian M. Thompson,Anton J. Bueschen,Bruce A. Lowe +11 more
TL;DR: The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.
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Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone.
Zoran Culig,Alfred Hobisch,Marcus V. Cronauer,Andrew C.B. Cato,Anton Hittmair,Christian Radmayr,J. Eberle,Georg Bartsch,Helmut Klocker +8 more
TL;DR: Data demonstrate that the exchange of a single valine into methionine at position 715 in the AR promoters trans-activation not only by testicular but also by adrenal androgens and progesterone may have significance in the process controlling the progression of prostatic carcinoma.