Gene Expression Analysis of Human Prostate Carcinoma during Hormonal Therapy Identifies Androgen-Responsive Genes and Mechanisms of Therapy Resistance
Jeff Holzbeierlein,Priti Lal,Eva Latulippe,Alex Smith,Jaya M. Satagopan,Liying Zhang,Charles J. Ryan,Steve Smith,Howard I. Scher,Howard I. Scher,Peter T. Scardino,Victor E. Reuter,William L. Gerald +12 more
TLDR
A genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance suggested that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones.Abstract:
The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance. Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide. This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells. These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor. Expression profiles of androgen ablation-resistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone. Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation. Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.read more
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Abiraterone and Increased Survival in Metastatic Prostate Cancer
Johann S. de Bono,Christopher J. Logothetis,Arturo Molina,Karim Fizazi,Scott North,Luis Chu,Kim N. Chi,Robert Jones,Oscar B. Goodman,Fred Saad,John Staffurth,Paul N. Mainwaring,S. J. Harland,Thomas W. Flaig,Thomas E. Hutson,Tina Cheng,Helen Patterson,John D. Hainsworth,Charles J. Ryan,Cora N. Sternberg,Susan Ellard,Aude Flechon,Mansoor N. Saleh,Mark C. Scholz,Eleni Efstathiou,Andrea Zivi,Diletta Bianchini,Yohann Loriot,Nicole Chieffo,Thian Kheoh,Christopher M. Haqq,Howard I. Scher +31 more
TL;DR: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
Journal ArticleDOI
Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy
Howard I. Scher,Karim Fizazi,Fred Saad,Mary-Ellen Taplin,Cora N. Sternberg,Kurt Miller,Ronald de Wit,Peter F.A. Mulders,Kim N. Chi,Neal D. Shore,Andrew J. Armstrong,Thomas W. Flaig,Aude Flechon,Paul N. Mainwaring,Mark D. Fleming,John D. Hainsworth,Mohammad Hirmand,Bryan Selby,Lynn Seely,Johann S. de Bono,B Ch +20 more
TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Journal ArticleDOI
Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy
Charles J. Ryan,Matthew R. Smith,Johann S. de Bono,Arturo Molina,Christopher J. Logothetis,Paul de Souza,Karim Fizazi,Paul N. Mainwaring,Josep M. Piulats,Siobhan Ng,Joan Carles,Peter F.A. Mulders,Ethan Basch,Eric J. Small,Fred Saad,D. Schrijvers,Hendrik Van Poppel,Som D. Mukherjee,Henrik Suttmann,Winald R. Gerritsen,Thomas W. Flaig,Daniel J. George,Evan Y. Yu,Eleni Efstathiou,Allan J. Pantuck,Eric Winquist,Celestia S. Higano,Mary-Ellen Taplin,Youn C. Park,Thian Kheoh,Thomas W. Griffin,Howard I. Scher,Dana E. Rathkopf +32 more
TL;DR: Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer.
Journal ArticleDOI
Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
Howard I. Scher,Susan Halabi,Ian F. Tannock,Michael J. Morris,Cora N. Sternberg,Michael A. Carducci,Mario A. Eisenberger,Celestia S. Higano,Glenn J. Bubley,Robert Dreicer,Daniel P. Petrylak,Philip W. Kantoff,Ethan Basch,William Kevin Kelly,William D. Figg,Eric J. Small,Tomasz M. Beer,George Wilding,Alison Martin,Maha Hussain +19 more
TL;DR: New consensus criteria for eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone are defined, with increasing emphasis on time-to-event end points as decision aids in proceeding from phase II to phase III trials.
Commentary on: Abiraterone in Metastatic Prostate Cancer Without Previous Chemotherapy
TL;DR: Abiraterone inhibits CYP-17, a crucial enzyme in androgen biosynthesis in the testes, adrenal glands, and in prostate cancer cells as discussed by the authors, and showed a strong trend toward improved survival.
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