Molecular Pathways: Inhibiting steroid biosynthesis in prostate cancer
TLDR
Given the drawbacks of 17α-hydroxylase inhibition, there is considerable interest in developing new CYP17A1 inhibitors that more specifically inhibit lyase activity and are therefore less likely to require glucocorticoid coadministration.Abstract:
A significant proportion of castration-resistant prostate cancers (CRPC) remain driven by ligand activation of the androgen receptor. Although the testes are the primary source of testosterone, testosterone can also be produced from peripheral conversion of adrenal sex hormone precursors dehydroepiandrosterone (DHEA) and androstenedione (AD) in the prostate and other tissues. CYP17A1 catalyzes two essential reactions in the production of DHEA and androstenedione: the hydroxylation (hydroxylase activity) and the subsequent cleavage of the C17-20 side-chain (lyase activity). Potent and selective inhibition of CYP17A1 by abiraterone depletes residual non-gonadal androgens and is an effective treatment for CRPC. Elucidation of the mechanisms that underlie resistance to abiraterone will inform on the development of novel therapeutic strategies post abiraterone. Preclinical evidence that androgen biosynthesis in prostate cancer cells does not necessarily follow a single dominant pathway and residual androgens or alternative ligands (including administered glucocorticoids) can reactivate androgen receptor signaling supports co-targeting of more than one enzyme involved in steroidogenesis and combining a CYP17A1 inhibitor with an anti-androgen. Furthermore, given the drawbacks of 17α-hydroxylase inhibition, there is considerable interest in developing new CYP17A1 inhibitors that more specifically inhibit lyase activity and are therefore less likely to require glucocorticoid co-administration.read more
Citations
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Journal ArticleDOI
Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer
Zhenfei Li,Andrew C. Bishop,Mohammad Alyamani,Jorge A. Garcia,Robert Dreicer,Dustin R. Bunch,JJ Liu,Sunil K. Upadhyay,Richard J. Auchus,Nima Sharifi +9 more
TL;DR: It is proposed that direct treatment with D4A would be more clinically effective than abiraterone treatment, because competitive androgen receptor antagonism by D2A is comparable to the potent antagonist enzalutamide and D3A also has more potent anti-tumour activity against xenograft tumours than abIRaterone.
Journal ArticleDOI
RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1
John R. Prensner,Shuang G. Zhao,Nicholas Erho,Matthew J. Schipper,Matthew K. Iyer,Saravana M. Dhanasekaran,Cristina Magi-Galluzzi,Rohit Mehra,Anirban Sahu,Javed Siddiqui,Elai Davicioni,Robert B. Den,Adam P. Dicker,R. Jeffrey Karnes,John T. Wei,Eric A. Klein,Robert B. Jenkins,Arul M. Chinnaiyan,Felix Y. Feng +18 more
TL;DR: In this paper, the authors conducted an unbiased analysis to identify RNA biomarkers associated with metastatic progression after prostatectomy and found that high SChLAP1 expression was significantly prognostic for metastatic disease progression of prostate cancer.
Journal ArticleDOI
Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone.
Diletta Bianchini,David Lorente,Alejo Rodriguez-Vida,Aurelius Omlin,Carmel Pezaro,Roberta Ferraldeschi,Andrea Zivi,Gerhardt Attard,Simon Chowdhury,J.S. de Bono +9 more
TL;DR: Preliminary case series data suggest limited activity of enzalutamide in the post-docetaxel and post-abiraterone patient population.
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Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations
E. David Crawford,Axel Heidenreich,Axel Heidenreich,Nathan Lawrentschuk,Bertrand Tombal,Antonio Carlos Lima Pompeo,Arturo Mendoza-Valdes,Kurt Miller,Frans M.J. Debruyne,Laurence Klotz +9 more
TL;DR: This review discusses the clinical profiles of the most up-to-date options for ADT, best practices for managing patients with advanced PCa and future directions in therapy, as well as investigating new drugs that inhibit androgen signaling in combination with traditional ADT.
Journal ArticleDOI
Evolution of androgen receptor targeted therapy for advanced prostate cancer
TL;DR: This Review aims to revisit the discovery and evolution of androgen receptor targeting therapeutics for the treatment of advanced-stage prostate cancer over the years and to discuss the upcoming future and challenges in the Treatment of this common cancer.
References
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Journal ArticleDOI
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
Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate
TL;DR: Gutman et al. as mentioned in this paper showed that the acid phosphatase of serum is reduced in metastatic carcinoma of the prostate by decreasing the activity of androgens through castration or estrogenic injections and that this enzyme is increased by injecting androgens.
Journal Article
Studies on Prostatic Cancer. I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate
TL;DR: It is demonstrated that a marked rise in acid phosphatase in serum is associated with the appearance or spread of roentgenologically demonstrable skeletal metastases and implies dissemination of the primary tumor and thus is of unfavorable prognostic significance.
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.
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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