Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer

Roberta Ferraldeschi, Nima Sharifi, Richard J. Auchus, Gerhardt Attard

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

A significant proportion of castration-resistant prostate cancers (CRPC) remains 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 DHEA and androstenedione 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 nongonadal androgens and is an effective treatment for CRPC. Elucidation of the mechanisms that underlie resistance to abiraterone will inform the development of novel therapeutic strategies postabiraterone. 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 cotargeting of more than one enzyme involved in steroidogenesis and combining a CYP17A1 inhibitor with an antiandrogen. 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 coadministration.

Original languageEnglish (US)
Pages (from-to)3353-3359
Number of pages7
JournalClinical Cancer Research
Volume19
Issue number13
DOIs
StatePublished - Jul 1 2013

Fingerprint

Androgens
Prostatic Neoplasms
Lyases
Dehydroepiandrosterone
Androstenedione
Castration
Steroids
Androgen Receptors
Mixed Function Oxygenases
Glucocorticoids
Testosterone
Ligands
Androgen Antagonists
Gonadal Steroid Hormones
Hydroxylation
Testis
Prostate
Enzymes
abiraterone
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Molecular pathways : Inhibiting steroid biosynthesis in prostate cancer. / Ferraldeschi, Roberta; Sharifi, Nima; Auchus, Richard J.; Attard, Gerhardt.

In: Clinical Cancer Research, Vol. 19, No. 13, 01.07.2013, p. 3353-3359.

Research output: Contribution to journalArticle

Ferraldeschi, R, Sharifi, N, Auchus, RJ & Attard, G 2013, 'Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer', Clinical Cancer Research, vol. 19, no. 13, pp. 3353-3359. https://doi.org/10.1158/1078-0432.CCR-12-0931
Ferraldeschi, Roberta ; Sharifi, Nima ; Auchus, Richard J. ; Attard, Gerhardt. / Molecular pathways : Inhibiting steroid biosynthesis in prostate cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 13. pp. 3353-3359.
@article{ba9f04a369d24113821d32a399fe87a8,
title = "Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer",
abstract = "A significant proportion of castration-resistant prostate cancers (CRPC) remains 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 DHEA and androstenedione 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 nongonadal androgens and is an effective treatment for CRPC. Elucidation of the mechanisms that underlie resistance to abiraterone will inform the development of novel therapeutic strategies postabiraterone. 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 cotargeting of more than one enzyme involved in steroidogenesis and combining a CYP17A1 inhibitor with an antiandrogen. 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 coadministration.",
author = "Roberta Ferraldeschi and Nima Sharifi and Auchus, {Richard J.} and Gerhardt Attard",
year = "2013",
month = "7",
day = "1",
doi = "10.1158/1078-0432.CCR-12-0931",
language = "English (US)",
volume = "19",
pages = "3353--3359",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

TY - JOUR

T1 - Molecular pathways

T2 - Inhibiting steroid biosynthesis in prostate cancer

AU - Ferraldeschi, Roberta

AU - Sharifi, Nima

AU - Auchus, Richard J.

AU - Attard, Gerhardt

PY - 2013/7/1

Y1 - 2013/7/1

N2 - A significant proportion of castration-resistant prostate cancers (CRPC) remains 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 DHEA and androstenedione 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 nongonadal androgens and is an effective treatment for CRPC. Elucidation of the mechanisms that underlie resistance to abiraterone will inform the development of novel therapeutic strategies postabiraterone. 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 cotargeting of more than one enzyme involved in steroidogenesis and combining a CYP17A1 inhibitor with an antiandrogen. 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 coadministration.

AB - A significant proportion of castration-resistant prostate cancers (CRPC) remains 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 DHEA and androstenedione 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 nongonadal androgens and is an effective treatment for CRPC. Elucidation of the mechanisms that underlie resistance to abiraterone will inform the development of novel therapeutic strategies postabiraterone. 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 cotargeting of more than one enzyme involved in steroidogenesis and combining a CYP17A1 inhibitor with an antiandrogen. 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 coadministration.

UR - http://www.scopus.com/inward/record.url?scp=84879134376&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879134376&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-12-0931

DO - 10.1158/1078-0432.CCR-12-0931

M3 - Article

C2 - 23470964

AN - SCOPUS:84879134376

VL - 19

SP - 3353

EP - 3359

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 13

ER -