Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer

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

doi:10.1158/1078-0432.ccr-12-0931

Cited by 93Prostate Cancer Treatment and ResearchCancer, Lipids, and MetabolismHormonal and reproductive studies

Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer

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Ferraldeschi, Roberta, Sharifi, Nima, Auchus, Richard J., Attard, Gerhardt·2013·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-12-0931PMC PMC3736095

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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 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 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. Clin Cancer Res; 19(13); 3353–9. ©2013 AACR.

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The metabolic alterations observed in malignancies involve changes in lipid metabolism, and steroid biosynthesis plays a critical role in lipid production, with genetic alterations associated with hormone-related tumors such as breast and prostate cancer.
“The metabolic alterations observed in malignancies involve changes in lipid metabolism, and steroid biosynthesis plays a critical role in lipid production, with genetic alterations associated with hormone-related tumors, such as breast and prostate cancer [27,28,29].”
From The Synergistic Effect of Proanthocyanidin and HDAC Inhibitor Inhibit Breast Cancer Cell Growth and Promote Apoptosis (2023) · cites this paper as [29]
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The Synergistic Effect of Proanthocyanidin and HDAC Inhibitor Inhibit Breast Cancer Cell Growth and Promote Apoptosis
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Authors: Ferraldeschi, R., Sharifi, N., Auchus, R. J., & Attard, G.
Affiliations: Cleveland Clinic (US)
Corresponding author: Attard, Gerhardt
ORCID: Sharifi, Nima
Auchus, Richard J.
Attard, Gerhardt
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2013-06-30
Volume: 19
Issue: 13
Pages: 3353-3359
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-12-0931
PMC: PMC3736095
OpenAlex: W2113192657
Cited by: 93
References: 60
Citations by year: 2026: 5 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 12 · 2017: 8 · 2016: 8 · 2015: 11 · 2014: 13 · 2013: 4
FWCI: 1.86
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Wellcome Trust
Cancer Research UK (13239, A13239)
National Institute for Health and Care Research (CL-2008-22-001)
National Cancer Institute (R01CA172382)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords: castration-resistant prostate cancer, androgen receptor, steroidogenesis, CYP17A1, abiraterone, abiraterone resistance, dehydroepiandrosterone, androstenedione, glucocorticoids
MeSH terms: Antineoplastic Agents, Humans, Male, Prostatic Neoplasms, Steroids, Signal Transduction, Biosynthetic Pathways, Translational Research, Biomedical

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Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer

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