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Inhibiting Steroid Biosynthesis in Prostate Cancer

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Inhibiting Steroid Biosynthesis in Prostate Cancer Published OnlineFirst March 7, 2013; DOI: 10.1158/1078-0432.CCR-12-0931 Clinical Cancer Molecular Pathways Research Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer Roberta Ferraldeschi1, Nima Sharifi2, Richard J. Auchus3, and Gerhardt Attard1 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 andro- stenedione 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 17a-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); 1–7. Ó2013 AACR. Background enzymes, have been used for over a decade to inhibit For the past 70 years, gonadal androgen depletion by androgen biosynthesis and induce tumor responses in medical or surgical castration has been the standard of care CRPC. The high doses of ketoconazole required to inhibit a for men with metastatic prostate cancer (1). Despite signif- cytochrome P450c17 (17 -hydroxylase/17,20-lyase, icant initial responses, patients invariably relapse, and sev- CYP17A1), however, are associated with significant toxicity eral studies suggest intratumoral androgens (most com- in up to 30% of patients. Moreover, CYP17A1 inhibition monly testosterone) in castration-resistant prostate cancer with ketoconazole is incomplete, and a rise in adrenal (CRPC) tumors are restored to equivalent levels found in androgens has been reported at disease progression (7). noncastrate prostates (2–4). Intratumoral testosterone The development of abiraterone as a specific and irreversible and/or dihydrotestosterone (DHT) in castrate men could inhibitor of CYP17A1 offered a less toxic and more effective be generated from conversion of circulating adrenal andro- option. Abiraterone acetate is now approved in combina- gens (4, 5) or could be synthesized de novo from cholesterol tion with prednisone for the treatment of CRPC, based on (6). The latter has been suggested in a number of preclinical demonstration of an improvement in survival when admin- models but remains unproven in patients. High doses of istered with prednisone to docetaxel-treated patients and € ketoconazole, which inhibits many cytochrome P450 progression-free survival in chemotherapy-na ve patients (8, 9). Abiraterone acetate and prednisone also significantly delay pain progression and skeletal-related events and Authors' Affiliations: 1Prostate Cancer Targeted Therapy Group and Drug improve quality of life and pain control (10). These data Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, Surrey, United Kingdom; 2Depart- have unequivocally confirmed that directly targeting andro- ment of Cancer Biology, Lerner Research Institute, Glickman Urological gen biosynthesis is a valid therapeutic option for prostate and Kidney Institute and Taussig Cancer Institute, Cleveland Clinic, Cleve- cancer. This review discusses the challenges of inhibiting land, Ohio, and Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; CYP17A1 and other enzymes involved in steroid synthesis and 3Division of Metabolism, Endocrinology, and Diabetes, Department of and reviews strategies that are being evaluated to further Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan improve results achieved to date with abiraterone. Corresponding Author: Gerhardt Attard, Drug Development Unit, The Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, Androgen biosynthesis pathways United Kingdom. Phone: 44-208-722-4413; Fax: 44-208-642-7979;E-mail: Steroidogenesis entails processes by which cholesterol is [email protected] converted to biologically active steroid hormones. Steroido- doi: 10.1158/1078-0432.CCR-12-0931 genesis begins with the irreversible cleavage of a 6-carbon Ó2013 American Association for Cancer Research. group from cholesterol, producing pregnenolone by www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst March 7, 2013; DOI: 10.1158/1078-0432.CCR-12-0931 Ferraldeschi et al. cytochrome P450scc (side-chain cleavage enzyme, from 17-hydroxyprogesterone (OHP) and 17-hydro- CYP11A1). A small repertoire of cytochrome P450 and xypregnenolone]. The latter activity requires the presence non-P450 enzymes then convert pregnenolone to other of adequate amounts of cytochrome b5 (12). Exploiting the 21-carbon steroids (including progestins, glucocorticoids, requirement of the 17,20-lyase, but not 17a-hydroxylase and mineralocorticoids), 19-carbon steroids (androgens), reaction for cytochrome b5, could allow development of and 18-carbon steroids (estrogens; ref. 11). The transforma- therapeutics that specifically inhibit the former reaction. As tions catalyzed by the P450s, 5a-reductases, and 3b-hydro- cytochrome b5 is involved in a multitude of other essential xysteroid dehydrogenase-D5/D4-isomerases (3bHSD) are all processes, this approach will be challenging but could be irreversible reactions, giving rise to the general pathways of possible because the critical residues of b5 for stimulating steroidogenesis (Fig. 1). In contrast, the 3a,11b, and 17,20-lyase activity are E48 and E49, and these are not 17bHSD reactions at the terminal stages of the pathways required for enhancing the activities of CYP2E1 or are reversible pseudoequilibria, with each isoenzyme CYP2C19 (13, 14). In addition to its two primary activities, strongly favoring either steroid oxidation or reduction in human CYP17A1 also 16a-hydroxylates progesterone dur- intact cells. In human beings, each steroidogenic P450 ing 25% of turnovers and cleaves pregnenolone and allo- derives from one gene yielding one isoform, whereas all pregnanolone directly to their D16, 19-carbon homologs in other enyzmes exist as two or more isoenzymes, each with a the presence of b5. unique cognate gene expressed in a tissue-specific fashion. Although small amounts of androstenedione, testoster- Consequently, steroidogenesis generally follows a canoni- one, and other 19-carbon steroid metabolites can be directly cal pathway up to a point, but the final steps vary among produced by the adrenal glands, most D4-androgens in the tissues and cells, particularly in cancer cells, where genetic castrated male are produced in peripheral tissues, where changes are frequent and ectopic expression of various 3bHSD converts DHEA to androstenedione and D5-andros- genes is typical. CYP17A1 is the key enzyme for the synthesis tenediol to testosterone, respectively (Fig. 1). In the testis, of 19-carbon sex steroid precursors from 21-carbon preg- 17bHSD3 efficiently converts androstenedione to testoster- nanes. CYP17A1 catalyzes both the 17a-hydroxylation one and DHEA to D5-androstenediol, respectively, but in (hydroxyl addition to pregnenolone and progesterone) and the adrenal and peripheral tissues, the much slower type the subsequent 17,20-lyase cleavage [side-chain cleavage 5-(17bHSD5) enzyme catalyzes these conversions, and Cholesterol 17-deoxy-21- 17-hydroxy-21-carbon steroids 19-Carbon steroids (androgens & metabolites) carbon steroids SULT2A1 CYP17A1 CYP17A1 Dehydroepi- DHEA sulfate Pregnenolone 17α-OH-pregnenolone androsterone STS (DHEAS) 17βHSD2 3βHSD 3βHSD 3βHSD1, 2 17βHSD3/5/1 Δ5-Andro- CYP17A1 CYP17A1 stenediol Progesterone 17α-OH-progesterone Δ4-Androstenedione 17βHSD3/5 17βHSD2 SRD5A 3βHSD1, 2 Testosterone 11-Deoxycorticosterone SRD5A SRD5A 11-Deoxycortisol 5α-Pregnane- 5α-Dihydrotestosterone 17α-ol-3, 20-dione 17βHSD3/5 Corticosterone AKR1C2 17βHSD6 17βHSD2 Cortisol AKR1C2 5α-Androstanediol 5α-Androstanedione 11βHSD 17βHSD2 17βHSD3/5 α 18-OH-corticosterone Cortisone 5 -Pregnane- CYP17A1 AKR1C2 3α, 17α-diol- Androsterone 20-one 17βHSD6 Aldosterone © 2013 American Association for Cancer Research Figure 1. Androgen biosynthesis pathway. The basic pathways are demarcated with respect to CYP17A1 and SRD5A activities. The 17-deoxy, 21-carbon steroids upstream of CYP17A1 are shown at left in the pink box, including 11-deoxycorticosterone. The 17-hydroxy, 21-carbon steroids are in the center in the peach box, and 19-carbon steroids are at the right in the green box, generated via 17-hydroxylase and 17,20-lyase reactions of CYP17A1, respectively.
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