Mechanisms of drug resistance that target the androgen axis in castration resistant prostate cancer (CRPC)

Penning, T.M.

doi:10.1016/j.jsbmb.2015.05.010

Cited by 46 publications

(40 citation statements)

References 72 publications

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“…Intratumoral metabolism can activate or inactivate key steroids and thus regulate AR activation via a pre-receptor mechanism [38]. Steroids can be inactivated via 3α-hydroxysteroid dehydrogenases (3αHSD), and/or by conjugation, such as the sulfation or glucuronidation reactions carried out by sulfotrasferase and uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes, respectively.…”

Section: Castration-resistant Prostate Cancer (Crpc)mentioning

confidence: 99%

Clinical significance of 11-oxygenated androgens

Turcu

Auchus

2017

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review The adrenal gland is considered a source of weak androgens, such as dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. Emerging evidence proposes a set of 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as clinically important androgens. Such steroids include: 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone and 11-ketotestosterone. This review will discuss the synthesis, androgenic activity and clinical implications of the 11oxC19 steroids. Recent findings The clinical relevance of the 11oxC19 steroids resides in two key characteristics: 1. the synthesis of all 11oxC19 originates predominantly in the adrenal cortex; and 2. 11-ketotestosterone and its 5α-reduced metabolite, 11-ketodihydrotestosterone are potent agonists of the human androgen receptor, similar to the classic androgens testosterone and dihydrotestosterone, respectively. Recent studies have demonstrated higher than normal circulating levels of 11oxC19 steroids in patients with 21-hydroxylase deficiency and in polycystic ovary syndrome. The 11oxC19 steroids are also thought to contribute to castration-resistant prostate cancer progression. Additionally, the 11oxC19 steroids might have clinical implications in adrenarche and postmenopausal women. Summary Future prospective studies are needed to establish the clinical utility of the 11oxC19 steroids for individualized patient care. Preliminary data suggest that these biomarkers hold promise to improve the evaluation and management of androgen excess disorders.

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Section: Castration-resistant Prostate Cancer (Crpc)mentioning

confidence: 99%

Clinical significance of 11-oxygenated androgens

Turcu

Auchus

2017

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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“…Expressed in all PCa and upregulated in CRPC [15] AKR1C3 Expressed 10-16 fold higher in several PCa cell lines with respect to healthy prostate cells and up to 3 fold in androgen responsive and androgen independent PCa cell xenografts upon androgen deprivation [9] Upregulated in CRPC, both within the tumor microenvironment and in soft-tissue metastasis [15][16][17]52,176,177] HSD17B3 Expressed almost exclusively in the testis, there are some reports of its over-expression in PCa tissues. HSD17B3 mRNA was increased over 30 fold in PCa biopsies and the enzyme has been shown to be upregulated 8-fold in LuCaP-23 and LuCAP-35 PCa cell lines, obtained from metastatic tissues of a patient resistant to castration therapy [15,22] SRD5 A1 During PCa development its expression increases.…”

Section: Cyp17a1mentioning

confidence: 99%

“…AKR1C3 plays a key role in producing DHT in each of the three pathways, since it can lead to the synthesis of DHT starting from AD and DHEA in the canonical pathway, from 5α-androstanedione in the 5α-dione pathway, and from androsterone in the backdoor pathway [ Figure 2]. Elevated levels of expression of AKR1C3 in CPRC provide a mechanism to divert trace androgens that remain after ADT to the potent AR ligand DHT via these three pathways intratumourally and may indirectly also impact on CYP17A1 inhibitor or AR antagonist resistance mechanisms [9] . Furthermore, AKR1C3 has also been discovered to play a role in resistance to radiation therapy [45] .…”

Section: Akr1c3mentioning

confidence: 99%

“…Evidence accumulated over the past decade clearly indicates that castration-resistant growth, to a large extent, is driven by continued AR signalling, despite castration resulting in only low levels of T in the serum. Emerging literature indicates a complex network of molecular players linked in part with amplification or mutations in androgen receptors allowing activation by progesterone, estrogens and androgen antagonists, generation of alternative splicing variants or with androgen neo-synthesis within the prostate tumour or adrenals [7][8][9][10] . Accordingly, both the management of PCa patients and complete abolition of androgens are difficult to achieve.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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“…Thus, pharmaceutical approaches that interfere with androgen production and/or which inhibit the transcriptional activity of AR have become frontline therapies in the treatment of this disease . Although most patients with advanced disease respond initially to androgen deprivation (GNRH agonists or abiraterone) or AR antagonists (bicalutamide or enzalutamide), they invariably progress to a castration‐resistant state . Paradoxically, the AR signaling axis remains intact in castration‐resistant prostate cancer (CRPC) although the actions of this receptor are manifest in a constitutive manner .…”

Section: Introductionmentioning

confidence: 99%