The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer
Graphical abstract
Introduction
Prostate cancer is the second leading cause of cancer mortality in men in the developed world. According to the Surveillance, Epidemiology and End Results (SEER) program registries, it is projected that there are nearly 3 million men living with prostate cancer in the United States and that 233,000 new cases will be diagnosed in 2014. Individuals diagnosed with high-risk prostate cancer are typically treated with surgery or a combination of radiation and androgen deprivation therapy (ADT). Many will inevitably relapse and ultimately develop castration-resistant prostate cancer (CRPC), which is responsible for the vast majority of prostate cancer mortalities. There is a need to improve therapies for this high risk population. The mechanisms of resistance are multi-factorial but the androgen receptor (AR) remains active in most cases, as illustrated by the initial efficacy of newer ADT agents such as abiraterone acetate (AA) and enzalutamide in the mCRPC setting. There is a body of evidence that indicates that the resistant tumor can adapt to castrate conditions imposed by ADT via the increased expression of enzymes that facilitate the intratumoral conversion of circulating adrenal androgen precursors to the active AR ligands. Further, there is evidence that AR mutations, splice variants and increased copy number represent putative mechanisms of resistance to therapy. Here, we review the data from our SID-LC/ESI/SRM/MS quantification of serum androgens in patients enrolled in the neoadjuvant TAPS and the neoadjuvant AA trials. In both trials, conventional ADT agents were effective at achieving castrate concentrations of T and DHT. In the neoadjuvant TAPS trial, drastic reductions in the adrenal androgen precursors such as DHEA-S were observed in the arm in which patients received the non-specific P450c17 inhibitor, ketoconazole. Similarly, in the neoadjuvant AA trial, DHEA-S levels were consistently reduced only in patients that received the specific P450c17 inhibitor, AA. However, despite the large reductions in adrenal androgen precursors following P450c17 inhibition, a significant depot of DHEA-S remains in the circulation. Therefore, we hypothesize that the DHEA-S depot may be utilized for intratumoral biosynthesis of T and DHT, which would present an opportunity for AKR1C3 inhibition in the ketoconazole and AA refractory mCRPC setting.
Section snippets
Prostate cancer and androgen deprivation therapy
In the 1940’s, Huggins and Hodges laid the foundation for the treatment of advanced, metastatic prostate cancer by successfully conducting surgical castration or orchiectomy to shrink prostate tumors [1]. This work extended Beatson’s pioneering efforts whereby oophorectomy was used to successfully treat select cases of advanced breast cancer [2]. The present day treatment of hormone-dependent cancers continues to build upon this legacy with the advent and development of pharmacological ADT. The
The problem – resistance to therapy
The mechanisms for CRPC include modifications in the AR via an increase in copy number [11], [12], [13], [14], mutations in the AR that may lead to ligand promiscuity [15], [16], [17], [18], [19] and the emergence of splice variants that may facilitate resistance to AR antagonists [20], [21], [22]. The primary focus of this review is the resistance that arises when castrate conditions trigger an adaptive response by up-regulating the expression of enzymes such as 5α-reductase type 1 and 2 [23],
Prostate specific antigen (PSA)
The clinical biomarker for prostate cancer is prostate specific antigen (PSA) and its implementation has facilitated early disease detection and monitoring of therapy. PSA is the primary clinical biomarker used in tracking the efficacy of ADT. It is our contention that quantification of serum and tissue androgen metabolites, both conjugated and unconjugated will greatly augment PSA measurements during the monitoring of ADT treatment and shed light on potential pre-receptor mechanisms of drug
Advances in P45017A1 inhibitors and AR antagonists as therapy
The emergence of mCRPC has led to the development and pursuit of additional ADT agents such as the P450c17 17α-hydroxylase/17, 20-lyase inhibitor, abiraterone acetate (AA) [29] and the latest addition to the AR antagonist family, enzalutamide [30]. AA increased the median survival of mCRPC patients by 3.9 months [31] and 4.6 months [32] and enzalutamide increased median survival of CRPC patients by 4.8 months [33], confirming that some of these tumors remained hormonally driven. However, tumors
AKR1C3 and prostate cancer
The 17β hydroxysteroid dehydrogenase type 5, also known as aldo–keto reductase 1C3 (17β-HSD5; AKR1C3) is the predominant 17β-HSD isoform expressed in the prostate [37]. AKR1C3 catalyzes the NADPH-dependent reduction of both Δ4-AD to T and 5α-androstane-3,17-dione to DHT (Scheme 1) [38]. AKR1C3 is up-regulated in prostate cancer and expression levels correlate with stage of disease [39]. In prostate cancer cell lines, natural and synthetic androgens down-regulate AKR1C3, whereas androgen
ADT clinical trials and androgen measurements
Several ADT clinical trials have monitored the reduction in a few serum androgens during the course of drug treatment [48], [49], [50], [51]. However, the clinical experience has shown that patients develop resistance to treatment in spite of castrate levels of serum T and DHT. The historic definition of castrate levels of serum androgens has been <50 ng/dL as this was the limit of quantification of previous analytical methods. The confounding factor in a number of these past analyses is that
The total androgen pathway suppression trial
The TAPS trial randomized intermediate to high-risk prostate cancer patients into one of four arms for a 12 week period prior to radical prostatectomy. Patients in arm 1 received goserelin, a leutinizing hormone releasing hormone agonist (LHRHa) and R-bicalutamide, an AR antagonist; patients in arm 2 received goserelin and dutasteride, a dual 5α-reductase type 1 and type 2 inhibitor; patients in arm 3 received, goserelin, R-bicalutamide and dutasteride; and patients in arm 4 received goserelin, R
The neo-adjuvant AA trial
Abiraterone acetate (AA) is one of the newest additions to the ADT armamentarium and acts by inhibiting P450c17, 17α-hydroxylase and 17,20-lyase activity. The primary endpoint of the neoadjuvant AA trial was to analyze the difference in prostate tissue hormones as a result of leuprolide treatment alone compared to leuprolide and AA, thus confirming an AA target effect in prostate tissue. In this trial, patients with localized high and intermediate-risk prostate cancer were randomly assigned to
Trends from the TAPS and AA trials
In arm 4 of the TAPS trial and the leuprolide and AA and prednisone arm of the neoadjuvant AA trial, castrate levels of serum T were achieved (95–99% reduction). The reduction in serum DHEA-S concentration following AA treatment was more robust (>90% reduction) than that seen with the non-specific P450c17 inhibitor, ketoconazole, used in the TAPS trial, (∼70% reduction). However, the reduction following AA treatment still left serum DHEA-S concentration in the ∼20 μg/dL range, which may serve as
Intratumoral androgen conversion and AKR1C3 inhibition
Under normal physiological conditions, circulating DHEA and DHEA-S is utilized in peripheral tissue for intracrine production of androgens and estrogens [56]. Likewise, the intratumoral conversion of circulating DHEA-S to yield potent AR ligands (T and DHT) requires the expression and activity of organic anion transporter polypeptides (OATPs) to facilitate transport of the conjugated androgen into the cell. The expression of steroid sulfatase (STS) is required to release unconjugated DHEA and
Transparency Document
Conflict of Interest
Dr. Tamae reports grants from National Cancer Institute during the conduct of the study. Dr. Mostaghel reports grants from National Cancer Institute during the conduct of the study; and personal fees from Janssen Pharmaceuticals outside the submitted work. Dr. Montgomery reports grants from Prostate Cancer Foundation, during the conduct of the study; and personal fees from Janssen Pharmaceuticals outside the submitted work. Dr. Nelson reports grants from National Cancer Institute, grants from
Acknowledgements
Grant support was from the following funding sources: the National Cancer Institute (NCI)/National Institutes of Health (NIH) Cancer Pharmacology Training Grant (R25 CA101871) to D.T.; Prostate Cancer Foundation Challenge Award (S.P.B. and P.N.), AA clinical trial support Janssen Pharmaceuticals, TAPS clinical trial support; the National Institute of Environmental Health Sciences/NIH Center of Excellence in Environmental Toxicology (P30-ES013508), the NCI Grant (P01-CA163227) and a Prostate
References (61)
On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases
Lancet
(1896)- et al.
Clinical effects of gonadotropin-releasing hormone analogue in metastatic carcinoma of prostate
Urology
(1985) - et al.
Prostatic cancer and SCH-13521: II. Histological alterations and the pituitary gonadal axis
J. Urol.
(1975) - et al.
Multicenter, randomized, double-blind, placebo controlled study to investigate the effect of finasteride (MK-906) on stage D prostate cancer
J. Urol.
(1992) - et al.
Ketoconazole therapy for advanced prostate cancer
Lancet
(1984) - et al.
Androgen receptor gene mutations in human prostate cancer
J. Steroid Biochem. Mol. Biol.
(1993) - et al.
Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum
J. Steroid Biochem. Mol. Biol.
(2013) - et al.
Pharmacology of novel steroidal inhibitors of cytochrome P450(17)α (17α-hydroxylase/C17-20 lyase)
J. Steroid Biochem. Mol. Biol.
(1994) - et al.
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study
Lancet Oncol.
(2012) - et al.
Structure-function aspects and inhibitor design of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)
Mol. Cell. Endocrinol.
(2001)
Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model
Am. J. Pathol.
The backdoor pathway to dihydrotestosterone
Trends Endocrinol. Metab.
DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology
Front. Neuroendocrinol.
Enhanced expression of organic anion transporting polypeptides (OATPs) in androgen receptor-positive prostate cancer cells: possible role of OATP1A2 in adaptive cell growth under androgen-depleted conditions
Biochem. Pharmacol.
Inhibition of dehydroepiandosterone sulfate action in androgen-sensitive tissues by EM-1913, an inhibitor of steroid sulfatase
Mol. Cell. Endocrinol.
A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer
Cell
Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland
Arch. Surg.
Leuprolide versus diethylstilbesterol for metastatic prostate cancer
N. Engl. J. Med.
The effect of flutamide on testosterone metabolism and the plasma levels of androgens and gonadotropins
J. Clin. Endocrinol. Metab.
ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen
J. Endocrinol.
The effects of the dual 5α-reductase inhibitor dutasteride on localized prostate cancer – results from a 4-month pre-radical prostatectomy study
Prostate
In vivo amplification of the androgen receptor gene and progression of human prostate cancer
Nat. Genet.
Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer
Cancer Res.
Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer
Cancer Res.
Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer
Br. J. Cancer
Androgen receptor gene mutations in human prostate cancer
Proc. Natl. Acad. Sci. U.S.A.
Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone
Mol. Endocrinol.
Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer
N. Engl. J. Med.
Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist
Cancer Res.
Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer
Cancer Res.
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Steroidogenesis in castration-resistant prostate cancer
2023, Urologic Oncology: Seminars and Original InvestigationsBack where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis
2021, Molecular and Cellular EndocrinologyCitation Excerpt :Treatment strategies would have to target both classic and C11-oxy adrenal androgen precursors to achieve a favourable patient outcome and to effectively treat CRPC. Abiraterone acetate inhibiting CYP17A1 showed promising results (Wright et al., 2020) and combined with AKR1C3 inhibition, uncovered a combinatorial treatment strategy with great potential (Tamae et al., 2015; Endo et al., 2020b). Unfortunately, abiraterone has also been shown to bind CYP21A2, inhibiting 21-hydroxylase activity (Malikova et al., 2017), which may lead to the increased production of 11OHP4, a steroid which has been associated with other clinical conditions, which could negatively impact PCa and CRPC upon treatment.
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2019, Cancer Treatment ReviewsCitation Excerpt :Hence, dehydroepiandrosterone (DHEA) and androstenedione (AD) are produced in the adrenal gland and can then be converted into testosterone and DHT in the prostate, activating the AR despite castration and competition from anti-androgens [33,34]. Abiraterone targets this conversion process and leads to the reduction of both DHEA and AD but residual androgens in other forms still remain and may reactivate the receptor [35]. Targeting other enzymes responsible for this conversion of adrenal androgens to DHT is a valuable avenue for future drug development in combination with the current CRPC treatments.
Potential impact of combined inhibition of 3α-oxidoreductases and 5α-reductases on prostate cancer
2019, Sustainability (Switzerland)Citation Excerpt :Hypertension, hypokalemia and peripheral edema occur with sufficient frequency that abiraterone is co-administered with prednisone [34–36]. The earlier clinical failure of abiraterone (and other CYP17A1 inhibitors) has been attributed to several mechanisms that involve AR splice variants [37], circulating DHEA-SO4 that remains in spite of abiraterone treatment [38], increased expression of CYP17A1 [39,40], or other primary [37,41] and/or secondary backdoor pathway [39] androgen metabolism enzymes. CYP17A1 inhibition induces progesterone accumulation, which competes with abiraterone for CYP17A1 [42].