Androgen synthesis in prostate cancer: do all roads lead to Rome?

Stuchbery, Ryan; Hovens, Christopher M.; Corcoran, Niall M.

doi:10.1038/nrurol.2016.221

Cited by 38 publications

(40 citation statements)

References 95 publications

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“…This was well maintained upon stimulation with elevated androgen levels, in line with the strong binding of darolutamide to the AR . This should be of advantage in tumors where steroid biosynthesis is upregulated, an important resistance mechanism observed in patients …”

Section: Discussionmentioning

confidence: 69%

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell‐based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto‐darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand‐binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen‐dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down‐regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC‐4 cell line‐derived xenograft and of the KuCaP‐1 patient‐derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.

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Section: Discussionmentioning

confidence: 69%

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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“…AR activation (dimerisation and phosphorylation) is regulated by both androgen-dependent (blue arrows) and androgen-independent pathways (red arrows). In the androgen-dependent pathway, T and DHT production is catalysed by the steroidogenic enzymes and occurs through the canonical, 5a-dione and backdoor pathways [24] . The androgen-independent pathway includes: (1) AR gain-function mutations; (2) activation by nonandrogen steroids or androgen antagonists; (3) activation by non-steroid growth factors (receptor tyrosine kinases are activated and both AKT and MAPK pathways, producing a ligand-independent AR); and (4) increase of AR co-regulators.…”

Section: Figurementioning

confidence: 99%

“…Their occurrence and relative importance in the development and progression of PCa remains controversial, since the experimental evidence comes mainly from preclinical cell culture models, where different results are obtained depending on the cell lines studied or where more clinically-relevant biopsy samples have been used for analysis. The current understanding of androgen synthesis and the evidence for its role in castration resistance, either supporting or rebutting the relevance of each pathway to patients with PCa were recently extensively reviewed by Stuchbery et al [24] .…”

Section: The Backdoor Androgen Synthesis Pathwaymentioning

confidence: 99%

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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“…Treatment resistance and response to treatment by individuals could be explained by studies that have established PCa as a heterogeneous disease [52]. Firstly, primary PCa is a heterogeneous entity in itself with multiple foci and individual clones [15,53].…”

Section: Systemic Treatment Resistancementioning

confidence: 99%

“…As discussed, prostate cancer is a heterogeneous disease with evolving biological nature in response to implementation of treatments [52]. For example, metastatic prostate cancer usually evolves into CRPC despite the implementation of ADT.…”

Section: Biomarkers In Advanced Prostate Cancermentioning

confidence: 99%

Androgen Deprivation Therapy (ADT), Metabolic Syndrome and Metastatic Prostate Cancer: In Vivo and In Vitro Assessments of Effects of Metformin

Rhee¹

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Research Title -In vivo In this translational research PhD project, we conducted a randomized, placebo-controlled clinical trial named ADT and Adjuvant Metformin (ADMET) trial to determine the metabolic and therapeutic effects of treating hyperinsulinaemia in men starting ADT using a diabetic medication called metformin. Men who had been diagnosed with metastatic PCa and commencing ADT as a standard strategy provided the opportunity to study the physiological and pathological impact of the acute rise in insulin levels resulting from the iatrogenic hypogonadism [6]. To assess for the therapeutic benefits of metformin, we used a variety of novel technologies such as circulating tumour cell (CTC) enumeration, culture, transcriptomic analysis, and molecular imaging.The clinical trial was commenced in September 2014 and was completed in March 2017. It concluded that hyperinsulinaemia and MS is a phenomenon that affects most patients when using ADT, although the changes can be ameliorated by metformin. The use of medication was associated with the reduced need for treatment of MS with agents such as statins and progression to CRPC. Further, the trial confirmed that insulin resistance at the time of starting treatment is associated with early development of CRPC and progression of the disease.Progression free survival was also demonstrated using a novel molecular imaging called Prostate Specific

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Androgen synthesis in prostate cancer: do all roads lead to Rome?

Cited by 38 publications

References 95 publications

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

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

Androgen Deprivation Therapy (ADT), Metabolic Syndrome and Metastatic Prostate Cancer: In Vivo and In Vitro Assessments of Effects of Metformin

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