Argeting CYP17: Established and novel approaches in prostate cancer

The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK.
Current Opinion in Pharmacology (Impact Factor: 4.6). 08/2008; 8(4):449-57. DOI: 10.1016/j.coph.2008.06.004
Source: PubMed


There is a growing body of evidence that although medical or surgical castration blocks the generation of gonadal testosterone in prostate cancer, androgens originating from other sources may continue to drive androgen receptor (AR) signaling. Recent studies have demonstrated high intratumoral levels of androgens and continued AR signaling in castration-resistant prostate cancer (CRPC), suggesting that androgens may also be synthesized de novo. Inhibiting the systemic biosynthesis of androgens in CRPC by targeting CYP17 may thus represent a rational therapeutic approach since this enzyme catalyses two key steroid reactions involving 17alpha-hydroxylase and C(17,20)-lyase in the androgen biosynthesis pathway. This review will discuss the rationale for and implications of targeting CYP17 in CRPC and focus on established and novel CYP17 inhibitors, including ketoconazole, abiraterone acetate, and VN/124-1, which are agents currently at different stages of development.

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    • "The cytochrome P450 enzymes CYP11A1 and CYP17A1 are involved in intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone [138]. CYP17A1 inhibitors, such as abiraterone acetate (Zytiga), are sought as a potential effective therapy for castrate resistance prostate cancer [117] [119]. However , a study in castration-resistant VCaP tumor xenografts shows development of abiraterone resistance. "
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    ABSTRACT: Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.
    BioMed Research International 11/2015; 2015(8). DOI:10.1155/2015/454837 · 2.71 Impact Factor
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    • "Bone pain can be relieved using bisphosphonate, denosumab, or radiopharmaceutical radium-223 chloride treatment [10– 12]. Until recently, chemotherapy has not been considered an effective treatment against prostate cancer; however, studies with docetaxel alone or combined with the estradiol derivative estramustine, the CYP17 inhibitor abiraterone acetate, and the androgen receptor (AR) antagonist enzalutamide demonstrated promising results against castration-resistant prostate cancer (CRPC) [13] [14] [15] [16]. New investigational drug compounds such as the AR inhibitor ODM-201 and the taxane analog cabazitaxel have also shown promising results in clinical trials [17] [18]. "
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    ABSTRACT: Prostate cancer is a very common malignancy among Western males. Although most tumors are indolent and grow slowly, some grow and metastasize aggressively. Because prostate cancer growth is usually androgen-dependent, androgen ablation offers a therapeutic option to treat post-resection tumor recurrence or primarily metastasized prostate cancer. However, patients often relapse after the primary response to androgen ablation therapy, and there is no effective cure for cases of castration-resistant prostate cancer (CRPC). The mechanisms of tumor growth in CRPC are poorly understood. Although the androgen receptors (ARs) remain functional in CRPC, other mechanisms are clearly activated (e.g., disturbed growth factor signaling). Results from our laboratory and others have shown that dysregulation of fibroblast growth factor (FGF) signaling, including FGF receptor 1 (FGFR1) activation and FGF8b overexpression, has an important role in prostate cancer growth and progression. Several experimental models have been developed for prostate tumorigenesis and various stages of tumor progression. These models include genetically engineered mice and rats, as well as induced tumors and xenografts in immunodeficient mice. The latter was created using parental and genetically modified cell lines. All of these models greatly helped to elucidate the roles of different genes in prostate carcinogenesis and tumor progression. Recently, patient-derived xenografts have been studied for possible use in testing individual, specific responses of tumor tissue to different treatment options. Feasible and functional CRPC models for drug responsiveness analysis and the development of effective therapies targeting the FGF signaling pathway and other pathways in prostate cancer are being actively investigated.
    Reproductive biology 03/2014; 14(1):16-24. DOI:10.1016/j.repbio.2014.01.002 · 1.52 Impact Factor
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    • "In sum, a variety of mechanisms ensure the continued dependence of CRPC on androgen stimulation and AR signaling, underpinning the recent surge in enthusiasm for developing drugs that target various steps along the androgen-AR pathway. To this end, abiraterone acetate is the first rationally designed drug that achieves antitumor effects (beyond those achieved with LHRH agonists alone) by suppressing extragonadal and intratumoral androgen synthesis.23 "
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    ABSTRACT: Treatment of castration-resistant prostate cancer remains an area of unmet medical need. Evidence suggests that this entity continues to be driven by androgens and androgen receptor (AR) signaling. Abiraterone acetate, a pregnenolone derivative, is an oral selective and irreversible inhibitor of the key steroidogenic enzyme CYP17. It possesses dual 17-α hydroxylase and C17,20-lyase blocking activity, the result of which is decreased gonadal and extra-gonadal androgen synthesis. Abiraterone was first approved by the US Food and Drug Administration (FDA) in 2011 following the demonstration of superior survival compared with placebo in the post-docetaxel population. Since that time, more evidence has been generated from preclinical studies and clinical trials which have considerably enhanced our understanding of this complex disease. In this paper, we review the development of abiraterone acetate, its pharmacological characteristics, and its effects on the androgen-AR signaling axis, along with the combined experience from clinical trials. We also discuss some of the ongoing trials using this agent, as well as potential mechanisms of abiraterone resistance, novel bio-marker development, and future directions using AR-directed therapies.
    07/2013; 2013(7):1-14. DOI:10.4137/CMU.S8337
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