Elsevier

Steroids

Volume 95, March 2015, Pages 80-87
Steroids

Review
CYP17A1 inhibitors in castration-resistant prostate cancer

https://doi.org/10.1016/j.steroids.2014.12.021Get rights and content

Highlights

  • •

    Androgen receptors and the current treatment of prostate cancer will be reviewed.

  • •

    Progression to castrate resistant prostate cancer (CRPC) and treatment are discussed.

  • •

    Basics of abiraterone acetate (AA) physiology are highlighted with clinical trials summarized.

  • •

    Alternative strategies to enhance AA therapy and novel CYP171A inhibitors are summarized.

Abstract

The majority of prostate cancer (PCa) cases are diagnosed as a localized disease. Definitive treatment, active surveillance or watchful waiting are employed as therapeutic paradigms. The current standard of care for the treatment of metastatic PCa is either medical or surgical castration. Once PCa progresses in spite of castrate androgen levels it is termed ‘castration-resistant prostate cancer’ (CRPC). Patients may even exhibit rising PSA levels with possible bone, lymph node or solid organ metastases. In 2010, the only agent approved for the treatment of CRPC was docetaxel, a chemotherapeutic agent. It is now known that cells from patients with CRPC express androgen receptors (AR) and remain continuously influenced by androgens. As such, treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront. The use of cytochrome P450c17 (CYP17A1) inhibitor underlies one of the most recent advances in the treatment of CRPC. Abiraterone acetate (AA) was the first CYP17A1 inhibitor approved in the United States. This review will discuss CRPC in general with a specific focus on AA and novel CYP17A1 inhibitors. AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy. Furthermore, the most recently identified CYP17A1 inhibitors Orteronel, Galeterone, VT-464, and CFG920 will also be explored.

Introduction

Since the discovery that prostate cancer (PCa) is influenced by androgen activity and could be treated by castration in 1941, the role of androgens in PCa has been the focus of studies and the basis of new therapies [1]. While enormous accomplishments have been made in the field, PCa remains the second most common cause of male cancer-related deaths in the United States [2]. Currently, 91% of men with PCa are diagnosed with localized, and mostly curable disease. However, a small percentage of men present with locally advanced disease, metastatic disease or have localized PCa that has become unresponsive to first line therapies [2], [3]. The primary treatment strategy for men with this type of advanced disease is androgen deprivation therapy (ADT). Removal of androgens from the circulation is accomplished via surgical (bilateral orchiectomy) or medical (gonadotropin releasing hormone agonist/antagonists or anti-androgens) modalities [4]. Unfortunately, ADT is rarely curative because only ∼80% of patients respond, and the majority of ADT responders will inevitably progress to castration-resistant disease [5], [6], [7]. If left untreated, castration-resistant prostate cancer (CRPC) is invariably fatal within 9–12 months [7], [8].

Prior to 2010, the best treatment option for CRPC patients was chemotherapy with docetaxel in combination with prednisone – a regiment that yielded only a modest survival advantage of 2–3 months [9], [10]. Recent studies have found that CRPC actually remains dependent on androgen receptor (AR) signaling [11], [12], [13], [14]. This discovery has led to the development of new strategies that inhibit AR signaling, thus diminishing CRPC growth. Indeed, by 2011, the United States Food and Drug Administration (FDA) approved abiraterone acetate (AA), the first specific inhibitor of the steroidogenic enzyme cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1 or P450c17). The basis for approval was several phase III clinical trials in men with CRPC that demonstrated an improved overall survival compared to placebo [11].

This review will discuss the role of androgens and the AR in PCa and the mechanisms by which men develop CRPC. Furthermore, specifically in regards to CYP17A1 inhibitors, the trials that led to the approval of CYP17A1 inhibitors, the pathways by which abiraterone exerts its effects, as well as novel CYP17A1 inhibitors currently under investigation will be reviewed.

Section snippets

Role of androgens and ar in prostate cancer

Androgens, through their effects of the AR, play a crucial role in cell proliferation and differentiation during prostate development. In normal prostatic tissue, cell growth and death are in equilibrium through the regulation of proliferation, differentiation and apoptosis [15]. The progression of prostatic epithelial cells into a malignant state involves the de-regulated expression of growth factors and their receptors, up-regulation of proto-oncogenes, and down-regulation of tumor

Current PCa treatment paradigms

Roughly 91% of the 234,460 men annually diagnosed with PCa in the United States will have localized disease [3]. These are men with T1 or T2 disease with no evidence of lymph node involvement or metastatic disease. For these men, a variety of surgical or radiotherapy options are available with treatment often being curative. Conservative management is considered for men with low-grade and small-volume tumors and/or a short (<10 years) life expectancy. Watchful waiting is best suited for patients

Mechanisms of progression to CRPC

Progression of PCa to CRPC involves a complex interaction between signaling molecules that collectively lead to a higher propensity for cell proliferation than cell death. It is important to recognize that while many mechanisms have been identified to cause tumor progression after ADT, they all lead to the activation of the AR signaling pathway. The six main categories for increased AR activation seen in patients with CRPC are as follows: (1) intracrine androgen production [25], [26], [27]; (2)

Treatment of CRPC

All of the aforementioned adaptive mechanisms that occur in PCa cells following ADT have left clinicians with the difficult challenge of treating CRPC. A condition that, if left untreated, will ultimately be fatal within 9–12 months [7], [8]. Few treatment options are available, and until 2010, chemotherapy with docetaxel and prednisone was the only therapy proven to prolong life in patients with CRPC. Unfortunately, this treatment regiment was only successful in prolonging survival to ∼19.2 

Abiraterone acetate development and physiology

While generalized ADT is effective at inhibiting the testicular production of T, the levels of T and DHT in CRPC remain high enough to activate AR signaling [39]. Although adrenal androgens account for 5–10% of circulating testosterone, another important source is the intracrine action of hormones from the prostate itself [40]. Indeed, prostatic tissue has the capacity to efficiently transform the inactive steroids DHEA-S, DHEA, and 4-dione into T and DHT without releasing them into circulation

Clinical trials with abiraterone acetate

The first human studies, conducted by O’Donnell et al. [63], were a series of phase I clinical trials that showed that a dose of 800 mg was sufficient to suppress T levels. However, this suppression was not sustained in all patients due to a compensatory rise in Luteinizing Hormone (LH). As such, it was suggested that higher levels of AA or concomitant use with GnRH agonists should be considered [63]. This initial study led to an open-label, dose-escalation phase I trial, published by Attard et

Alternative strategies to enhance AA therapy

Although previous studies demonstrated a clear and significant improvement with AA, the effects are finite, and disease progression will inevitably occur. To overcome this, future studies are required to ascertain mechanisms of resistance and solutions to overcome these pathways. One potential mechanism for AA resistance is via increased T/DHT by enzymes involved in steroidogenesis or through the use of an alternative pathway of DHT synthesis. Indeed, preclinical studies have shown increased

Novel CYP171A inhibitors

A more recently designed CYP17A1 inhibitor, Orteronel (TAK-700; Millennium Pharmaceuticals), was derived from naphthylmethylimidazole and formulated to have highly selective c17,20-lyase inhibition [84]. Preclinical in vitro (human and monkey adrenal cells) and in vivo (monkeys) studies have documented a 5.4 times more potent inhibition of c17,20-lyase than 17α-hydroxylase as well as a greater reduction in T and DHEA compared to cortisol [85]. The potential benefit for this greater c17,20-lyase

Conclusion

This review has focused on CRPC and the novel therapies designed to treat this advanced stage of PCa. In 2010, the only agent approved for therapy was docetaxel; however, treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have recently come to the forefront. Specifically, the CYP17A1 inhibitor abiraterone has emerged as an important therapeutic modality in CRPC. Current clinical trials examining other novel CYP17A1

Financial support

JRK is a Male Reproductive Health Research Career (MHRH) Development Physician-Scientist Scholar (K12, HD073917-01) awarded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program to DJL. DJL also holds NIH Grants P01HD36289 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development at the National Institutes of Health and 1R01DK078121 from the National Institute of Kidney and Digestive Diseases.

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