Androgen-targeting Therapy
Targeting androgens in PCa has been a goal of treatment since the 1940s, with new classes of antiandrogens developed as knowledge of androgen biosynthesis and signalling has increased (Figure 1). Nonsteroidal antiandrogens were developed to target AR without the nonspecific effects of their steroidal predecessors. While these drugs are safer, they have a disadvantage of lower affinity for AR, leaving about 5–10% of DHT uninhibited and able to bind and activate AR. Newer generations of antiandrogens were developed to address this issue. These next-generation agents include abiraterone, an inhibitor of cytochrome P17 (CYP17), and enzalutamide. CYP17 is required in the androgen biosynthesis pathway, and its inhibition leads to decreased levels of DHT. The history and development of antiandrogen therapies are described more extensively in other reviews.[81]
Figure 1.
AR signalling pathways and therapeutic targets of AR. Androgens such as T are produced from cholesterol. CYP17A1 is the enzyme responsible for converting precursors to DHEA, and T is converted to DHT through 5a-reductase. DHT activates AR, resulting in its release from HSP70/90. AR then dimerizes and translocates to the nucleus where it can bind to AREs and modulate the transcription of target genes. Abiraterone irreversibly inhibits CYP17A1 activity. Bicalutamide and enzalutamide are AR antagonists that block the binding of DHT to AR. Enzalutamide also inhibits the nuclear translocation of AR. Abbreviations: GnRH—gonadotropin-releasing hormone, LH—luteinizing hormone, T—testosterone, ACTH—adrenocorticotropic hormone, DHEA—dehydroepiandrosterone, ARE—androgen response element, and PSA—prostate-specific antigen
Evidence of a role for androgens and AR in BC development and progression has led to considerable interest in AR as a potential therapeutic target. Antiandrogens such as bicalutamide and enzalutamide have shown early success in preclinical and clinical trials of antitumour response, and further trials have enrolled both ER– and ER+ anti-oestrogen-resistant patients.[24,82,83] The goal of using ADT as a therapy in these patients is to block the activation of AR and associated pathways such as ErbB that are involved in BC progression. However, anti-AR strategies in BC have yet to be established due to a lack of consistent positive trial data and, as detailed below, this can partly be explained by the biological complexity of AR signalling in BC.
In contrast to strongly AR+ TNBC, low-level AR expression has been associated with more aggressive forms of TNBC, suggesting that in at least some subtypes of BC, ADT may have a tumour-promoting effect.[84] Cochrane et al. presented clinical data that a high nuclear ratio of AR relative to ER in patients treated with tamoxifen (an anti-oestrogen therapy) predicted failure in therapy. They then went on to show that enzalutamide treatment decreased growth in both ER+ and ER−/AR+ tumours, suggesting a role for antiandrogens in hormone resistant cancers.[85] They were the first to show that androgen-targeted therapies could have clinical benefit in ER– BC, either alone or in combination with tamoxifen and/or AIs. They also suggest a role for targeting AR in recurrent ER+ BC, where selective targeting of the ER pathway could lead to the tumour cells switching to androgen dependence.
Clinically, however, data do not support AR as a biomarker for selecting anti-oestrogen therapy. Results from NCT00004205 show that in postmenopausal ER+ BC patients, AR expression did not predict treatment efficacy of anti-oestrogen therapy monotherapy. Alternatively, AR expression has been shown to be useful in predicting the efficacy of antiandrogen therapy, including AR positivity in TNBC predicting response to enzalutamide.[86,87] While much attention has been focused on drugs that block androgens, research is also looking into the efficacy of 17α hydroxylase/17–20 lyase (CYP17) inhibitors (i.e. abiraterone) that block androgen, oestrogen and glucocorticoid synthesis. Early results from these trials show mixed responses and the studies are ongoing. These studies are covered in more detail by other reviews.[24,82,83]
There are currently multiple clinical trials evaluating the use of AR antagonists in BC. In one study of AR+ TNBC, patients were treated with bicalutamide 150 mg daily. The results showed clinical benefit (defined as a complete or partial response or stable disease) of 19%, with a median progression-free survival of 12 weeks.[49] This study was the first proof that AR antagonist treatment is beneficial in AR+ TNBC. Additional phase II trials are ongoing testing bicalutamide and enzalutamide in AR+ TNBC, showing a clinical benefit of 20% for bicalutamide (NCT00468715) and 28–33% for enzalutamide.[86] Further studies are evaluating enzalutamide in combination with other therapeutics such as trastuzumab in AR+/HER2+ BC (NCT02091960), and paclitaxel in early-stage AR+ TNBC (NCT02689427). Many of these trials show promise of alternate therapeutic options for TNBC beyond cytotoxic chemotherapy alone.
While most AR-targeted therapies are aimed at inhibiting signalling, there is evidence of AR activation producing growth repression. This has been well demonstrated in some PCas, especially those that have adapted to low androgen environment growth. In the case of PCas, there is typically a biphasic growth where either ADT or supraphysiologic androgens produce growth suppression.[88,89] This has been replicated in BC exposed to high concentrations of oestrogen.[90,91] Several mechanisms have been proposed for the observation of growth repression at high concentrations of androgens including cMyc activation and activation of negative regulators of the cell cycle.[92] High doses of androgens have been shown to induce DNA damage. This is consistent with previous reports that AR activation results in transient double-strand DNA breaks to release DNA topologies that inhibit the function of RNA polymerase during transcription.[93] Because of its ability to promote DNA damage, AR is also a promising target for combined therapeutics with radiation (discussed later). Due to the ability of AR to act as either a positive or negative regulator of cell growth and proliferation depending on the molecular features of the BC and the presence of oestrogens, both AR agonists and antagonists are being actively tested as potential therapies. While synthetic androgens have proven to have undesired side effects, selective AR modulators (SARMs) have promising preclinical effects on reducing tumour burden in ER+ BC and have fewer side effects.[94] Recently it was shown in a patient-derived xenograft (PDX) model of BC that treatment with a SARM, but not an AR antagonist, inhibited cell proliferation. This was further shown to occur through a reprogramming of the ER cistrome to an AR cistrome, likely through a FOXA1-dependent mechanism.[95] This was further corroborated by Hickey et al. findings that AR agonist treatment could be combined with standard of care in ER+ BC to enhance antitumour response. They showed that activation of AR in this context alters the genomic distribution of ER as well as other co-activators leading to decreased expression of ER-regulated cell cycle genes and upregulation of AR-regulated tumour suppressor genes.[96] Evaluation of SARMs in ER+ and AR+ BC is currently under further investigation in a phase II trial (NCT02463032).
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