Introduction
This essay will seek to discuss the role of androgen receptor therapy in advanced prostate cancer. Prostate cancer and the androgen receptor (AR) will be discussed, namely the origins of androgen receptor targeted therapy, its development and role in treatment of advanced prostate cancer today, and the future of targeted therapy. Androgen receptor targeted therapy is utilised in advanced prostate cancer to improve morbidity and mortality. The role of AR targeted therapies have evolved over the past 80 years to become more selective, more efficacious and more favourable. As our understanding of the AR itself grows, so too does our ability to modulate it and improve treatments. From the discovery that prostate cancer was androgen-dependent in 1941, to current treatment methods for advanced prostate cancer, the role of the androgen receptor in treating these cancers has evolved significantly. This essay aims to discuss the evolution of targeted therapies for the AR and to give context in the current treatment of advanced prostate cancer today.
The Prostate Gland
The prostate is an exocrine gland of the male reproductive system, located at the base of the bladder surrounding the urethra. The name “prostate” derives from the ancient Greek προστάτης (pro-státēs), which means “one who stands before/guardian” in reference to its location at the base of the bladder. The prostate is primarily involved in production of prostatic fluid, which is one of the main components of semen. Prostate specific antigen (PSA) is released by prostatic epithelial cells. It is involved in liquefying semen facilitating the motility of sperm. PSA is also an important biomarker of prostate cancer, and is used in screening programmes. Measuring the PSA level in prostate cancer is important, as high serum PSA levels correlate with poorer outcomes. Low serum PSA levels have been shown to generally correlate with more positive outcomes .
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Prostate cancer *A lot more detail here – mention CRPC, the Ahmed paper was succinct*, also mention androgen sensitive and androgen-independent cancers.
Prostate cancer is a life-threatening disease. Worldwide, prostate cancer has the second highest incidence of cancer in males at a rate of 31.1 per 100,000 . In the EU in 2012, there were 345,000 new cases of prostate cancer, which accounted for 24% of all newly diagnosed cancers. It also resulted in 72,000 deaths, 10% of all cancer deaths that year . Thus, prostate cancer poses a significant threat to public health. Prostate cancer often remains clinically silent until later stages of the disease, when rates of survival are often lower. Traditionally, the term ‘advanced prostate cancer’ was used to describe cancer which had metastasized into surrounding tissues, pelvic lymph nodes, and bone. However, it is now more accurately characterised as cancer which has spread beyond the capsule of the prostate, with stages as low as T3/N0/M0 to reflect the significant risks of progression and death . Diagnosis of prostate cancer usually occurs following abnormal results of a PSA screening test or digital rectal exam (DRE). A biopsy is then taken, and if cancer is present, it can be given a Gleason grade to assess tumour size, margin status and pathologic stage . Prostate cancers metastasize most commonly to surrounding lymph nodes, bone, the lungs, and the liver . While prostate cancers can initially be treated with androgen deprivation therapy (ADT), all cancers will eventually become resistant, and are then dubbed castration-resistant prostate cancers (CRPC). This process will be discussed in the context of the AR itself later in this essay.
Ligands for the AR
Understanding the ligands for the AR gives a Testosterone and 5-dihydrotestosterone (DHT) are the main androgens activating the AR, and they are synthesised in the adrenal glands and the testes. Androgen synthesis is regulated by Gonadotropin-releasing hormone (GnRH) (also known as luteinizing hormone releasing hormone (LHRH)). GnRH is released by the hypothalamus and travels to the anterior pituitary gland via the hypophyseal portal system. This results in production of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the anterior pituitary, which enter the bloodstream. Upon reaching the testes, LH targets Leydig cells in the interstitial space, stimulating testosterone release. GnRH release from the hypothalamus also stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary, which causes the adrenal glands to synthesise and release testosterone. Testosterone displays a negative feedback loop of GnRH and LH release from the hypothalamus and pituitary gland. Several hormonal therapy treatments in advanced prostate cancer target this pathway.
Approximately 90% of testosterone is produced by the testes, and between 5-10% is produced by the adrenal glands. A portion of free testosterone is converted to DHT in prostate cells via the action of 5-alpha-reductase. DHT is a more potent form of the hormone, and has a higher affinity for the AR.
The androgen receptor
The AR is a ligand-dependent nuclear transcription factor, and is a member of the nuclear receptor family. The AR gene is located on the X-chromosome, meaning there is only one copy in males. It has displayed more mutations than any other gene, it is suggested that this is because mutation in the AR is not incompatible with life . Structurally, the AR has 4 regions: an NH2 transactivation domain (NTD) a DNA-binding domain (DBD), a ligand-binding domain (LBD), and a hinge region which connects the LBD and DBD . The ligands which act on the AR are testosterone and 5-dihydrotestosterone (DHT). They bind to the LBD of the AR in the cytosol, which causes a conformational change of the receptor, releasing the heat shock proteins which were acting as chaperone molecules, and allows translocation of the AR to the nucleolus . In the nucleus, the androgen/AR complex dimerises and the DBD binds to androgen receptor elements (AREs) via two zinc fingers, allowing the regulation of gene transcription pathways . These pathways include those responsible for cell proliferation, differentiation and anti-apoptotic pathways.
In the healthy prostate, epithelial AR supplies secretory proteins to the prostate gland, such as prostate-specific antigen (PSA). Stromal AR plays a role in the growth of the prostate.
In prostate cancer, upregulation of transcription factors leads to increased action of the AR. This leads to the promotion of growth, explaining the increased size of the prostate on DRE. It also accounts for the increased level of PSA found in the blood, allowing for its use as a biomarker of prostate cancer.
Initiation of prostate cancer can occur due to dysregulation of several pathways. These include RAS/RAF and PI3K pathways, and upregulation of the ETS family of transcription factors. The expression of the tumour suppressor PTEN is commonly lost in prostate cancer. The upregulation of ETS factors may prime the prostate epithelium to respond to upstream signals such as PTEN loss. Abnormal AR signalling promotes neoplastic growth as the balance between cell proliferation and apoptosis is lost.
A historical perspective of androgen receptor targeted therapy
The fundamental concept that prostate cancer is androgen sensitive was established by Huggins and Hodges in 1941. They established that androgen deprivation had a beneficial impact on metastatic prostate cancer outcomes. Huggins was awarded the 1966 Nobel prize in physiology or medicine for ”his discoveries concerning hormonal treatment of prostatic cancer” . Their results set the standards of care for prostate cancer: bilateral orchiectomy or administration of oestrogen.
In 1967, the Veterans Administration Cooperative Urological Research Group (VACURG) showed that orchiectomy and administration of the synthetic oestrogen diethylstilboestrol (DES) were equally efficacious in treating prostate cancer. However, DES was later associated with an increased risk of cardiovascular disease and thromboembolic events, leading to a decrease in its use .
In 1971, Schally explained the structure of GnRH and began researching synthetic agents which could act as agonists of the hormone. Increased levels of GnRH agonists lead to decreased pituitary receptors for the hormone, leading to suppression of FSH and LH. This process leads to a decrease in testosterone levels to castration-equivalent levels . Leuprolide is an example of a GnRH agonist.
Antiandrogens
Antiandrogens are a type of androgen receptor therapy. They are also known as androgen antagonists as they prevent the androgens from exerting their effects on the AR. Antiandrogens are mainly used to counteract androgens made locally in the prostate that are of adrenal origin, as testicular androgens are easily depleted by medical or surgical castration
Steroidal antiandrogens were developed before their non-steroidal counterparts. Cyproterone (CPA) was the first steroidal antiandrogen, and was used in advanced prostate cancer. It acts on the AR by competitively blocking DHT and testosterone from binding. CPA was as effective in treating advanced prostate cancer as orchiectomy and DES . Steroidal antiandrogens also displayed many unwanted side effects; mainly due to the lowering of testosterone levels which resulted in a decrease in libido and impotence. As a result of these unwanted effects, development of non-steroidal antiandrogens began.
Non-steroidal antiandrogens target the AR alone and do not display the side effects shown by CPA. First generation antiandrogens were the first to be developed. This essay will look at Flutamide was initially indicated as a bacteriostatic drug, but later trials demonstrated its antiandrogenic effects . It was first nonsteroidal antiandrogen to be approved in the United States by the FDA in 1989 for prostate cancer. Its use was combined with either chemical or surgical castration. A trial in the US administering daily flutamide along with leuprolide (GnRH agonist) to patients with newly diagnosed advanced prostate cancer resulted in a median survival increase of 36 months versus 28 months in patients treated with leuprolide alone . Side effects of flutamide include diarrhoea and anaemia, and the FDA mandated that liver enzymes be measured due to hepatotoxicity seen in some patients.
Nilutamide was shown to improve outcomes in advanced prostate cancer when used in combination with orchiectomy versus orchiectomy alone . This led to the approval of nilutamide in combination with orchiectomy or co-administration of a GnRH agonist by the FDA in 1996.
Bicalutamide is another first generation nonsteroidal antiandrogen and was first approved in the treatment of prostate cancer in 1995 which also inhibits the AR selectively. Bicalutamide has a longer half-life than the other agents, 7 days versus 6-8 hours for flutamide. Due to the increase in testosterone and oestrogen levels in bicalutamide treatment, it is associated with gynaecomastia, breast pain, impotence, and hot flashes.
With continued treatment of first generation antiandrogens in advanced prostate cancer, resistance can occur. It has been suggested that this resistance may be due to AR overexpression, or due to mutations in the LBD of the AR which can alter the response of the receptor and cause the first generation antiandrogens to act as partial agonists. As a result of these limitations, research on the second generation agents began.
Enzalutamide is an example of a second generation nonsteroidal antiandrogen. It is a selective agonist of the AR with a high affinity for the LBD. It was developed following research into antiandrogens which could still function when the AR is overexpressed, one mechanism of CRPC. When enzalutamide binds to the AR, it inhibits translocation of the receptor to the cell nucleus. This prevents the recruitment of cofactors in the AR and prevents the AR binding to DNA. It displays a 5-8 times greater affinity for the AR compared to bicalutamide, and also induced tumour shrinkage and bicalutamide only slowed tumour growth . Enzalutamide has been shown to be efficacious in treatment of advanced CRPC. The PREVAIL study found that disease progression was reduced by 81% in the enzalutamide group compared to the placebo group. When the study finished, 72% of the enzalutamide group were alive compared to 63% of the placebo group; equating to a 29% reduction in risk of death for the group size . The adverse effects seen in enzalutamide therapy include back pain, hot flushes, and most commonly, fatigue.
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