Lecture 23 - Therapy for prostate cancer

What is the prostate and where is it located?

• Accessory male sex organ

  • Secretes fluid which is a major constituent of the ejaculatory fluid  

• Located below the bladder 

What are the three zones of the prostate?

• Transition

  • Surrounds urethra

• Central

  • Surrounds ejaculatory ducts

• Peripheral

  • Encompasses transmission and central zones

Which zone do most prostate cancers arise from?

• Most prostate cancers arise in the peripheral zone 

What is the role of androgens for the prostate/prostate cancer?

• Development and growth are dependent on androgens 

  • Often prostate cancers are dependent on androgens for their growth

What is the lifetime risk of prostate cancer in men?

• ~12%

What is the lifetime risk of death by prostate cancer in men?

• ~2.5%

What are examples of established risk factors of prostate cancer?

• Age 

• Ethnic origin  

• Country of residence  

• Family history  

• Diet 

How does age play a large role in prostate cancer?

• Disease of elderly men 

• 50% of men diagnosed are over the age of 70 

• Generally, very slow growing cancers  

  • 10-15 years 

Where is the highest incidence rate of prostate cancer globally?

• Highest incidence rate, standardised to population, occurs in Western Europe and North America  

Are most prostate cancers hereditary or sporadic?

• Sporadic

What is a common cause of early-onset prostate cancer?

• I.e. in younger men

• Hereditary factors for prostate cancer due to polymorphisms/mutations

What are common polymorphism targets in hereditary prostate cancers?

• Androgen receptor (AR) 

• Vitamin D receptor  

• 5-alpha reductase  

• BRCA1/2 

What are examples of protective dietary factors against prostate cancer?

• Soya beans (phytoestrogens) 

• Vitamin E 

• Green tea 

• Lycopenes 

• Selenium (NO?) 

What are examples of negative dietary factors for prostate cancer?

• Red meats 

• Obesity  

How can the gut microbiota impact prostate cancer risk?

• Butyrate-generating Ruminococcaceae over-represented in patients with high tumour burden and aggressiveness  

  • Butyrate increases development and differentiation of intestinal regulatory T-cells, migrate to tumour site and cause local immunosuppression  

How can the gut microbiota lessen the impact of androgen deprivation therapy?

• Therapy tries to remove androgens from the body 

  • However, it has been shown that bacteria in the gut are capable of using steroids and turning them into androgens 

    • This can then help keep the cancer growing by supplying androgens

What is the structure of the prostatic duct?

• Basal cells and luminal cells surround the prostatic ducts 

  • Basal lamina membrane surrounds the cells 

What is PIN in the context of prostate cancer?

Prostatic intraepithelial neoplasia 

• Proliferation of cancerous prostate cells while still being contained by the basement membrane

• Not yet invasive

What occurs following PIN development?

• As the tumour progresses, the basement membrane begins to break down and the proliferating cells are able to break out the duct

• Can metastasise to the lymph nodes before eventually metastasising to the bones

What is the Gleason Grading System?

• Five distinct patterns of decreasing tissue differentiation

• Gleason score is calculated by summing the two most common grades seen under the microscope

  • E.g. most common cell grade is a 4 but some grade 3 cells are also seen

    • 4+3 = Gleason score of 7

Does the order of the grades added to create the Gleason score matter?

• Example: 3+4 and 4+3 both equal a score of 7

YES

• In the case of a Gleason score of 7, the order of the scores matters

• A 3+4 is generally less-aggressive whereas a 4+3 is more aggressive

What does a high Gleason score suggest?

• High score/poorly differentiated tumours have worst prognosis and increased prostate cancer-specific mortality  

What is PSA?

• Prostate Specific Antigen

  • Androgen-regulated serine protease which is produced by luminal cells in the prostate

Why is PSA a useful prostate cancer biomarker?

• PSA is prostate but not prostate cancer, specific

• Disruption of the basal cell layer/basement membrane enables PSA to enter peripheral circulation where it’s level can be measured

  • Allows detection, staging and monitoring of prostate cancer 

What are other causes of high PSA other than prostate cancer?

• Benign Prostatic Hyperplasia (BPH)

• Prostatitis

• Urinary retention

• Sexual activity  

In a normal prostate gland, what role does androgen have?

• Blood brings androgens to the prostate 

• Androgens act on the androgen receptors in stromal cells 

  • This then causes release of survival factors and growth factors  

  • These have paracrine effects on basal cells and luminal cells 

In a prostate cancer, what role does androgen have?

• The basement membrane breaks down 

• Androgen no longer acts on only stromal cells 

• Androgen can move across into the epithelium and activate luminal cells directly resulting in promotion of proliferation

What does the hypothalamus produce to initiate androgen production?

• Hypothalamus produces Gonadotropin-releasing hormone (GnRH) which acts on pituitary cells 

What does GnRH act on and what does it cause?

• GnRH acts on pituitary cells 

• The pituitary cells then secrete luteinizing hormone (LH) which travels into the blood 

• LH then acts on the testes  

  • Specifically, the leydig cells

What is the role of Leydig cells and what can act on them?

• The pituitary cells then secrete LH which travels into the blood 

  • LH then acts on the testes  

    • Specifically, the leydig cells  

• Leydig cells will produce testosterone in response to LH

What androgens are produced by the adrenal glands?

Dehydroepiandrosterone and androstenedione

• OR DHEA and A4 for simplicity

In the blood, most androgen is found in what form?

• Most androgen are bound to serum proteins 

  • E.g. sex hormone binding globulin (SHBG)

5-alpha reductase is found where in the cell?

• 5-alpha reductase is a membrane bound protein which converts testosterone to dihydrotestosterone (DHT)

What is the role of 5-alpha reductase?

• 5-alpha reductase is a membrane bound protein which converts testosterone to dihydrotestosterone (DHT)

Once testosterone is converted to dihydrotestosterone (DHT), what happens?

• DHT can the bind to androgen receptor in the cytoplasm 

  • When DHT binds, the receptor releases and undergoes conformational changes 

  • Receptor then localises to nucleus  

  • Receptor binds to androgen-regulated genes and turns on expression

When no androgen ligand is present, how is the androgen receptor found?

• When no ligand is present, the receptor is held in a complex with other proteins 

Which chromosome is the androgen receptor found on?

• X chromosome

What 4 domains make up the androgen receptor gene?

• Transactivation domain  

  • Involved in transcriptional activation 

• DNA binding domain  

  • Involved in DNA binding 

• Hinge domain  

• Ligand binding domain  

  • Involved in binding androgen ligand  

What are examples of genes commonly mutated in early prostate cancer?

• SPOP

• ERG oncogene fusion with androgen-regulated genes

What is the role of SPOP and what does its mutation cause in prostate cancer?

• Normally involved in ubiquination of certain proteins such as the androgen receptor

• When it’s mutated in prostate cancer, it can impair its ability to degrade the androgen receptor as well as other oncoproteins

What is the role of ERG and what does its fusion cause in prostate cancer?

• Normally a transcription factor critical in stem cell self-renewal and vascular development

• When it fuses with androgen-regulated genes, it can be over expressed

  • Plays a role in activating oncogenic signalling, promoting cell invasion and promoting epithelial-to-mesenchymal transition (EMT)

What are examples of mutations commonly seen later in prostate cancer development?

• TP53

• MYC

• Androgen receptor

What is Castrate resistance disease?

• Refractory to castration therapy from outset 

• Cancer acquires resistance to castration therapy and AR antagonist therapy 

What are common aberrations in androgen receptor pathway which allows cancers to gain castrate resistance?

• Many have amplification of androgen receptor  

• ~20% have alteration of ligand binding site 

• Some have mutations in proteins involved in androgen receptor signalling rather than the receptor itself 

  • Knockout of co-repressors of the androgen receptor 

What is androgen receptor amplification?

• Excessive expression of the androgen receptor which can make the cancer cell hypersensitive to androgen ligands.

How can mutations in the androgen receptor cause increased activation of the receptor?

• Promiscuous pathway 

  • Mutations in the binding domain can allow it to be activated by numerous other steroids alongside androgens 

How can the androgen receptor be activated independent of steroids?

• Outlaw pathway 

  • Can allow for activation of other signalling pathways (e.g. growth factor receptor) which causes activation of androgen receptor  

  • PI3K and MAPK can phosphorylate the androgen receptor and keep it activated 

    • No androgen ligand binding needed 

Why is castration a common intervention for prostate cancer?

• Castrate men to take away the main source of androgens  

  • In the past, surgical castration was performed 

  • More recently, chemical castration is performed  

    • Can block the production of androgens by the testes  

How do anti-androgens work?

• Can bind to the androgen receptor binding domain which competitively inhibits and blocks activation of the androgen receptor 

What is Abiraterone?

• Hormone therapy used to treat high-risk metastatic prostate cancer

• Binds to the CYP17 enzyme and blocks activity

  • This enzyme is involved in activation of adrenal gland androgens

  • Blocks androgen production

What three broad groups are prostate cancer patients staged into?

• Localised

• Locally advanced

• Metastatic

What is the common clinical management of patients characterised as ‘Localised’?

• Observation

  • Observe the tumour every so often to track progress

• Curative

  • Surgery (removal of the prostate)

  • Radiotherapy

  • Adjuvant hormone ablation therapy

Why are localised prostate cancers often only observed and not treated?

• As many patents are old, they may die before the tumour becomes an issue 

  • Many tumours are slow growing 

What is the common clinical management of patients characterised as ‘Locally advanced’?

• Surgery + neoadjuvant hormone ablation therapy 

• Radiotherapy + hormone ablation therapy 

• Hormone ablation therapy 

What is the common clinical management of patients characterised as ‘Metastatic’?

Patients placed on palliative care and given treatments like:

• Hormone ablation therapy 

• Chemotherapy 

• Radiotherapy 

• Bisphosphonates  

What are Bisphosphonates?

• Medications which preferentially bind to bone surfaces undergoing active remodelling  

  • Inhibit osteoclast maturation and suppress osteoclast function  

  • Inhibit osteoclast recruitment  

  • Inhibit tumour cell invasion and adhesion  

What are the future research directions for prostate cancer?

• Anti-androgens extend survival, but resistance can develop 

  • Chemoprevention 

  • Earlier detection  

  • Better staging 

  • New prognostic indicators 

  • New therapies 

  • Immunotherapy