Hormone-dependant cancers: Prostate cancer Flashcards
main function of the prostate
produce prostatic fluid that creates semen when mixed with the sperm produced by the testes.
What type of gland is a prostate gland
an EXOCRINE GLAND
what are the phases of Prostate gland development
hormone-independent from embryonic development up to puberty
enlargement during puberty
hormone-dependent maintenance thereafter in adulthood
And – reactivation of prostate growth in old age – leading to hyperplasia and prostate cancer
Development of Prostate Abnormalities
Inflammation, e.g. due to infection
- Prostatitis - linked to infertility
Dysregulated growth of prostate
- Benign: Benign Prostatic Hyperplasia (BPH)
- Malignant: Prostate Cancer
Symptoms of Prostate abnormalities (including cancer)
- frequent trips to urinate
- poor urinary stream
- urgent need to urinate
- hesitancy whilst urinating
- lower back pain
- blood in the urine (rare)
Where does prostate cancer start?
Detecting Prostate Cancer
Digital rectal examination (DRE)
PSA test (Blood sample: antibody-based assay )
Ultrasound
Describe the Prostate Cancer staging
N+: Tumour in lymph nodes
N0 =. No cancer cells found in any lymph nodes
N1 = 1 positive lymph node < 2cm across
N2 = >1 positive lymph node or 1 between 2-5cm across
N3 = Any positive lymph node > 5 cm across
M+: Metastatic (has the cancer metastasised)
M1a = Non-regional lymph nodes
M1b = bones
M1c = Other sites
Histology of Prostate Cancer
Loss of glandular structure / irregular structure
Prostate Cancer Grading
TheGleason grading systemis used to help evaluate theprognosisof men using prostate biopsy samples.
The samples are examined by a clinical histologist.
Prostate cancer staging predicts prognosis and helps guide therapy.
Cancers with a higher Gleason score are more aggressive and have a worse prognosis.
Prostate cancer treatments
- “Watchful waiting” = Low grade tumour, older patients
- Radical prostatectomy = Stage T1 or T2 (confined to prostate gland)
• Radical radiotherapy = External up to T3 (spread past capsule) Internal implants (brachytherapy) for T1/2
• Hormone therapy = Metastatic prostate cancer
Current Therapies for Prostate Cancer
Watchful weighting
For older men when
unlikely cancer will affect their natural lifespan.
If the cancer is in its early stages and not causing symptoms, you may decide to delay treatment and wait to see if any symptoms of progressive cancer develop.
Active surveillance
Aims to avoid unnecessary treatment of harmless cancers while still providing timely treatment for men who need it.
Active surveillance involves having regular PSA tests, MRI scans and sometimes biopsies to ensure any signs of progression are found as early as possible.
Risk Factors for Prostate Cancer
Age Race / ethnicity Geography Family History Gene Changes / Inherited
Other general risk factors
Diet - Men who eat a lot of dairy products
Obesity -obese men have a lower risk of getting a low-grade (slower growing) form of the disease, but a higher risk of getting more aggressive (faster growing) prostate cancer.
Chemical exposures
Inflammation of the prostate - Prostatitis (inflammation of the prostate gland)
Sexually transmitted infections - they can lead to inflammation of the prostate.
Prostate Cancer Gene Mutations
There are several genes associated with prostate cancer
e.g. BRCA1 mutations and PTen loss
Men with lynch syndrome
PTen
PTEN is a phosphatase that antagonizes the phosphatidylinositol 3-kinase signalling pathway.
As PTEN is the only known 3′ phosphatase counteracting the PI3K/AKT pathway.
Loss of PTen results in increased growth factor signalling.
TMPRSS2 – ERG fusion
TMPRSS2-ERG fusion gene is the most frequent, present in 40% - 80% of prostate cancers in humans.
What does the growth and development of the prostate gland depend on…
- the presence of androgens (male hormones).
- The most common is testosterone (produced in the testes)
Histology of Prostate gland
Brown staining for Androgen Receptor expression in the luminal epithelial cells
Androgen Receptor (AR) signalling
AR is located in the cytoplasm associated with many chaperone proteins.
Testosterone is converted to a more potent agonist as it crosses into the prostate
Dihydrotestosterone (DHT) then binds the AR by an enzyme
It then binds the AR with a high affinity, causing the AR to be activated and dimerised.
The AR translocates into the nucleus to bind Androgen response element in the DNA sequence. It recruits co-activators
This will lead to target protein generation and thus cell growth.
Targeting AR in Prostate Cancer
The prostate gland is an androgen sensitive and dependent tissue
Prostate cancer cells retain this sensitivity and dependency – androgens are a key driver of prostate cancer growth.
Therefore, this can be used as an inherent vulnerability that can be exploited for treatment.
Switch off AR signalling, switch off the the cancer growth.
AR targeting is the “Achilles Heel” of prostate cancer.
Inhibition of Testosterone Synthesis
The adrenal androgen production can be inhibited, thus depriving the testes of testosterone precursors.
Abiraterone-(acetate)
Can inhibit the two main enzymes required to make androgens
What is the control of hormone production? (testosterone)
GnRH secreted from hypothalamus triggers pituitary to release FSH and LH which circulate in the blood to reach testes to stimulate more testosterone. The hypothalamus is sensitive to testosterone levels and will secrete more if insufficient levels – Feedback loop.
Synthetic peptides interrupt the hypothalamic-pituitary axis.
Goserelin – super agonist
Abarelix – antagonist
Overall the actions of superagonists and antagonists are similar – they depress testosterone production in the testes
Inhibition of Testosterone Conversion to DHT
Agent can be used to interrupt conversion from Testosterone à DHT. This agent is called Finasteride or Dutasteride (Avodart).
Finasteride resembles an androgenic intermediate which can be used to inhibit 5 alpha-reductase enzyme and stop DHT production.
More commonly 5 alpha-reductase inhibitors are used for Benign Prostate Hyperplasia (BPH).
Competitive inhibitors of androgen binding to the receptor
Competitive anti-androgens / androgen blockers
Compete for active site
Bicalutamide
Enzalutamide
Flutamide
Nilutamide
Why do hormone therapies for cancer over time fail?
Homogenous cancer cells develop various mechanisms to overcome hormonal starvation.
Mechanism #1 Hormone overproduction / or local synthesis
Some breast and prostate advanced tumour start to synthesise their own steroid hormones.
Mechanism #2 - Ligand binding site mutations
Ligand binding site mutations make the receptors promiscuous
allows other hormones to bind
Mechanism #3 - Receptor Amplification
Signal amplification, and increased sensitivity to low hormone levels
Mechanism #4 - Receptor phosphorylation / activation in the absence of ligand
Cross over with other signal pathways e.g. growth factors can phosphorylate and activate receptors
- Prevalent for breast cancers
Mechanism #5 - Androgen Receptor transcript variants: activation in the absence of ligand
e.g.
AR – variant 7 (V7)
Truncated AR without
C terminus
Active without ligand in prostate cancer
Mechanism #6 - Receptor bypass – unknown mechanisms
Possible switch to
Other transcription factors, or oncogenes
Mechanism #7 - Receptor cofactor amplification
Cofactor amplification can amplify the signal from steroid receptors in response to a low level of steroid hormone.
Mechanism #8 - Antagonists become agonists via LBD mutations
Antagonists used for prostate cancer treatment can become potent activators of a mutant androgen receptor.
