Prostate cancer SD Flashcards
where is the location of the prostate gland?
The prostate gland surrounds the neck of the
bladder and urethra, weighs about 20g and is
enclosed in a fibrous capsule
what are the 3 zones of the prostate gland?
*The peripheral zone accounts for 70%
*The transition zone 5%
*The central zone 25%.
what zone in the prostate generally enlarges with age?
The transition zone gradually enlarges with
age
what zone of the prostate gland does cancer mostly arise from?
peripheral zone
what is the prostates function?
part of the male reproductive system
*Major role in seminal fluid production
what surrounds the prostate?
fibro-muscular stroma
–Muscular contraction during ejaculation
This contains a thick sheet of connective tissue and a layer of smooth muscle surrounding the entire prostate gland.
where does testosterone bind on the androgen receptor?
in the ligand binding domain
what does 5ar convert testosterone to?
diHydro testosterone
what does most prostatic diseases cause and result in?
cause enlargement of the prostate,
–Compression of the intraprostatic portion of the urethra
–Impaired urine flow
–Increased risk of urinary infections
–Acute retention of urine requiring urgent relief by catheterisation.
what are the 3 major prostate pathologies?
prostatitis, BPH, prostatic carcinoma
how does genetics increase your chances of developing prostate cancer?
A family history of the disease is relevant: 2-3 fold risk if a first-degree relative was diagnosed with PCa under 50 years of age.
what race are most at risk of prostate cancer?
3 fold risk for African or Caribbean men compared to caucasian; the risk in
China and Japan is lower.
how do you diagnoise prostate cancer?
digital rectal examination
what are advantages and disadvantages oof DRE?
Immediate, very quick, cheap test, once a mass is identified additional tests can occur
Downside - Mass has already reached certain size to be detected by touch
what is PSA?
Prostate Specific Antigen (PSA)
Blood Test
PSA is a 34 kDa serine protease (KLK3 gene) primarily produced by the prostatic ductal epithelium – AR REGULATED GENE
what would an abnormal PSA show?
Abnormal prostate - Increased AR = increased PSA
what can PSA levels be affected by?
Prostate Biopsy, DRE, Ejaculation, BPH, Prostatitis, intense exercise
how is PSA measured? what are the limits?
Measured in serum which usually has an upper limit set at 3-4 ng/ml for
normal serum PSA.
what is the main purpose of PSA?
We use PSA to monitor effectiveness of treatment – “is the drug working?”
what are the limitations of PSA?
20% of patients missed
PSA levels could be raised by BPH or urinary tract infection
what is TRUS?
Trans Rectal Ultra Sonography (TRUS) / Biopsy
Follow up from positive DRE and PSA test
*Ultrasound allows imaging of prostate
what is the gleason grade?
For stratifying prostate cancer
the most common grade of the cells in a tissue sample may
be grade 3 cells, followed by grade 4 cells.
what does prostatic bone metastases often present as?
as localised
bone pain, back pain from vertebral
metastases being a common initial
manifestation of the tumour.
when may some patients decide to do waitful watching?
where some cancer do not progress/ spread- they have been growing very slowly
willl be monitored closely for changes
if the situation changes then treatment can begin
what are the ways of removing the prostate?
Keyhole surgery by hand – surgeon makes five or six small incisions and
removes the prostate using a thin, lighted tube with a small camera on the
tip and special surgical tools
*Robot-assisted surgery – surgeon uses three robotic arms (one for the
camera and two for the surgical tools) to do the operation. The ‘Da Vinci®
Robot’.
how is prostate surgery done by the da vinci robot?
Complex blood vessels and nerves surround the prostate
*Less infection, blood loss, faster healing, Less time in hospital
*Freeman and Sunderland Royal both now have these systems
what is androgen deprivation therapy?
LHRH agonists (Chemical Castration)
Luteinizing hormone-releasing hormone
(LHRH) agonists are drugs that lower the
amount of testosterone made by the
testicles.
*E.g. Zoladex
how does zoladex work?
Goserelin is a synthetic decapeptide hormone analogue of LHRH.
–The continuous agonist presence leads to DECREASED levels of LHRH
Receptor levels on pituitary gland
how does casodex work?
Potent AR inhibition
*Leads to tumour shrinkage
Binds AR directly
–AR STILL ENTERS THE NUCLEUS
–Casodex prevents gene transcription
what does casodex lower?
Does NOT lower testosterone levels – blocks AR
what are prostate cancer cells driven by?
androgens
what is a resistance mechanism or CRCP?
Ligand Binding Domain mutation – resistance mechanism
what does the ligand binding domain mutation allow?
Allows OTHER hormones to bind to AR: allows multiple agonists to activate
AR
–Oestrogens, Progesterone, Glucocorticoids
–Antagonists can become AGONISTS…. E.g. 1st gen anti-androgen
flutamide became a strong agonist with T877A mutation
–T877A Allows conformational change of the receptor to activate genes
what is taxanes/ docetaxal used for?
commonly used for
men with advanced prostate cancer.
after relapse what can cells becoeme resistant to?
bicalutamide
when is enzalutamide reserved for?
patients with metastasis, CRPC disease
how does enzalutamide work?
enzalutamide inhibits AR- testosterone binding with higher affinity than bicalutamide
this inhibition blocks the change induced by AR-testosterone binding
it inhibits AR-testosterone nuclear transloactionand DNA transcription
it lacks partial AR agonist activity that occurs with bicalutamide resistance
what does Abiraterone do?
it prevents testosterone biosynthesis
what is the MOA of abiraterone?
inhibits CYP17 (effects 17-
hydroxylase/lyase activity) which
prevent conversion of progestens to
androgens = No substrate for AR
Decreases cortisol ACTH is activated
Increased mineralocorticoids
Treat with prednisone/dexamethasone
to lower ACTH
what are AR variants resistant to?
Resistant to ADT, Enzalutamide & Abiraterone
what do AR variants lead to?
Lead to enhanced migratory capacity,
invasiveness, elevated resistance to apoptosis
how do AR variants work?
Works Independent of testosterone (No LBD)
