Wk 13: Prostate cancer Flashcards
What is the role of the prostate?
- Male reproductive system
- Seminal fluid prod
Which part of the androgen receptor does testosterone bind to?
Ligand binding domain
What happens due to enlargement of the prostate?
- Compression of intraprostatic portion of urethra
- Impaired urine flow
- Inc risk of urinary infections
- Acute retention of urine: urgent relief via catheterisation
What are the 3 major pathologies of prostate cancer?
- Prostatitis (infection)
- Benign prostatic hyperplasia (enlargement w/ age)
- Prostatic carcinoma (cancer)
What is used to treat urinary problems caused by an enlarged prostate?
Trans urethral resection of the prostate (TURP)
What are the risk factors of prostate cancer?
- Age
- Genetic: 1st degree fam diagnosed before 50
- Race: african/caribbean
- Diet: red meat inc, soya protective
What are the advantages/disadvantages of digital rectal examination?
+ Quick, very cheap
- Embarrassment, mass already reached certain size to be detected
What is prostate specific antigen - PSA?
34 kDa serine protease prod. by prostatic ductal epithelium
Levels of PSA can be affected by what?
- Prostate biopsy
- DRE
- Ejaculation
- BPH
- Prostatitis
- Intense exercise
What is used to monitor effectiveness of a drug?
PSA levels
What are the limitations of PSA?
Raised levels may not be due to prostate cancer - benign prostatic hyperplasia/prostatitis/urinary infection
What is followed by a positive DRE + PSA test?
Transrectal ultrasonography (TRUS)/biopsy
- Allows for imaging
- Highly invasive
- Frustrating if false positive
How is the gleason score determined?
Adding 2 most typical grades
How is bone metastases often presented as?
Localised bone pain + back pain from vertebral metastases
What are the ways of removing the prostate surgically?
- Keyhole surgery by hand
- Robot assisted surgery
What is the keyhole surgery?
- 5-6 small incisions
- Remove prostate using thing, lighted tube w/ small camera
What is the robot assisted surgery?
- Surgeon uses robotic arm
- Less infection + blood loss, faster healing + less time in hospital
What are the consequences of surgically removing the prostate?
Infertility, erectile dysfunction, impotence + urinary incontinence
What is used for first line LHRH agonist?
Goserelin (zoladex)
What is the mechanism of action of goserelin (zoladex)?
- Initially: causes inc LH + testosterone (testosterone flare)
- Constant inc: pituitary gland gets rid of LHRH receptor
- Shuts down LH —> shuts down testosterone production
What is used as an AR inhibitor?
Casodex (bicalutamide):
- Doesn’t lower testosterone levels - blocks AR
- Greater dec in PSA + tumour shrinkage
What is the mechanism of action of casodex (bicalutemide)?
- Binds directly to AR
- AR still enters nucleus
- Casodex prevents gene transcription
What is castrate resistant prostate cancer?
Ligand binding domain mutation
- Allows other hormones (oestrogen, progesterone + glucocorticoid) to bind to AR
- No longer requires testosterone to activate AR
- Antagonist become agonist (inc cancer cells)
What are the 3 mechanisms for castrate resistant prostate cancer?
- Hypersensitive: to small amounts of testosterone
- Promiscuous: don’t need testosterone
- Outlaw: activated by other activating pathways
What is used for advanced prostate cancer?
Docetaxel (Taxotere) w/ prednisolone
- targets cell division + microtubules
What are the side effects of docetaxel (taxotere)?
- Neutropenia
- Anaemia
- Hair loss
- Fluid retention
- Di + nausea
- Finger nail changes
What medication is used for metastasis + CRPC?
Enzalutamide + abiraterone (w/ pred)
What are the mechanisms of action of enzalutamide?
- Inhibit AR testosterone binding + has higher affinity than casodex
- Blocks activational change induced by AR testosterone binding
- Inhibits nuclear translocation + DNA transcription
- Lacks partial AR agonist activity tf avoids mutations
What is the mechanism of action of abiraterone acetate (zytiga)?
- Prevents progesterone -> testosterone
- Inhibits CYP17 - preventing conversion of progestens to androgens
Why is abiraterone given with prednisolone/dexamethasone?
Abiraterone causes mineralcorticoid excess
- Dec cortisol -> ACTH activated
- Inc mineralocorticoids
What is an androgen receptor variants?
Some advanced patients don’t have ligand binding domain - AR drugs unable to bind + don’t need testosterone to activate
The emergence of AR variants in prostate cancer poses a huge clinical challenge. Why?
- AR-V7 resistent to enzalutamide + abiraterone
- AR-V7 lacks LBD that testosterone + ADT therapies bind to
