Wk 13: Prostate cancer

Question 1

What is the role of the prostate?

Answer 1

• Male reproductive system
• Seminal fluid prod

Question 2

Which part of the androgen receptor does testosterone bind to?

Answer 2

Ligand binding domain

Question 3

What happens due to enlargement of the prostate?

Answer 3

• Compression of intraprostatic portion of urethra
• Impaired urine flow
• Inc risk of urinary infections
• Acute retention of urine: urgent relief via catheterisation

Question 4

What are the 3 major pathologies of prostate cancer?

Answer 4

• Prostatitis (infection)
• Benign prostatic hyperplasia (enlargement w/ age)
• Prostatic carcinoma (cancer)

Question 5

What is used to treat urinary problems caused by an enlarged prostate?

Answer 5

Trans urethral resection of the prostate (TURP)

Question 6

What are the risk factors of prostate cancer?

Answer 6

• Age
• Genetic: 1st degree fam diagnosed before 50
• Race: african/caribbean
• Diet: red meat inc, soya protective

Question 7

What are the advantages/disadvantages of digital rectal examination?

Answer 7

+ Quick, very cheap

• Embarrassment, mass already reached certain size to be detected

Question 8

What is prostate specific antigen - PSA?

Answer 8

34 kDa serine protease prod. by prostatic ductal epithelium

Question 9

Levels of PSA can be affected by what?

Answer 9

• Prostate biopsy
• DRE
• Ejaculation
• BPH
• Prostatitis
• Intense exercise

Question 10

What is used to monitor effectiveness of a drug?

Answer 10

PSA levels

Question 11

What are the limitations of PSA?

Answer 11

Raised levels may not be due to prostate cancer - benign prostatic hyperplasia/prostatitis/urinary infection

Question 12

What is followed by a positive DRE + PSA test?

Answer 12

Transrectal ultrasonography (TRUS)/biopsy

• Allows for imaging
• Highly invasive
• Frustrating if false positive

Question 13

How is the gleason score determined?

Answer 13

Adding 2 most typical grades

Question 14

How is bone metastases often presented as?

Answer 14

Localised bone pain + back pain from vertebral metastases

Question 15

What are the ways of removing the prostate surgically?

Answer 15

• Keyhole surgery by hand
• Robot assisted surgery

Question 16

What is the keyhole surgery?

Answer 16

• 5-6 small incisions
• Remove prostate using thing, lighted tube w/ small camera

Question 17

What is the robot assisted surgery?

Answer 17

• Surgeon uses robotic arm
• Less infection + blood loss, faster healing + less time in hospital

Question 18

What are the consequences of surgically removing the prostate?

Answer 18

Infertility, erectile dysfunction, impotence + urinary incontinence

Question 19

What is used for first line LHRH agonist?

Answer 19

Goserelin (zoladex)

Question 20

What is the mechanism of action of goserelin (zoladex)?

Answer 20

• Initially: causes inc LH + testosterone (testosterone flare)
• Constant inc: pituitary gland gets rid of LHRH receptor
• Shuts down LH —> shuts down testosterone production

Question 21

What is used as an AR inhibitor?

Answer 21

Casodex (bicalutamide):

• Doesn’t lower testosterone levels - blocks AR
• Greater dec in PSA + tumour shrinkage

Question 22

What is the mechanism of action of casodex (bicalutemide)?

Answer 22

• Binds directly to AR
• AR still enters nucleus
• Casodex prevents gene transcription

Question 23

What is castrate resistant prostate cancer?

Answer 23

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)

Question 24

What are the 3 mechanisms for castrate resistant prostate cancer?

Answer 24

• Hypersensitive: to small amounts of testosterone
• Promiscuous: don’t need testosterone
• Outlaw: activated by other activating pathways

Question 25

What is used for advanced prostate cancer?

Answer 25

Docetaxel (Taxotere) w/ prednisolone

• targets cell division + microtubules

Question 26

What are the side effects of docetaxel (taxotere)?

Answer 26

• Neutropenia
• Anaemia
• Hair loss
• Fluid retention
• Di + nausea
• Finger nail changes

Question 27

What medication is used for metastasis + CRPC?

Answer 27

Enzalutamide + abiraterone (w/ pred)

Question 28

What are the mechanisms of action of enzalutamide?

Answer 28

• 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

Question 29

What is the mechanism of action of abiraterone acetate (zytiga)?

Answer 29

• Prevents progesterone -> testosterone
• Inhibits CYP17 - preventing conversion of progestens to androgens

Question 30

Why is abiraterone given with prednisolone/dexamethasone?

Answer 30

Abiraterone causes mineralcorticoid excess

• Dec cortisol -> ACTH activated
• Inc mineralocorticoids

Question 31

What is an androgen receptor variants?

Answer 31

Some advanced patients don’t have ligand binding domain - AR drugs unable to bind + don’t need testosterone to activate

Question 32

The emergence of AR variants in prostate cancer poses a huge clinical challenge. Why?

Answer 32

• AR-V7 resistent to enzalutamide + abiraterone
• AR-V7 lacks LBD that testosterone + ADT therapies bind to