Androgen Receptor

Question 1

What are the 3 sources of androgen in the body as they relate to prostate cancer?

Answer 1

Testes (90-95%)
Adrenal glads (5%)
Intracrine androgen production in prostate cancer cells themselves

Question 2

What is the structure/ function of the androgen receptor?

Answer 2

AR is cytoplasmic protein bound to hsp

• when AR binds testosterone -> hsp dissociates and AR enters nucleus
• AR homodimerizes -> binds to androgen responsive elements of DNA
• AR recruits co-activaors -> gene expression occurs

Question 3

How can prostate cancers become resistant to hormone therapy?

Answer 3

1. AR activated via non-gonadal testosterone
   (t from adrenals/ cancer cells enough to maintain activation)
2. Overexpression of AR
3. AR mu leads to promiscuous activation
   (more than just t activates)
4. Trunicated form of AR - constitutive activation

Question 4

How does abiraterone affect advanced prostate cancer?

Answer 4

Inhibits CYP17 (at 2 points)
- blocks ALL testosterone production
=> build up of precursors
(logarithmically) & testosterone to below detectable levels

• statistically significant improvement in survival
• improved quality of live

SE:

• hypokalemia
• edema
• hypertension

Question 5

How does enzalutamide affect advanced prostate cancer?

Answer 5

5-8x greater affinity for AR binding

• inhibits nuclear translocation
• inhibits co-activator recruitment
• inhibits DNA binding of AR
• Statistically significant improvement in survival
• improved quality of life

50-90% decline in PSA

Increased reported side effect w/ placebo v. drug (natural disease progression?)