Androgen receptor

Question 1

3 Sources of Androgen in the body

Answer 1

1. Testis: 90-95% of systemic T
2. Adrenal glands: 5-10% of systemic T
3. Intracrine androgen production in prostate cancer cells themselves

Question 2

What is the key to testosterone production?

Answer 2

CYP 17

-blocking this cytochrome blocks T production from all 3 sources.

Question 3

Structure of androgen receptor gene and protein

Answer 3

AR gene has 8 exons with 919 amino acids

4 structural parts to protein:

1. N-terminus transactivation domain (NTD)
2. DNA binding domain (DBD)
3. Hinge region
4. C-term ligand binding domain (LBD)

Question 4

Stepwise Function of androgen receptor

Answer 4

1. Inactivated AR in cytoplasm
2. Ligand (androgen/testosterone) binds
3. Inhibitory chaperones dissociate and AR moves to nucleus (KEY)
4. AR homodimerizes
5. AR recruits co-activators and gene expression (txn) occurs

Blocking any of the 4 steps can prevent step 5: txn

Question 5

2 methods of Hormonal therapy in prostate cancer

Answer 5

reduce testosterone by :
1. blocking receptor activity with an anti-androgen
or
2. target the 3 main sources of androgen themselves

3. Unlikely option: cut the dick off

Question 6

Mechanism of resistance to traditional endocrine therapy for prostate cancer

Answer 6

1. AR activation via non-gonadal testosterone
2. Overexpression of AR
3. AR mutation leading to promiscuous AR activation
4. Truncated form of AR, with constitutive activation of the ligand binding domain

(hyperactive AR!)

Question 7

Enzalutamide

-what is it and 3 of its function

Answer 7

“New gen” androgen receptor antagonist:

1. inhibit nuclear translocation of T
2. inhibits co-activator recruitment
3. inhibits DNA binding AR

Question 8

abiraterone

Answer 8

CYP17 inhibitor and along with standard hormonal therapy, it can reduce systemic testosterone levels to near 0

Question 9

Ketoconazole

Answer 9

Treats fungal infections.

- also suppresses adrenal production

Question 10

bicalutamide, flutamide

Answer 10

The “lutamides”

anti-androgen: binds to AR and prevents activation by competing with agonists

Question 11

Flutamide

Answer 11

anti-androgen; blocks the receptor

not terribly efficient

Question 12

Definition of hormone-refractory prostate cancer

Answer 12

<50 ng/dl of testosterone

2-ary hormone maneuvers such as anti-androgens and ketoconazole

Question 13

what is a potent inhibitor of CYP17?

Answer 13

abiraterone