Androgen Receptors Vignette

Question 1

1. Identify the sources of androgen in the body relevant to prostate cancer.
2. Describe the structure and function of the androgen receptor in prostate cancer.
3. Describe the mechanisms of resistance to traditional endocrine therapy for prostate cancer, including enzalutamide and abiraterone’s effect on these mechanisms.

Answer 1

x

Question 2

docetaxel

Answer 2

Microtubule targeted agent (chemo)

Question 3

Lupron

Answer 3

Testosterone sequestering agent.

Question 4

PSA =

Answer 4

Prostatic Specific Antigen

Question 5

PSA test good as a ______ mediocre as a ______.

Answer 5

Tumor marker; screening test

Question 6

4 structural parts to the Androgen Receptor protein/gene

Answer 6

Has 8 exons, 919 AA length
– N‐terminus transactivation domain (NTD) 
– DNA binding domain (DBD)
– Hinge region
– C‐terminus ligand binding domain (LBD)

Question 7

Describe the lifecycle of the Androgen Receptor (AR) protein.

Answer 7

AR is localized in the nucleus and bound to an inhibitory HSP chaperone. Upon binding of androgen ligant (DHT or T), receptor relocates to nucleus. There it homodimerizes with a second AR/T protein which recruits co-activators and transcription commences.

Question 8

3 sources of T

Answer 8

1) 90-95% from the testicles (systemic ie blood draw)
2) 5-10% from the adrenal glands
3) Intracrine androgen production (prostate cancer cells themselves make T)

Question 9

How to reduce testosterone?

Answer 9

1) Surgical orchiectomy or
2) medical castration (e.g. leuprolide)
3) Block receptor activity with an anti‐androgen (e.g. bicalutamide)

Question 10

Mechanisms of resistance to hormone therapy in PCA (4)

Answer 10

1. AR activation via non‐gonadal testosterone [adrenal glands increase expression]
2. Overexpression of AR [cells adapt to low T levels]
3. AR mutation leading to promiscuous AR activation [aren’t very common, but receptor can signal w/o T]
4. Truncated form of AR, with constitutive activation of the ligand binding domain [ligand binding domain is missing, AR is constitutively activated]

Question 11

What is the importance of Cytochrome C 17 (CYP 17)? What drug targets this?

Answer 11

CYP 17 plays a key role in androgen production. If you can block it, you will shut town T production from all three sources.

Abiraterone is a specific and potent inhibitor of CYP 17

Question 12

What is the combined effect of Abiraterone and leuprolide?

Answer 12

Testosterone drops nearly to 0. Down to 7 on leuprolide alone. [normal levels 250-600]

Question 13

Enzalutamide

Answer 13

Has 5‐8 fold great affinity than bicalutamide for
AR binding.
– Inhibits nuclear translocation
– Inhibits Co‐activator recruitment 
– Inhibits DNA binding of AR

Question 14

Describe the mechanisms of resistance to traditional endocrine therapy for prostate cancer, including enzalutamide and abiraterone’s effect on these mechanisms.

Answer 14

“The real benefit we see here is removal of the secondary source of testosterone (cell production and adrenal)”

Patients who lack ligand binding domain on AR, none of the drugs work. That’s a key part of the resistance.