Androgen Receptors Clinical Vignette

Question 1

1. Identify the sources of androgen in the body relevant to prostate cancer.

Answer 1

• Prostate cancer = most common cancer in men, ~30,000 die/year.
• Mainstay of management for PCA = hormonal therapy targeting the AR to decrease testosterone levels.
• Previously tried castration and ketoconazole, GNRH agonists, anti-androgens –> not as effective.
• Three main sources of androgen in the body:
• Testis (90-95%)
• Adrenal glands (5-10%)
• Intracrine androgen production from the prostate cancer cells themselves.
• Testis + adrenal glands = systemic sources.

Question 2

2. Describe the structure and function of the androgen receptor in prostate cancer.

Answer 2

-AR gene has 8 exons and 919 amino acids.

4 structural parts:

• N-terminus transactivation domain (NTD)
• DNA binding domain
• Hinge region
• C-terminus ligand binding domain (LBD)
• AR is in the cytoplasm in the absence of androgen.
• When testosterone arrives, binds the AR (and inhibitory Hsp chaperones dissociate from AR).
• Testosterone + AR go to nucleus.
• AR undergoes homodimerization and binds the androgen response elements of DNA –> recruits co-activators –> gene expression.

-So there’s a lot of steps in the process drugs can target, but the most popular target is preventing testosterone from binding AR in the first place.
-We like AR-antagonists that block testosterone’s access (competitive).
EX) Flutamide, bicalutamide = 1st gen antagonists.

Question 3

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

Answer 3

Resistance to hormone therapy can happen various ways:

• AR activation via non-gonadal testosterone (like from adrenals):
• Overexpression of AR
• AR mutation causing promiscuous AR activation
• Truncated form of AR with constitutive activation of LBD

-Cytochrome P = key player in androgen production.

Abiraterone:

• Specific/potent inhibitor of CYP17 –> blocks testosterone production.
• Actually fantastic at reducing testosterone levels.
• Unfortunate side effects include:
• hypokalemia
• edema
• HTN (probably due to excess production of mineralcorticoid, a precursor molecule in the testosterone synthesis pathway. By blocking testosterone, we get excess precursors).

Enzalutamide (MDV3100):
-Targets the AR directly with new generation anti-androgens –> It has 5-8x greater affinity for AR binding than bicalutamide.
Works by:
-Inhibiting the nuclear translocation of AR,
-Can inhibit co-activator recruitment
-And inhibits DNA binding of AR.
-It has no known partial agonist properties; tries to block testosterone from binding AR (so it doesn’t actually decrease levels of testosterone).
Very robust response!