Androgen Receptor Vignette

Question 1

Body sources of Androgens relevant to Prostate Cancer (3)

Answer 1

Testes (90-95%)
Adrenal Glands (5-10%)
Cancer cells, intracrine production

Question 2

Structure of Androgen Receptor

Answer 2

8 exon protein with 919 AAs
N terminus transactivation domain
DNA binding domain
Hinge region
C terminus ligand binding domain

Question 3

AR Function

Answer 3

AR is sequestered to cytoplasm by heat shock protein blocking NLS. Binding of androgen causes Hsp dissociation and AR translocation to nucleus where it forms homodimer and binds to androgen response elements. Cofactors are recruited and gene expression occurs.

Question 4

Mechanisms of resistance to AR therapy (3)

Answer 4

AR activation via non-gonadal androgen

AR mutations causing promiscuous activation

Truncated AR with constitutively active ligand binding domain

Question 5

Abiraterone

Answer 5

Cytochrome P 17 inhibitor. Prevents global androgen production because Cyc P 17 is required by synthesis enzymes.

Question 6

Enzalutamide

Answer 6

AR antagonist with much higher binding affinity than 1st gen drugs, inhibits AR nuclear translocation, cofactor recruitment, and DNA binding.
NO partial agonist effects

Question 7

Leuprolide

Answer 7

Example of 1st gen AR antagonist