Lecture 12- therapy resistance

Question 1

Describe prostate cancer

Answer 1

most common cancer in men
invariably driven by androgen receptor (AR)
standard treatment for 70 yrs has been androgen deprivation therapy (chemical or surgical castration)
e.g. abiraterone inhibits androgen synthesis
anti-androgens bind ligand-binding domain (LBD) of AR & prevents its actn e.g. enzalutamide
Surgical castration often preferred over chemical because it has less side effects
In response to androgens such as testosterone AR enters nucleus dimerises and activates Target genes including MYC
Androgen deprivation standard approach

Question 2

Describe the mechanisms that lead to CRPC

Answer 2

multiple mechanisms can cause progression to castration resistance
AR locus is often amplified in CRPC or sometimes just an enhancer region that stimulates transcription of AR gene
AR overexpression allows response to low residual androgen levels that persist during hormonal therapy
splice site mutations sometimes generate constitutively active AR variants with no ligand-binding domain (LBD)

Question 3

Explain how PROTACs Have Potential for CRPC

Answer 3

Proteolysis-targeting chimera (PROTAC) drugs recruit ubiquitin ligases to target proteins to catalyze their proteosomal degradation
E.g. ARV-771 uses VHL ubiquitin ligase to destroy BRD4

Lowers BRD4 & suppresses expression of MYC in mice with CRPC xenografts

Note heterogeneity of response between individual mice – a major challenge

PROTAC targeting Androgen Receptor entered clinical trials in 2020 – may counteract AR overexpression

Question 4

Explain how GR Induction Can Allow AR Bypass in CRPC

Answer 4

AR binds & represses gene encoding glucocorticoid receptor (GR)
AR inhibition by hormonal therapy releases GR from repression
high GR levels are often observed in metastatic CRPC & correlate with more rapid relapse
glucocorticoids are given to CRPC patients to suppress nausea, inflammation & expression of adrenal androgens
GR binds & activates many AR target genes, bypassing therapies that target AR
ongoing clinical trial combining GR inhibitor with AR inhibitor enzalutamide