Prostate Cancer Flashcards
(20 cards)
Primary symptom of prostate cancer
Problems with urination
Where do prostate adenocarcinomas arise?
Luminal epithelial cells
Basal epithelial layer is absent
Component in fluid which is useful to detect
Prostate specific antigen (PSA)
Hormone driven development of prostate
Sertoli cells= secrete anti mullerian hormone, mullerian ducts regression
Leydig cells = secrete T, formations of vas deferens and seminal vesicles
DHT- drives growth of prostate
At puberty, prostate grows significantly
GnRH and T secretion
GnRH➡️anterior pituitary ➡️LH➡️ acts on testis to secrete T➡️ targets prostate
Structure of androgen receptors
DNA binding domain (DBD) in the middle
Ligand binding domain (LBD)-binds to T and DHT
AF1 domain binds cofactors
Androgen cell receptor signalling
AR sits in the cytoplasm when no ligand around
DHT binds to AR ➡️ dimerisation of receptor
Moves into nucleus
Binds to androgen response element
Cofactor proteins bind to AR and activate or repress transcription
What do therapies target
Androgens.
They caus growth of the prostate and cell division and growth of tumour
Genes implicated in prostate cancer
PTEN - TSG lost in prostate cancer.
BRCA2 - familial prostate cancer
What does high PSA suggest?
Secretion of PSA into blood suggests disruption of basal lamina - tumour disruption of tissue?
What is PSA
Serine protease
Clears seminal vesicles
Regulated by androgens
Where does prostate cancer metastasise to
Bone
Treatments for different grades?
Low grade: surveillance
Confined to prostate: surgery
Confined or local spread: RT
Metastatic: hormone therapy
Types of therapies
Anti GnRH - busrelin
Anti androgen - enzalutamide, inhibits growth of androgen dependent prostate cancer
Anti synthesis - abiraterone
Pituitary down regulator therapy
GnRH analog
Initial rise in LH and T
After a while - inhibition of LH ant T
Analogues dont give receptors chance to get degraded - become internalised. Pituitary becomes resistant to stimulation
Anti androgen therapy
Bind to AR in LBD and inhibit it Competition with ligand for binding Stop nuclear localisation of AR Could prevent dimerisation of DNA and DNA binding Promote corepressors
Anti-synthesis therapy
Get rid of androgens from all sources
Inhibit androgen synthesis
Used with chemical castration
Side effects of inhibiting androgens
Osteoporosis
Loss of muscle and libido
Hot flushes
Prostate cancer therapy resistance
Loss of ligand specificity - mutation of AR, becomes activated by other hormone ligands
Alterations in cofactor levels - corepressors expelled from nucleus they cant bind to DNA, treatment not effective
AR over expression
Future therapies
New antagonists with tissue specific activity - no SEs
Peptide inhibitors of receptor/coactivator interactions
Targeting other signalling pathways that crosstalk with AR signalling
