Mechanisms of castrate resistant prostate cancer

1. Metastatic Castrate-Resistant
Prostate Cancer
Urology Unit
LASUTH.

2. OUTLINE
• Introduction
• Epidemiology
• Mechanisms of resistance
• Management
• Current trends
• LASUTH experience

3. Introduction
• Androgen deprivation is the mainstay of
advanced prostate cancer treatment.
• Despite initial responses, almost all patients
progress to castrate-resistant prostate cancer.
• Understanding of the biology of CRPC
remained driven by androgen receptor(AR).

4. • Castrate resistant-prostate cancer
• there is biochemical and/or radiological
evidence of disease progression
• Castrate level testosterone obtained
( testosterone level < 50ng/dl or 1.7nmol/L)

5. Criteria for progression
• Castrate serum level of testosterone
• Two consecutive rise of PSA, 1 week apart with at
least 50% rise over the nadir PSA.
• Anti-androgen withdrawal for at least 4 weeks for
flutamide and for at least 6 weeks for
bicalutamide.

6. • Progression of osseous lesion : Progression or
appearance of 2 or more lesions on bone scan
or soft tissue lesions node > 2cm in diameter.
• Worsening bone pain or onset of new bone
pain.

7. Epidemiology
• Incidence 2.3%-6%
• 124-250/100,000 in African American
• 2nd most common cause of death.
• 75% are elderly.
• 37,000 men die of Ca prostate yearly, most from
CRPC.
• 80-90% of Ca prostate respond initially to ADT for
about 12-48months before resistance set in.

8. Mechanisms of Resistance
• Androgen ablation precipitate apoptosis in
subpopulation of prostate cancer cells.
• Despite high initial response rate, remission is
temporary.
• The cells acquire the ability to survive and
proliferate in the absence of androgens.

9. Theories
• Hypersensitive pathway
• Outlaw pathway
• Promiscuous pathway
• Co-activators and Co-repressors
• Bypass pathways

10. • Hypersensitive pathway
• AR extremely sensitive
• Mutation
• Over amplification
• Increased 5 α reductase enzyme level.
• Outlaw Pathway
• AR activated by growth factors and receptor
thyrosine kinase
• Her 2 neu,IGF,KGF
• IL 4,IL 6

11. • Promiscuous Pathway
• AR receptive to ligands other than DHT
• Non androgenic steroid, anti-androgen.
• Mutation in AR
• Co-activator & Co-repressor
• Increase level of co-activator
• Increase sensitivity of AR
• ARA 70,ARA 55,SRC-1,GRIP1/TIF 2

12. • Bypass pathway
• “ bypass” AR pathway
• Activation of oncogenes or inactivation of
tumor suppresor genes
• Bombesin activate prostate cancer cell growth
• Bcl 2 gene activation