Metastatic Castrate-Resistant Prostate Cancer

Urology UnitLASUTH.

OUTLINE• Introduction

• Epidemiology

• Mechanisms of resistance

• Management

• Current trends

• LASUTH experience

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).

• 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)

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.

• 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.

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.

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.

Theories

• Hypersensitive pathway

• Outlaw pathway

• Promiscuous pathway

• Co-activators and Co-repressors

• Bypass pathways

• 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

• 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

• Bypass pathway

• “ bypass” AR pathway

• Activation of oncogenes or inactivation of

tumor suppresor genes

• Bombesin activate prostate cancer cell growth

• Bcl 2 gene activation