ORLANDO, FL USA (UroToday.com) - Resurgent AR activity drives the transition to castration-resistant prostate cancer (CRPC). Tumors use multiple mechanisms to restore AR function. This includes mutation, aberrant modification, alternate splicing, intracrine androgen biosynthesis and amplification. High AR level expression correlates with increased death from disease. The retinoblastoma tumor suppressor (RB) constrains the transition to CRPC by suppressing AR expression and activity. RB negatively regulates AR expression at the transcriptional level by E2F1. Gene expression analysis shows that RB1 expression correlates to AR expression. Depleting RB in human xenografts is sufficient to drive the transition to CRPC, Dr. Knudsen showed. RB mRNA loss is overrepresented in CRPC and not apparent in primary CaP. Immunohistochemical studies confirm that RB is lost in CRPC samples. She sought to detect a gene signature of 159 genes to determine if RB was active in patients. The RB-loss signature correlated with CRPC, i.e. RB dysfunction was frequent in CRPC. Clinically this correlated with reduced patient survival.
She hypothesized that RB deficient tumors are hypersensitive to selective chemotherapy and this is presently under investigation.
Presented by Karen Knudsen, PhD at the 2011 Genitourinary Cancers Symposium, General Session III: Translational Science Session: New Targets for Prostate Cancer Therapy - February 17-19, 2011 - Orlando World Center Marriott, Orlando, Florida USA