TARGETED THERAPY FOR UROLOGIC MALIGNANCIES

Abstract

We determined the predictive value of NRAMP1 and hGPX1 gene polymorphisms for cancer recurrence and response to intravesical Bacillus Calmette-Guerin (BCG) immunotherapy in non-muscle-invasive bladder cancer (BC) patients, by performing single nucleotide polymorphisms analysis of their peripheral blood DNA. We show that patients with NRAMP1 (D534N and (GT)n genotypes) and hGPX1 gene polymorphisms have higher cancer recurrence, and were therefore unlikely to respond to BCG. We then investigated mTOR inhibiton as a potential new therapy for BC. The mTOR inhibitor RAD001 (everolimus) was shown to inhibit BC cell growth in vitro, caused non-apoptotic cell death and induced autophagy selectively. RAD001 was effective in vivo, when using a nude mice subcutaneous BC model. We demonstrated additive/synergistic therapeutic effect of combining RAD001 with autophagic inhibitors and chemotherapeutic agents, and show efficacy of silencing mTOR using SiRNA on BC cells. Our results suggest that mTOR is potentially a new therapeutic target for BC.