Purpose: Mammalian target of rapamycin (mTOR) is a key intracellular signaling molecule that is frequently activated in many forms of cancer, although its effect in bladder carcinoma is unknown. The goals of this study were to elucidate the expression and predictive value of phosphorylated mTOR (P-mTOR) and its downstream effector p70S6kinase-1 (S6K) in urothelial carcinoma (UCC) of the bladder and to determine the effects of mTOR inhibition on UCC cell growth in vitro. Experimental Design: We examined 121 muscle-invasive UCC patient specimens and associated regional lymph node metastases by immunohistochemical analysis and performed statistical analysis to determine association between P-mTOR and P-S6K status with patient outcomes. We also characterized the effects of dose-dependent mTOR inhibition (rapamycin administration) on 4 UCC cell lines (RT4, T24, J82 and UMUC3) by determining effects on cell proliferation in vitro. Results: Expression of P-mTOR and P-S6K occurred in 74% (90/121) and 55% (66/121) of UCC specimens, respectively, with a significant increase in P-S6K intensity and percentage of positive cells in paired lymph node metastases (p=0.00035 and p=0.01, respectively). P-mTOR intensity and % positive cells were significantly associated with decreased length of survival (P=0.0001, respectively) and P-mTOR intensity corresponded to increased pathologic stage (p=0.0001). Treatment of UCC cell lines with the general mTOR inhibitor rapamycin showed a dose-dependent reduction in cellular proliferation of up to 88% at 1 nM rapamycin in J82, T24 and RT4 cells (p=0.002, p=0.002, p=0.03, respectively) and a significant reduction at 10 nM in UMUC3 cells (p=0.03). Reduced proliferation rates corresponded to a reduction in P-S6K levels by western blot analysis. Conclusions: Activation of the mTOR pathway commonly occurs in UCC and is associated with worsened pathologic stage and shorter survival. The marked reduction in proliferation associated with mTOR inhibition in vitro suggests the potential clinical utility of mTOR inhibition in the treatment of patients with invasive UCC.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2744.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009