Abstract 4653: Modulation of mTOR and p53 signaling using rapamycin plus CP-31398 inhibits growth and progression of urothelial carcinoma in-vivo

Abstract

Abstract Bladder cancer is the second most common genitourinary cancer worldwide. Despite multidisciplinary treatment advances, muscle-invasive bladder cancer continues to have high mortality. Since dysregulation of p53 and mTOR signaling in urothelium is associated with tumor initiation, growth and invasiveness, we investigated whether up-regulation of TP53 plus inhibition of mTOR additively or synergistically inhibits tumor growth and progression in vivo. Transgenic UPII-SV40T male mice (n = 15/group) were generated, genotyped and fed control or experimental diets containing the mTOR inhibitor rapamycin (8 or 16 ppm) and/or the p53 stabilizing agent CP31398 (150 ppm) starting at 6 weeks of age. After 34 weeks, control diet fed transgenic mice developed urothelium-specific high-grade, invasive transitional cell carcinoma (TCC) with significant increase in bladder weights (140.2 ± 9.8 mg; p<0.0001) compared with wild type (27.3 ± 0.8 mg). Rapamycin (8 or 16 ppm) reduced tumor weight by ∼ 67% or 77% and CP31398 decreased it by >70%. The combination of CP31398 with 8 ppm rapamycin decreased tumor weight by ∼83% (16.47 ± 5.4 mg; p<0.0001). Rapamycin (8 or 16 ppm) suppressed tumor invasion by 53% (p<0.005) or 66% (p<0.0005). CP-31398 alone failed to inhibit tumor invasion; however its combination with low-dose rapamycin inhibited tumor invasion >71% (p<0.0001). Molecular analysis of tumors via real-time PCR, IHC and western blotting showed synergistic inhibition by the drug combination of tumor growth and invasion with suppression of mTOR signaling (mTOR, pmTOR, raptor, rictor, Akt, pAkt); induction of p53 expression; and decreased expression of proliferation (PCNA), cell cycle regulators (cyclin D1, cyclin A), pro-survival molecules (Hif1a, Vegf) and androgen receptor. The combination of CP-31398 and rapamycin appears to be a promising approach for preventing urothelial TCC invasion. (Supported in part by NCI-CN53300) Note: This abstract was not presented at the meeting. Citation Format: Venkateshwar Madka, Altaf Mohammed, Qian Li, Yuting Zhang, Laura Biddick, Jagan M.R. Patlolla, Stanley Lightfoot, Xue-Ru Wu, Vernon Steele, Levy Kopelovich, Chinthalapally V. Rao. Modulation of mTOR and p53 signaling using rapamycin plus CP-31398 inhibits growth and progression of urothelial carcinoma in-vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4653. doi:10.1158/1538-7445.AM2015-4653