Bladder cancer (BC) is the second most common genitourinary cancer and a leading cause of death globally. Muscle invasive BC (MIBC) has high mortality (>85% patients) leading to death within 2 years of diagnosis, if untreated. Although new treatment options were approved recently, it is still very challenging and most expensive to manage. Preventing BC is highly desirable to reduce recurrence, mortality and improve quality of life. Inactivation of p53 signaling and chronic inflammation are frequent hallmarks of MIBC. In spite of the promising chemopreventive effects of non-steroidal anti-inflammatory agents (NSAIDs), their clinical translation is hampered due to side-effects associated with their chronic intake and higher doses. Here we investigated a combinatorial approach to modulate inflammation with NSAIDs (licofelone or NO-Naproxen) and p53 signaling pathways using CP-31398 (CP) for preventing MIBC bladder in-vivo. Transgenic UPII-SV40T mice developing spontaneous MIBC were generated and fed control or experimental diets containing the licofelone (150ppm), NO-naproxen (300 ppm), CP (150ppm) alone or in combination starting at early tumor stage (6 weeks age). After 34 weeks of agent administration, mice were euthanized and urinary bladders were evaluated. Control diet fed transgenic mice developed high grade, muscle invasive, urothelial transitional cell carcinoma (TCC) leading to 3-5 fold increase in bladder weights (140.2±9.8 mg Vs 27.3±0.8 mg; p<0.0001) and (34.2±0.8 mg vs 14.8±0.53 mg; p<0.0001) in males and females compared with wild type mice. These tumors had dysregulated cell cycle and inflammation markers similar to human tumors. Treatment with licofelone, NO-Naproxen or CP alone led to significant suppression of bladder tumor. While NSAIDs had significant inhibitory effect in males (65% - 78%; p<0.0001) and females (31% - 34%; p<0.01-p<0.0001) compared to control group, CP had strongest tumor growth suppressive effect (80%; p<0.0001 and 36%; p<0.0001) in both genders. CP had no effect on invasion in male mice while in females ~50% inhibition was observed, while moderate effect of licofelone (12% - 42% inhibition; p<0.005) and NO-Naproxen (38% - 42% inhibition; p<0.001) was observed. Importantly, the combination of two agents led to a synergistic effect leading to significant inhibition of both tumor growth (~80% in males; p<0.0001 and 55% females; p<0.0001) and invasion ~62% inhibition (p<0.0001) in both genders. Molecular analysis of urothelial tumors showed inhibitory effect on proliferation and inflammatory markers (PCNA, Cyclins, p53, p21, COX2, and IL1β). Our results suggest that safer dose combination of targeted agents may yield better chemopreventive effects than higher dose of individual agents. Specifically, NSAID plus CP may be a promising combination for preventing MIBC. (Supported in part by NCI-PREVENT program - NCI-CN-53300)

Citation Format: Venkateshwar Madka, Yuting Zhang, Nandini Kumar, Gopal Pathuri, Nicole Stratton, Stanley Lightfoot, Adam S. Asch, Vernon E. Steele, Altaf Mohammed, Chinthalapally V. Rao. Pharmacological modulation of inflammation and p53 signaling synergize to prevents muscle invasive bladder cancer in-vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5065.