Abstract 4989: Efficacy of erlotinib and/or naproxen when administered by intermittent dosing schedules in the prevention of chemically induced urinary bladder cancers
Authors: Mohammed Altaf , Miller Mark S. , Lubet Ronald A. , Suen Chen , Sei Shizuko , Shoemaker Robert H. , Grubbs Clinton J. 
Published: August 2018

Abstract
Inflammation and epidermal growth factor receptor (EGFR) signaling dysregulation plays an important role in urinary bladder cancer development. We have previously shown that single agent regimens with erlotinib (EGFR inhibitor) or naproxen (nonsteroidal anti-inflammatory drug; NSAID) when given continuously were highly effective in the prevention of OH-BBN-induced urinary bladder cancers in rats. Better tolerated chemoprevention regimens can be obtained by reducing doses and frequency of administration. Low dose combinations may also achieve substantial efficacy with minimal toxicity by targeting complementary pathways. Female Fischer-344 rats were obtained at 28 days of age, placed on Teklad (4% fat) diet, and received OH-BBN (150 mg/gavage) 2x/week for 8 weeks beginning at 56 days of age. In the first study, beginning one week after the final OH-BBN treatment the rats (25/group) received either:
Group 1, erlotinib (42 mg/kg BW, 1x/week); Group 2, naproxen (30 mg/kg BW/day, 3 weeks on/ 3 weeks off); Group 3, the combination of erlotinib and naproxen (using the same treatment regimens), and Group 4, vehicle. The rats were palpated for urinary bladder tumors, weighed 1x/week and observed daily for signs of toxicity. At the end of the study (10 months after the initial OH-BBN), the average weights of the urinary bladders (bladder plus tumors combined) were determined. The weights in Groups 1-4 were: 194*, 186*, 136* and 354 mg (*P &lt;0.05, Wilcoxon Rank test). This was accompanied by an increase in tumor latency, a decrease in tumor multiplicity, and a decrease in the number of rats with large palpable tumors (&gt; 200 mg). The second study used the same treatment regimens, but administration of the agents was delayed until three months after the final OH-BBN treatment, at which point microscopic transitional cell carcinomas were present. At the end of the study (11 months after the initial OH-BBN), the weights of the individual bladders in Groups 1-4 were: 584, 234*, 138* and 779 mg (*P&lt; 0.05, Wilcoxon Rank test). Thus, naproxen and particularly the combination were still highly effective. This was accompanied by an increase in tumor latency and a decrease in the number of rats with large palpable tumors (&gt; 200 mg). These studies demonstrate that in protocols meant to reduce the toxicity of agents (weekly erlotinib or intermittent dosing with naproxen), high chemopreventive efficacy was achieved. Of importance, starting erlotinib and/or naproxen intermittent treatments at the time microscopic cancers were present still reduced the size of the urinary bladder cancers without showing observable toxicity. The latter is of particular interest based on the clinical FAP trial showing great efficacy of erlotinib and sulindac. Supported by NCI contract number HHSN261201500036I, Task Order HHSN26100002.
Citation Format: Altaf Mohammed, Mark S. Miller, Ronald A. Lubet, Chen Suen, Shizuko Sei, Robert H. Shoemaker, Clinton J. Grubbs. Efficacy of erlotinib and/or naproxen when administered by intermittent dosing schedules in the prevention of chemically induced urinary bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4989.