Prevention By Tolfenamic Acid And Characterization Of The Molecular Targets In Pirc And Fap Colorectal Adenomas

A critical need exists in sporadic and high-risk colorectal cancer patients for endoscopic screening combined with safe and effective preventive agents. To prioritize molecular targets for prevention studies in vivo, RNA-seq analyses were conducted on colorectal adenomas from familial adenomatous polyposis (FAP) patients, and from the Apc-mutant polyposis in rat colon (Pirc) model. Using a new murine endoscopic polypectomy methodology (F.U. Ertem et al., Gastrointest Endosc 2016;83:1272-6), we evaluated agents that might substitute for the current standard of care, Sulindac, and identified tolfenamic acid (TA) as a promising candidate for further investigation. At clinically-relevant doses in the Pirc model, TA suppressed tumorigenesis significantly both in the small intestine and in the colon. Inhibition by TA of colonic crypt cell proliferation, and the concomitant activation of apoptosis, coincided with reduced expression in target tissues of β-catenin, cyclin D1, Survivin and matrix metalloproteinase 7. Based on the oncogene candidates defined by RNA-seq analysis, endoscopic tracking revealed the time-course of tumor suppression by TA, and the temporal changes in S100a9, Nppb, Aldh1a3 and Mmp7, highlighting their value as potential early biomarkers for prevention in the clinical setting. As an “old drug” repurposed from migraine, TA appears to offer an exciting new therapeutic avenue in FAP and other high-risk colorectal cancer patient populations. This work was supported in part by NIH grants CA090890, CA122959, ES00210, ES023512, the John S. Dunn Foundation, and a Chancellor’s Research Initiative. 1 Citation Format: Furkan U. Ertem, Wenqian Zhang, Kyle Chang, Wan-Mohaiza Dashwood, Praveen Rajendran, Deqiang Sun, Ala Abudayyeh, Maen Abdulrahim, Eduardo Vilar, Roderick H. Dashwood. Prevention by tolfenamic acid and characterization of the molecular targets in Pirc and FAP colorectal adenomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2229. doi:10.1158/1538-7445.AM2017-2229