Persistent STAT3 activation contributes to 10 of 14 hallmarks of cancer, including inflammation; successful targeting of STAT3 has the potential to prevent and/or treat cancer. However, no small molecule that directly targets STAT3 has been FDA approved. The Tweardy lab used computer-based docking of drug-like compounds into the SH2 domain of STAT3, along with hit-to-lead optimization and medicinal chemistry, to identify TTI-101; TTI-101 treatment was safe, hit its target in tumor cells, and resulted in clinical benefit in a Phase I trial of patients with advanced solid tumors.

The incidence of colorectal cancer (CRC) is increased 20-30 fold in patients with inflammatory bowel disease (IBD), while 90% of hepatocellular carcinomas (HCC) arise in the setting of chronic inflammation. To assess the contribution of STAT3 to CRC secondary to IBD and to HCC, we performed immunohistochemistry (IHC) staining and computer-based scoring for activated STAT3 (phosphorylated on Y705, pY-STAT3) of epithelial and stromal cells within colonic endoscopic biopsies and surgically resected CRC from IBD patients, as well as of tumor cells and hepatocytes within surgically resected HCC tumors. Compared to epithelium of normal tissue, levels of pY-STAT3 were increased 1.9-fold in dysplastic epithelium (p=0.05) and 1.8-fold in the stroma of normal tissue (p<0.0001). In surgically resected HCC tumors, lower pY-STAT3 scores in tumor cells, but not hepatocytes, correlated with longer recurrence free survival (RFS; p=0.003).

TTI-101 administration in three AOM-DSS mouse models of IBD resulted in a dose-dependent reduction in polyps, adenomas, and/or adenocarcinomas. TTI-101 administration to the HepPten- mouse model of NASH-induced HCC resulted in a dose-dependent reduction in liver pY-STAT3 levels. Thus, STAT3 may be a valid target for chemoprevention using TTI-101 in CRC arising from IBD and in HCC.

We thank Tvardi Therapeutics for providing TTI-101 for these studies.

Citation Format: Prema Robinson, Leticia Hamana, Laura Beretta, Moses Kasembeli, Uddalak Bharadwaj, Yun Shin Chun, Yinghong Wang, Xeumei Wang, Laura Reyes, Luisa Solis, Asif Rashid, Dipen Maru, Eduardo Vila, Apostolia Tsimberidou, Ahmed Kaseb, Scott Kopetz, David Tweardy. Targeting STAT3 with TTI-101, an oral small molecule, to prevent colorectal and hepatocellular cancer [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA004.