Journal Article

STAT3 Inhibition to Treat Ulcerative Colitis-Associated Colorectal Cancer

Kasembeli, Moses, Rodriguez, Emma, Zorrilla, Leticia Hamana, Italia, Zal, Hoang, Tan, Robinson, Prema, Tweardy, David J., Soto, Luisa Maren Solis, Eckols, T. Kris, Mahalingam, Rajasekaran, Italia, Zara

2025

Overview

In patients with inflammatory bowel disease (IBD), colorectal cancer (CRC) occurs with 20-to-30-fold higher frequency, is more advanced at diagnosis, and has a worse prognosis than in the general population. To improve their treatment options, we determined if targeting STAT3 with TTI-101, a small-molecule STAT3 inhibitor, was beneficial in the azoxymethane (AOM)-disodium sulfate (DSS) mouse model of colitis-associated CRC. C57BL/6 mice received a single intraperitoneal injection of AOM followed by three cycles of 5% DSS in drinking water before receiving TTI-101 (50 mg/kg by oral gavage, OG, and daily) or vehicle for 28 days. TTI-101 treatment reduced adenoma numbers by 89% from 1.14 ± 1.07 in vehicle-treated mice to 0.13 ± 0.35 in TTI-101-treated mice (p ≤ 0.05, Kruskal–Wallis test). Levels of activated STAT3 (pY-STAT3) were increased 3.3-fold in the epithelium and stroma of dysplastic mucosa (147 ± 46; mean ± SD; and n = 4) vs. normal mucosa (45 ± 26; n = 7; and p ≤ 0.05, Kruskal–Wallis test) and were correlated with the adenoma number. TTI-101 was detected at pharmacologically relevant levels in the plasma and colons of TTI-101-treated AOM-DSS mice and was concentrated within colon tissue; plasma TTI-101 levels inversely correlated to pY-STAT3 levels. Importantly, TTI-101 normalized the colon transcriptome of AOM-DSS mice and reduced the expression of STAT3- and STAT1-upregulated genes associated with CRC oncogenesis. Thus, TTI-101 treatment may benefit IBD patients with CRC.

• Publisher: MDPI AG
• Subject: Analysis / Animals / Azoxymethane / Colitis, Ulcerative - chemically induced / Colitis, Ulcerative - complications / Colitis, Ulcerative - drug therapy / Colitis, Ulcerative - metabolism / Colitis-Associated Neoplasms - drug therapy / Colitis-Associated Neoplasms - etiology / Colitis-Associated Neoplasms - metabolism / Colitis-Associated Neoplasms - pathology / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - etiology / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / Cytokines / Dextran Sulfate / Disease Models, Animal / Drinking water / Genes / Humans / Inflammatory bowel disease / Male / Mice / Mice, Inbred C57BL / Mortality / Peptides / Plasma / Polyps / Prognosis / STAT3 Transcription Factor - antagonists & inhibitors / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Sulfates / Tumors / Ulcerative colitis