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STAT3 Inhibition to Treat Ulcerative Colitis-Associated Colorectal Cancer
Prema Robinson1, Zal Italia1, Zara Italia1
1Departments of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Abstract:
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.
Insights
STAT3 inhibition with TTI-101 significantly reduced colorectal cancer (CRC) development in a mouse model of inflammatory bowel disease (IBD). This STAT3 inhibitor shows promise for treating IBD-associated CRC.
Area of Science:
- Oncology
- Gastroenterology
- Pharmacology
Background:
- Inflammatory bowel disease (IBD) patients have a significantly higher risk of developing colorectal cancer (CRC).
- Colorectal cancer in IBD patients is often diagnosed at a later stage and has a poorer prognosis.
- Targeting STAT3 signaling is a potential therapeutic strategy for IBD-associated CRC.
Purpose of the Study:
- To evaluate the efficacy of TTI-101, a small-molecule STAT3 inhibitor, in a mouse model of colitis-associated colorectal cancer.
- To determine if targeting STAT3 with TTI-101 can reduce tumor development and modulate relevant molecular pathways.
Main Methods:
- The azoxymethane (AOM)-disodium sulfate (DSS) mouse model was used to induce colitis-associated CRC.
- Mice were treated with TTI-101 (50 mg/kg) or vehicle via oral gavage for 28 days.
- Adenoma numbers, levels of activated STAT3 (pY-STAT3), and colon transcriptome were analyzed.
Main Results:
- TTI-101 treatment reduced adenoma numbers by 89% compared to vehicle control (p ≤ 0.05).
- Activated STAT3 levels were elevated in dysplastic mucosa and correlated with adenoma number.
- TTI-101 was detected in plasma and colon tissue, with levels inversely correlating to pY-STAT3.
- TTI-101 normalized the colon transcriptome and reduced expression of oncogenic STAT3/STAT1-upregulated genes.
Conclusions:
- TTI-101 effectively suppresses tumor development in a colitis-associated CRC mouse model.
- STAT3 signaling is a key driver in IBD-associated CRC oncogenesis.
- TTI-101 demonstrates potential as a therapeutic agent for IBD patients with CRC.
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