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.

Doxorubicin (Dox) is considered one of the most effective treatments for triple-negative breast cancer (TNBC); however, it can cause limited efficacy, recurrence/chemoresistance, and cardiotoxicity. Using a murine preclinical MDA-MB-231 TNBC model, we determined that targeting the substance P/neurokinin-1 receptor signaling axis can increase efficacy of the standard-of-care treatment currently used for TNBC, i.e., doxorubicin (Dox), while also attenuating Dox-induced, cardiotoxicity in TNBC. The in vivo studies outlined in this manuscript validate aprepitant (AP), a neurokinin-1 receptor antagonist, as a safe, dual-purpose chemosensitizer and cardioprotectant. These studies provide preclinical evidence supporting further evaluation of a continuous daily AP regimen in TNBC models in combination with Dox, laying the groundwork for future investigations into its safety, dosing, and potential clinical application. Because AP is already FDA-approved for single-dose anti-emetic use, repurposing it for chronic administration offers a rapid path to clinical translation, with the potential to redefine chemotherapy paradigms and tangibly improve survival and quality of life in TNBC.

Colorectal cancer (CRC) occurs with higher frequency in patients with inflammatory bowel disease (IBD) and has increased morbidity and mortality compared with CRC in patients in the general population. STAT3 has been implicated in CRC development, but strategies to target it have yet to be employed to prevent its occurrence in groups at high risk for CRC. Our group developed TTI-101, a small-molecule STAT3 inhibitor, which was effective in treating colitis in the dextran sodium sulfate (DSS) mouse model. In the current study, we examined the ability of TTI-101 to prevent CRC in the azoxymethane (AOM)-DSS mouse model of CRC. Mice received AOM followed by DSS and were treated with either TTI-101 or vehicle control for 10 weeks. While vehicle-treated AOM-DSS mice developed polyps and adenocarcinomas, TTI-101-treated AOM-DSS mice did not. Levels of activated STAT3 (pY-STAT3) were increased in both the epithelial and stromal compartments of adenocarcinomas vs. normal colon mucosa and correlated with adenocarcinoma burden. Pharmacologically relevant concentrations of TTI-101 were detected in plasma and colon; plasma levels correlated with colon levels and correlated inversely with adenocarcinoma number. Transcriptomic analyses revealed that TTI-101 normalized expression of AOM-DSS-induced CRC-associated genes in the colon, many of which are regulated by STAT3. The addition of DSS to AOM resulted in a distinct cecal microbiome diversity and composition that was muted by the addition of TTI-101. Thus, TTI-101 prevented colitis-associated CRC in the AOM-DSS model through targeting STAT3’s pro-oncogenic effects on the colon transcriptome and modulating colitis-associated dysbiosis; targeting STAT3 in patients with IBD merits consideration for CRC prevention, as well as IBD treatment.