Abstract 6341: Inhibition of 15-PGDH prevents tumor development in the AOM/DSS model

Patients with ulcerative colitis (UC) face a cumulative risk of developing colitis-associated cancer (CAC) that is significantly higher than that of the general population. This increased risk is directly associated with the inflammatory process that occurs throughout the disease, creating the appropriate environment for the development of neoplastic lesions and impacting treatment decisions for these patients. Therefore, developing a drug capable of both mitigating the inflammatory response associated with ulcerative colitis and preventing tumor development would be an ideal therapeutic approach for UC patients. Using the murine dextran sulfate sodium (DSS) model of acute colitis, the Markowitz lab has previously demonstrated that inhibition of 15-PGDH, the primary enzyme responsible for PGE2 degradation, can markedly enhance tissue repair capacity in the colon as well as multiple additional organs (Science, 2015. PMID: 26068857). We demonstrated that treatment with (+)-SW033291 (‘291), a small molecule 15-PGDH inhibitor, increased the levels of tissue PGE2, near completely reversed colitis mucosal damage and promoted mucosal regeneration by sustaining colonocyte proliferation. We now aim to evaluate the safety of this 15-PGDH inhibitor in the context of CAC by testing ‘291 efficacy in the azoxymethane (AOM)/DSS model. Colon carcinogenesis was induced by a single dose of AOM (10 mg/kg) on day 1 of the experiment followed by 7 days of DSS treatment in drinking water (from days 8 to 15). Animals were treated with daily injections of ‘291 (10 mg/kg, twice daily, i.p.) or it is vehicle for 15 days (from days 8 to 22) and were monitored for signs of disease. Euthanasia occurred on day 47 of the experiment. At the time of sacrifice, colons were isolated and analyzed for the presence of macroscopic lesions and then fixed for histopathology and IHC staining (analyses that are in progress). Macroscopic evaluation of the colons demonstrated that inhibiting 15-PGDH reduced tumor number and tumor burden in the ‘291-treated mice when compared to vehicle controls by 50 and 60%, respectively. Additionally, treatment with ‘291 prevented body weight loss (p=0.02) during the disease course. This data indicates that ‘291 can not only reverse epithelial damage after DSS-induced colitis, but also be an effective strategy in preventing the development of colitis-associated dysplastic lesions in the AOM/DSS model. This data reinforces the rationale for developing a 15-PGDH inhibitor therapeutic to be used for patients with UC with the ultimate goal of mitigating colitis symptoms and preventing neoplastic lesion formation. Citation Format: Mariana Franco Fragoso, Filip Goshevski, Stephen P. Fink, Won Jin Ho, Sanford D. Markowitz. Inhibition of 15-PGDH prevents tumor development in the AOM/DSS model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6341.