Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP. Prevention Relevance: This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo , and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.

中文翻译：

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舒林酸和贝沙罗汀联合用于预防家族性腺瘤性息肉病的肠道癌变

家族性腺瘤性息肉病 (FAP) 是一种遗传性结直肠癌综合征，会导致数百个腺瘤性息肉覆盖胃肠道。NSAIDs 降低了 FAP 患者的息肉负担，合成 rexinoids 已证明能够调节细胞因子介导的炎症和 WNT 信号传导。本研究探讨了联合使用 NSAID（舒林酸）和 rexinoid（贝沙罗汀）作为减少 FAP 结肠息肉病以预防结直肠癌发展的持久方法。对 FAP 患者队列中的结直肠息肉和匹配的正常粘膜进行了全转录组分析，以确定预防 FAP 的潜在目标。评估了舒林酸和贝沙罗汀在细胞系和患者来源的类器官中的药物剂量协同作用，该药物组合在两种不同的小鼠模型中进行了测试。这项工作探索了 mRNA 作为 FAP 中这种组合的潜在预测血清生物标志物。总体而言，转录组分析揭示了炎症和细胞增殖途径的显着激活。与正常黏膜相比，在主要靶向息肉组织的 FAP 结肠类器官中观察到舒林酸 (300 μmol/L) 和贝沙罗汀 (40 μmol/L) 的协同作用。这种组合转化为 ApcMin/+ 和 ApcLoxP/+-Cdx2 小鼠的息肉发育显着减少。最后，报告的数据表明 miRNA-21 可以作为 FAP 患者息肉病负担的预测血清生物标志物。这些发现支持将舒林酸和贝沙罗汀联合作为 FAP 患者的治疗方式的临床开发。预防相关性：本研究确定了一种结合舒林酸和贝沙罗汀的新型化学预防方案，以使用计算机工具、离体和体内模型减少 FAP 患者的息肉病。这项调查为将这种药物组合推进临床试验提供了必要的基础。