Prebiotic effect of eicosapentaenoic acid treatment for colorectal cancer

项目总结/摘要 结直肠癌（CRC）是美国癌症死亡的第二大原因。 患者发生肝转移（CRCLM），这是CRC相关死亡的主要原因。作为手术切除 CRCLM变得越来越常规，改善CRCLM切除术后患者的结局是一个高度优先事项。 二十碳五烯酸（EPA），一种天然存在的海洋omega-3多不饱和脂肪酸，可以保护 反对CRC。我们小组最近的一项II期随机安慰剂对照试验（RCT）显示，EPA 补充可改善局部癌症和CRCLM患者的生存率。但具体 EPA影响术后生存的机制还不清楚。最近的数据 我们小组和其他人支持EPA的抗CRC益处可能是通过其在以下方面的多效性作用介导的： 调节肠道微生物群和改善肿瘤容许的免疫抑制机制，包括 抑制调节性T细胞（TCFs）和髓源性抑制细胞（MDSC）的活性，和 产生炎症介质，如前列腺素E2（PGE 2）和趋化因子（C-C基序）配体2 （CCL2）。膳食脂肪组成也是肠道微生物群落结构的主要驱动力。用一种 高EPA饮食证明肠道细菌如双歧杆菌和乳酸杆菌丰度增加 属，其支持宿主免疫保护系统并提高癌症免疫疗法的功效，以及 减少引发慢性炎症的脂多糖（LPS）产生细菌的丰度， 促进《儿童权利公约》。这些数据共同支持了我们的假设，即EPA的益生元效应消除了肿瘤内的 免疫抑制和改善全身炎症，以提高手术患者的生存率 CRCLM切除术。为了验证这一假设，我们将利用我们最近推出的每日4克的III期RCT EPA-乙酯治疗448例因CRCLM接受肝切除手术的患者（EPA用于 转移试验2，EMT 2），其中参与者在CRCLM手术前至少2周开始治疗， 肝切除术后持续2-4年。使用从治疗后肝脏收集的组织标本 切除术，以及在随机化、手术和每6个月采集一次血液、尿液和粪便样本， 我们将询问与生存有关的免疫和微生物途径。我们将讨论因果关系， 表征EPA影响宿主-微生物相互作用以增强抗肿瘤活性的机制 免疫和抑制CRCLM在新的“化身”无菌CRCLM小鼠模型中的作用 RCT参与者。通过这些综合研究，我们的研究可能会开辟新的途径， 基于EPA的CRC治疗组合策略。该策略的临床效用特别 由于其成本和安全优势而吸引人。

PROJECT SUMMARY / ABSTRACT Colorectal cancer (CRC) is the second leading cause of cancer death in the U.S. Approximately 30-50% of CRC patients develop liver metastasis (CRCLM), a major contributor to CRC-related death. As surgical resection of CRCLM becomes increasingly routine, improving outcomes for patients post-CRCLM resection is a high priority. Eicosapentaenoic acid (EPA), a naturally-occurring marine omega-3 polyunsaturated fatty acid may protect against CRC. A recent Phase II randomized placebo-controlled trial (RCT) by our group showed that EPA supplementation improves survival in patients with regional cancer and CRCLM. However, the specific mechanisms through which EPA influences post-operative survival are not well understood. Recent data from our group and others support that the anti-CRC benefit of EPA may be mediated by its pleiotropic roles in modulating the gut microbiota and ameliorating tumor-permissive immunosuppressive mechanisms, including inhibition of the activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and production of inflammatory mediators such as prostaglandin E2 (PGE2) and chemokine (C-C motif) ligand 2 (CCL2). Dietary fat composition is also a major driver of the gut microbial community structure. Mice fed with a high-EPA diet demonstrate increased abundance of gut bacteria, such as Bifidobacterium and Lactobacillus genera, that support the host immunoprotective system and improve the efficacy of cancer immunotherapy, and decreased abundance of lipopolysaccharide (LPS)-producing bacteria that trigger chronic inflammation and promote CRC. These data together support our hypothesis that the prebiotic effect of EPA abrogates intratumoral immunosuppression and ameliorates systemic inflammation to improve survival of patients with surgical resection of CRCLM. To test this hypothesis, we will leverage our recently launched, phase III RCT of 4-g daily EPA-ethyl ester treatment among 448 patients undergoing liver resection surgery for CRCLM (EPA for Metastasis Trial 2, EMT2), in which participants start treatment at least 2 weeks prior to CRCLM surgery and continue for 2-4 years post-liver resection. Using tissue specimens collected from the post-treatment liver resection, and blood, urine, and stool samples collected at randomization, surgery, and at 6-monthly intervals, we will interrogate immune and microbiome pathways in relation to survival. We will address causality and characterize the mechanisms by which EPA influences the host–microbial interactions to potentiate antitumor immunity and suppress CRCLM in a novel ‘avatar’ germ-free CRCLM mouse model humanized with stool from RCT participants. Through these integrated investigations, our study may open new avenues for developing EPA-based combinatorial strategies for CRC treatment. The clinical utility of this strategy is particularly appealing due to its cost and safety advantages.