Prebiotic effect of eicosapentaenoic acid treatment for colorectal cancer

二十碳五烯酸治疗结直肠癌的益生元作用

• 批准号: 10620849
• 负责人: Andrew T Chan
• 金额: $ 59.91万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620849
• 关键词: Address; Aftercare; Anti-Inflammatory Agents; Bacteria; Bifidobacterium; Biological Markers; Blood; Blood specimen; CTLA4 gene; Cancer Etiology; Cessation of life; Chronic; Clinical; Colorectal Adenoma; Colorectal Cancer; Colorectal Surgery; Data; Diet; Dietary Fats; Dinoprostone; Dose; Eicosapentaenoic Acid; Escherichia coli; Esters; Etiology; Excision; Feces; Food; Frequencies; Funding; Fusobacterium nucleatum; Germ-Free; Gnotobiotic; Growth; Human; Human Microbiome; Immune; Immunosuppression; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Investigation; Lactobacillus; Ligands; Lipopolysaccharides; Liver; Mediating; Metabolic; Metastatic Neoplasm to the Liver; Microbe; Morbidity - disease rate; Mus; Myeloid-derived suppressor cells; Neoplasm Metastasis; Omega-3 Fatty Acids; Operative Surgical Procedures; Outcome; Participant; Pathway interactions; Patient Recruitments; Patient-Focused Outcomes; Patients; Phase; Placebo Control; Plasma; Postoperative Period; Probiotics; Production; Prognosis; Progression-Free Survivals; Property; Randomized; Regional Cancer; Regulatory T-Lymphocyte; Research; Resources; Role; Safety; Specimen; Standardization; Structure; Supplementation; System; Testing; Tissues; Transplant Recipients; Tumor Burden; Tumor Escape; Tumor Immunity; Urine; adenoma; anti-tumor immune response; beneficial microorganism; biobank; cancer immunotherapy; cancer survival; chemokine; cohort; colon cancer patients; colorectal cancer progression; colorectal cancer treatment; combinatorial; cost; density; dietary; dietary supplements; experience; fecal transplantation; follow-up; gut bacteria; gut microbiota; host-microbe interactions; immune checkpoint; immunoregulation; improved; improved outcome; insight; marine; microbial; microbiome; microbiome research; microbiota; mouse model; new therapeutic target; novel; patient subsets; permissiveness; phase III trial; prebiotics; predicting response; predictive marker; programmed cell death protein 1; prospective; randomized placebo controlled trial; responders and non-responders; response; stool sample; systemic inflammatory response; tumor; tumor growth; tumor microenvironment; tumorigenic; urinary

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.

项目概要/摘要 结直肠癌 (CRC) 是美国癌症死亡的第二大原因，约占 CRC 的 30-50% 患者出现肝转移（CRCLM），这是结直肠癌相关死亡的一个主要原因。作为手术切除 CRCLM 变得越来越常规，改善 CRCLM 切除后患者的预后是当务之急。 二十碳五烯酸 (EPA) 是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。我们小组最近进行的一项 II 期随机安慰剂对照试验 (RCT) 显示，EPA 补充可提高局部癌症和 CRCLM 患者的生存率。不过，具体 EPA 影响术后生存的机制尚不清楚。最近的数据来自 我们的小组和其他人支持 EPA 的抗 CRC 益处可能是通过其多效性作用介导的 调节肠道微生物群并改善肿瘤允许的免疫抑制机制，包括 抑制调节性 T 细胞 (Treg) 和骨髓源性抑制细胞 (MDSC) 的活性，以及 产生炎症介质，例如前列腺素 E2 (PGE2) 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因素。小鼠喂食 高 EPA 饮食显示肠道细菌丰度增加，例如双歧杆菌和乳酸杆菌 支持宿主免疫保护系统并提高癌症免疫治疗功效的属，以及 减少引发慢性炎症的产生脂多糖（LPS）的细菌的丰度 推广CRC。这些数据共同支持了我们的假设，即 EPA 的益生元作用消除了肿瘤内 免疫抑制并改善全身炎症，以提高手术患者的生存率 CRCLM 切除术。为了检验这一假设，我们将利用最近推出的每日 4 克的 III 期随机对照试验 EPA-乙酯治疗 448 名接受 CRCLM 肝切除手术的患者（EPA for 转移试验 2，EMT2），其中参与者在 CRCLM 手术前至少 2 周开始治疗，并且 肝切除后继续2-4年。使用从治疗后肝脏收集的组织标本 切除，并在随机、手术中每隔 6 个月收集一次血液、尿液和粪便样本， 我们将探讨与生存相关的免疫和微生物途径。我们将解决因果关系和 描述 EPA 影响宿主-微生物相互作用以增强抗肿瘤作用的机制 在一种新型“阿凡达”无菌 CRCLM 小鼠模型中抑制 CRCLM，该模型用来自粪便的人源化 随机对照试验参与者。通过这些综合调查，我们的研究可能会为发展开辟新途径 基于 EPA 的 CRC 治疗组合策略。该策略的临床效用尤其显着 由于其成本和安全优势而有吸引力。