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: 10406256
• 负责人: Andrew T Chan
• 金额: $ 60.58万
• 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/10406256
• 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; Lead; Ligands; Lipopolysaccharides; Liver; Malignant neoplasm of 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; Time; Tissues; Transplant Recipients; Tumor Burden; Tumor Escape; Tumor Immunity; Urine; adenoma; anti-tumor immune response; base; 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; microbial; microbiome; microbiome research; microbiota; mouse model; new therapeutic target; novel; patient subsets; 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.

项目摘要 /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％ 患者发生肝转移（CRCLM），这是导致CRC相关死亡的主要贡献者。作为手术切除 CRCLM变得越来越常规，改善CRCRM切除后患者的预后是很高的重点。 eicosapentaenoic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。我们组最近的II期随机安慰剂对照试验（RCT）表明EPA 补充可改善区域癌和CRCLM患者的生存。但是，具体 EPA影响术后生存的机制尚不清楚。最新数据来自 我们的小组和其他人支持EPA的抗CRC益处可能是由其多效性角色介导的 调节肠道微生物群和改善肿瘤验证的免疫抑制机制，包括 抑制调节性T细胞（TREG）和髓样衍生的抑制细胞（MDSC）的活性和 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）。饮食脂肪成分也是肠道微生物群落结构的主要驱动力。喂养的小鼠 高EPA饮食表明肠道细菌的抽象增加，例如双歧杆菌和乳酸杆菌 属，支持宿主免疫保护系统并提高癌症免疫疗法的效率，并 脂多糖（LPS）的抽象降低，产生了引发慢性炎症和的细菌 促进CRC。这些数据共同支持了我们的假设，即EPA的益生元作用废除了肿瘤内 免疫抑制和改善全身性炎症以改善手术患者的存活率 切除CRCLM。为了检验这一假设，我们将利用我们最近推出的第三阶段RCT每天的III期RCT 在接受肝切除手术的448例CRCLM的患者中，EPA-乙基酯治疗（EPA的 转移试验2，EMT2），其中参与者在CRCLM手术前至少2周开始治疗 肝后切除后2 - 4年。使用从治疗后肝收集的组织标本 切除，血液，尿液和粪便样品在随机化，手术和6个月间隔收集， 我们将询问与生存有关的免疫和微生物组途径。我们将解决偶然性和 表征EPA影响宿主与微生物相互作用的机制 免疫和抑制新颖的“阿凡达”无细菌crclm小鼠模型，用粪便人性化。 RCT参与者。通过这些综合调查，我们的研究可能为发展开辟新的途径 基于EPA的CRC治疗策略。该策略的临床实用性尤其是 由于其成本和安全优势而吸引人。