Colorectal Cancer (CRC) Prevention by Urolithin A in Rodent CRC models

在啮齿动物 CRC 模型中通过尿石素 A 预防结直肠癌 (CRC)

基本信息

批准号：
10885222
负责人：
MARGIE L. CLAPPER
金额：
$ 103.9万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-10 至 2026-07-09
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10885222
关键词：
APC gene Adult Affect American Cancer Society Biological Models C57BL/6 Mouse CD8-Positive T-Lymphocytes Cancer Etiology Cancer Model Cessation of life Chemoprevention Chemoprotective Agent Clinical Research Colectomy Colon Carcinoma Colonic Diseases Colonoscopy Colorectal Cancer Colorectal Polyp Death Rate Detection Development Diagnosis Disease Dose Duodenum Eicosapentaenoic Acid Ellagic Acid Enterocytes FDA approved FRAP1 gene Familial Adenomatous Polyposis Syndrome Familial colorectal cancer Gastric Polyp Gastrointestinal tract structure Genetic Engineering Incidence Inflammation Inflammatory Intestinal Neoplasms Intestinal Polyps Left Lesion Life Style Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of thyroid Morbidity - disease rate Muscle function Non-Steroidal Anti-Inflammatory Agents Oral Oral Administration Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phytochemical Polyps Proliferating Rectal Cancer Reporting Risk Risk Factors Rodent Rodent Model SDZ RAD Signal Transduction Sirolimus Skeletal Muscle Sulindac Supplementation Syndrome Tumor Suppressor Genes United States Variant WNT Signaling Pathway Woman cancer diagnosis cancer prevention cancer therapy celecoxib clinical effect colorectal cancer prevention colorectal cancer treatment dextran sulfate sodium induced colitis early screening fruits and vegetables improved interest lifetime risk mTOR Inhibitor mTOR inhibition men microbiota metabolites mortality mouse model muscle aging polyphenol polyposis preclinical study predicting response predictive marker premalignant prevent prophylactic sex standard of care tumor growth tumor initiation young adult

项目摘要

Colorectal cancer (CRC) is the third most common cancer diagnosed in the United States as per the current estimates of The American Cancer Society. The number of CRC cases in the United States for 2022 are 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer. The lifetime risk of developing CRC is about 1 in 23 (4.3%) for men and 1 in 25 (4.0%) for women. CRC is also the third leading cause of cancer-related deaths in men and in women, and the second most common cause of cancer deaths when numbers from both sexes are combined. Although changes in lifestyle-related risk factors, improved CRC treatments, and early screening has helped reduce the diagnosis and overall death rates considerably over the years, there has been a steady increase in CRC incidence and death rate among younger adults (<55 years). Familial adenomatous polyposis (FAP) is a hereditary CRC syndrome caused by germline pathogenic variants of the APC tumor suppressor gene . FAP affects the gastrointestinal tract and is characterized by the development of hundreds to thousands of precancerous colorectal polyps. FAP patients when left untreated carry a 100% risk of developing CRC. The current standard of care for FAP patients includes frequent colonoscopies and prophylactic colectomy upon detection of advanced lesions. However, colectomy is associated with significant morbidity and does not prevent extra- colonic disease manifestations including gastric polyposis, duodenal polyposis and cancer, and thyroid cancer . While some clinical studies have demonstrated chemoprotective benefit of the NSAIDs including sulindac, celecoxib and eicosapentaenoic acid (EPA) for FAP, there are no FDA-approved drugs for this indication. In line with the growing interest in phytochemicals for cancer treatment and prevention , recent studies have demonstrated that Ellagic acid (EA), a polyphenol found in fruits and vegetables and its microbiota metabolites, the urolithins, suppress cancer associated pathways and inflammation in various model systems . Out of all urolithins, Urolithin A (UA) has been shown to display high bioactivity against cancer signaling and related inflammatory diseases in preclinical studies. A recent report demonstrated that oral administration of UA suppresses intestinal tumor growth in a sporadic CRC mouse model through induction of mitophagy and Wnt-signaling in CD8+ T cells. Oral administration of UA has also been shown to prevent TNBS- and DSS- induced colitis in C57BL/6 mice by enhancing the gut barrier integrity through activation of Nrf2 pathway. There has been a growing interest in the field on exploiting mTOR inhibition in chemoprevention of FAP. The mTORC1 pathway is activated in intestinal polyps of FAP mouse models, activation of which has been shown to be required for the proliferation of APC-deficient enterocytes . Blocking mTORC1 pathway with mTOR inhibitors rapamycin and everolimus limited intestinal tumor initiation, polyp formation, and reduced mortality in FAP mouse models. Oral administration of UA decreased activation of mTOR signaling and inhibited tumor growth while improving survival in a genetically engineered pancreatic cancer interception mouse model. UA has been studied clinically for effects on various diseases, including aging and skeletal muscle function . These clinical studies have shown that direct supplementation with UA is well tolerated and can yield high systemic concentrations in healthy adults.

根据美国癌症学会目前的估计，结直肠癌（CRC）是美国第三大常见的癌症。 2022年美国的CRC病例数为106,180例新结肠癌病例和44,850例新病例直肠癌。患有CRC的终身风险约为男性中的23分（4.3％），女性为25（4.0％）。 CRC也是男性和女性癌症相关死亡的第三大主要原因，当两性数字合并时，癌症死亡的第二大最常见原因。尽管与生活方式相关的危险因素，改善CRC治疗和早期筛查的变化有助于多年来大大降低诊断和总体死亡率，但年轻人的CRC发病率和死亡率稳步上升（<55岁）。家族性腺瘤性息肉病（FAP）是由APC肿瘤抑制基因的种系致病变异引起的遗传性CRC综合征。 FAP影响胃肠道，其特征是成千上万至数千个癌前大息息肉的发展。 FAP患者未经治疗后，患有100％的CRC风险。当前针对FAP患者的护理标准包括频繁的结肠镜检查和预防性结肠切除术。然而，结肠切除术与明显的发病率有关，并不能预防结肠外疾病表现，包括胃息肉病，十二指肠息肉病和癌症以及甲状腺癌。尽管一些临床研究表明NSAID的化学保护益处在内，包括Sulindac，Celecoxib和Eicosapentaenoic Acid（EPA）用于FAP，但对于此指示，没有FDA批准的药物。根据对植物化学对癌症治疗和预防的兴趣的日益兴趣，最近的研究表明，在水果和蔬菜中发现的多酚及其微生物群代谢产物，尿石素，尿石素，抑制癌症相关的途径和炎症。在所有尿线虫中，尿石素A（UA）已被证明在临床前研究中对癌症信号传导和相关炎症性疾病表现出很高的生物活性。最近的一份报告表明，口服UA通过在CD8+ T细胞中诱导线粒体和WNT信号来抑制零星CRC小鼠模型中的肠道肿瘤的生长。还显示出口服UA通过通过激活NRF2途径来增强肠道屏障的完整性，以防止C57BL/6小鼠中TNBS和DSS诱导的结肠炎。对于在FAP化学预防中利用MTOR抑制作用的领域越来越感兴趣。 MTORC1途径在FAP小鼠模型的肠道息肉中激活，其激活已被证明是APC缺陷型肠细胞增殖所必需的。用MTOR抑制剂雷帕霉素和依维洛司限制肠道肿瘤的起始，息肉形成和降低FAP小鼠模型死亡率，阻止MTORC1途径。口服UA降低了MTOR信号传导的激活和抑制肿瘤的生长，同时在基因工程胰腺癌截距小鼠模型中改善了生存率。 UA已在临床上研究了对各种疾病的影响，包括衰老和骨骼肌肉功能。这些临床研究表明，对UA的直接补充是良好的耐受性，并且可以在健康的成年人中产生高度的全身浓度。