TARGETING TRYPTOPHAN METABOLISM IN COLITIS ASSOCIATED CANCER

针对结肠炎相关癌症中的色氨酸代谢

基本信息

批准号：
9083887
负责人：
MATTHEW AARON CIORBA
金额：
$ 34.31万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-05 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9083887
关键词：
Abdomen Address Affect Apoptotic Boxing Cancer Model Cancer Patient Cells Cessation of life Chronic Colitis Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Complication Cytotoxic Chemotherapy Data Decision Making Development Dioxygenases Dysplasia Enzymes Epithelial Epithelial Cells Epithelium Figs - dietary Fluorouracil Fostering Generations Genetic Goals Growth Human Immune Tolerance Immunologic Surveillance In Vitro Inflammatory Inflammatory Bowel Diseases Injury Intestines Knock-out Kynurenine Lead Link Malignant Neoplasms Methods Mus Neoplasms Neoplastic Cell Transformation Neoplastic Epithelial Cell Organoids Outcome Pathogenesis Pathway interactions Patients Play Proto-Oncogene Proteins c-akt Radiation Radiation therapy Regulation Role Sampling Signal Transduction Specificity Testing Therapeutic Toxic effect Tryptophan Metabolism Pathway base beta catenin biobank cancer therapy cell type chemotherapy clinically relevant colitis associated cancer colon cancer cell line combinatorial cytotoxic effective therapy glycogen synthase kinase 3 beta improved outcome in vivo indoleamine inhibitor/antagonist innovation knock-down neoplastic novel novel strategies novel therapeutics outcome forecast personalized approach predictive marker public health relevance response trait tumor tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colitis associated cancer (CAC) is a major complication and cause of early death in patients with chronic inflammatory bowel disease. There is an unmet need for new therapies that specifically treat CAC but spare the normal epithelium. We found that indoleamine 2, 3 dioxygenase (IDO1), an enzyme that initiates tryptophan metabolism along the kynurenine pathway (KP), is activated in chronic colitis and promotes CAC development. Our new data identify the colon epithelium as the key IDO1 expressing cell type promoting CAC growth. We also find that kynurenine, the initial IDO1-KP metabolite, activates important transcriptional pathways of colon neoplasia. Finally, we demonstrate that colon neoplastic transformation leads to constitutive activation of IDO1, which in turn promotes growth in a cell-intrinsic manner. Based on these observations, our overarching hypothesis is that "Inhibiting the IDO1-kyurenine pathway in the neoplastic epithelium of established CAC can selectively enhance cytotoxic therapy, while not adding toxicity to the normal epithelium". Our overall goal is to determine how to best target the IDO1-KP as a novel CAC therapy. We propose to address the following questions. Can IDO1 inhibition synergize with cytotoxic CAC therapies to enhance outcomes, but not toxicity? What are the mechanisms by which IDO1 and KP metabolites promote CAC growth and how does the KP affect normal epithelial cells differently than neoplastic? Are there more suitable targets for CAC therapy upstream from IDO1 or within the KP, either with greater efficacy or less toxicity? We will use innovative approaches including intestinal specific IDO1 knockout (IDO-iKO) mice, human organoid culture (tumoroids, colonoids and enteroids), a new IDO1 inhibitor with high potency and specificity, and a unique Biobank of human CAC and colitis-associated dysplasia samples. The significance is that completion of our studies will identify how the IDO1-KP may be targeted as a novel, precision approach to CAC therapy with the goal of limiting toxicity to the normal intestine. As IDO1 is also expressed in a subset of sporadic colorectal cancers (CRC) where it portends a poor prognosis, our findings may also apply beyond CAC.

描述（由申请人提供）：结肠炎相关癌症（CAC）是慢性炎症性肠病患者的主要并发症和早期死亡的原因，我们发现对治疗 CAC 但专门保护正常上皮的新疗法的需求尚未得到满足。吲哚胺 2, 3 双加氧酶 (IDO1) 是一种沿犬尿氨酸途径 (KP) 启动色氨酸代谢的酶，在慢性结肠炎中被激活并促进CAC 发展。我们的新数据确定结肠上皮是促进 CAC 生长的关键 IDO1 表达细胞类型，我们还发现犬尿氨酸（IDO1-KP 的初始代谢物）可激活结肠肿瘤转化的重要转录途径。导致 IDO1 的组成型激活，进而以细胞固有的方式促进生长。根据这些观察，我们的总体假设是“抑制已建立的 CAC 肿瘤上皮中的 IDO1-kyurenine 通路可以选择性地增强细胞毒性治疗，同时不会增加正常上皮的毒性。”我们的总体目标是确定如何最好地靶向 IDO1-KP 作为一种新型 CAC 疗法。我们建议解决以下问题：IDO1 抑制能否与细胞毒性 CAC 疗法协同作用以增强疗效，但不增强毒性？IDO1 和 KP 代谢物促进 CAC 生长的机制是什么？ KP 对正常上皮细胞的影响与对肿瘤细胞的影响不同吗？ IDO1 上游或 KP 内部是否有更合适的 CAC 治疗靶点，或者具有更高的疗效或更低的毒性？我们将使用包括肠道特异性 IDO1 敲除 (IDO-iKO) 小鼠在内的创新方法。、人类类器官培养物（类肿瘤、类结肠和类肠）、一种具有高效力和特异性的新型 IDO1 抑制剂，以及人类 CAC 和结肠炎相关发育不良样本的独特生物库。重要的是，我们研究的完成将确定如何将 IDO1-KP 作为一种新颖、精确的 CAC 治疗方法，以限制对正常肠道的毒性，因为 IDO1 也在散发性结直肠癌中表达。 (CRC) 预示着预后不良，我们的研究结果也可能适用于 CAC 之外的情况。