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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：
9270026
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/9270026
关键词：
Abdomen Address Affect Alpha Cell Apoptotic Cancer Model Cancer Patient 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 Fluorouracil Fostering Generations Genetic Genetic Transcription Goals Growth Human Immune Evasion Immune Tolerance Immunologic Surveillance In Vitro Inflammatory Bowel Diseases Injury Intestines Knockout Mice Kynurenine Lead Link Malignant Neoplasms Methods Mus Neoplasms Neoplastic Cell Transformation Neoplastic Epithelial Cell Organoids Outcome Pathogenesis Pathway interactions Patients Pharmacology Play Proto-Oncogene Proteins c-akt Radiation Radiation therapy Regulation Role Sampling Signal Transduction Specificity Testing Therapeutic Toxic effect Treatment-Related Cancer Tryptophan Metabolism Pathway base beta catenin biobank 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 therapeutic target 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.