TARGETING TRYPTOPHAN METABOLISM IN COLITIS ASSOCIATED CANCER

针对结肠炎相关癌症中的色氨酸代谢

• 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
• 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

 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（由适用提供）：与结肠炎相关的癌症（CAC）是慢性炎症性肠病患者早期死亡的主要并发症和原因。对新疗法的需求未满足，可以专门治疗CAC，但要避免正常的上皮。我们发现，吲哚胺2，3二加氧酶（IDO1）是一种酶，该酶在慢性结肠炎中激活并促进CAC发育。我们的新数据将结肠上皮确定为表达细胞类型的关键IDO1，促进CAC生长。我们还发现，初始IDO1-KP代谢产物Kynurenine激活结肠肿瘤的重要转录途径。最后，我们证明结肠肿瘤转化会导致IDO1的组成型激活，进而促进细胞中的生长。基于这些观察结果，我们的总体假设是“在已建立的CAC的肿瘤上皮中抑制IDO1-京素途径可以有选择地增强细胞毒性疗法，同时不在正常上皮上添加毒性”。我们的总体目标是确定如何将IDO1-KP作为一种新颖的CAC疗法确定。我们建议解决以下问题。 IDO1抑制是否可以与细胞毒性CAC疗法协同作用，以增强结果，但不是毒性？ IDO1和KP代谢产物促进CAC生长的机制是什么？KP对正常上皮细胞的影响与肿瘤有何不同？是否有更合适的靶标从IDO1上游或KP内进行CAC治疗，效率更高或毒性更低？我们将使用创新的方法，包括肠道特异性IDO1敲除（IDO-IKO）小鼠，人体器官培养（肿瘤，结石和肠菌素），具有高效力和特异性的新的IDO1抑制剂，以及独特的人类CAC和与结肠炎相关的生物群体相关的生物群。意义在于，我们的研究的完成将确定如何将IDO1-KP作为一种新型的CAC治疗方法，目的是将毒性限制在正常肠道上。由于IDO1在零星结直肠癌（CRC）的一部分中也表达了预后不良的预后，因此我们的发现也可能适用于CAC。