TARGETING TRYPTOPHAN METABOLISM IN COLITIS ASSOCIATED CANCER

 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原因。对于特异性治疗CAC但不损伤正常上皮的新疗法存在未满足的需求。我们发现吲哚胺2，3双加氧酶（IDO 1），一种沿着犬尿氨酸途径（KP）启动色氨酸代谢的酶，在慢性结肠炎中被激活并促进CAC的发展。我们的新数据确定结肠上皮细胞是促进CAC生长的关键IDO 1表达细胞类型。我们还发现，犬尿氨酸，初始IDO 1-KP代谢产物，激活结肠肿瘤的重要转录途径。最后，我们证明了结肠肿瘤转化导致IDO 1的组成性激活，这反过来又促进了细胞内在方式的生长。基于这些观察结果，我们的总体假设是“抑制已建立CAC的肿瘤上皮中的IDO 1-kyurenine途径可以选择性地增强细胞毒性治疗，同时不增加对正常上皮的毒性”。我们的总体目标是确定如何最好地靶向IDO 1-KP作为一种新的CAC疗法。我们建议处理以下问题。IDO 1抑制剂能否与细胞毒性CAC疗法协同作用以增强结局，但不增强毒性？IDO 1和KP代谢产物促进CAC生长的机制是什么？KP如何影响正常上皮细胞而不是肿瘤细胞？在IDO 1上游或KP内是否有更合适的CAC治疗靶点，疗效更高或毒性更低？我们将使用创新的方法，包括肠道特异性IDO 1敲除（IDO-iKO）小鼠，人类类器官培养（类肿瘤，类结肠和类肠），具有高效力和特异性的新型IDO 1抑制剂，以及人类CAC和结肠炎相关异型增生样本的独特生物库。重要的是，我们研究的完成将确定IDO 1-KP如何作为CAC治疗的一种新的精确方法，以限制对正常肠道的毒性为目标。由于IDO 1也在散发性结直肠癌（CRC）的一个子集中表达，预示着预后不良，我们的发现也可能适用于CAC之外。

 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.