TARGETING TRYPTOPHAN METABOLISM IN COLITIS ASSOCIATED CANCER

 描述(申请人提供)：结肠炎相关性癌症(CAC)是慢性炎症性肠病患者早期死亡的主要并发症和原因。对于专门治疗CAC但保留正常上皮的新疗法的需求尚未得到满足。我们发现吲哚胺2，3双加氧酶(IDO1)是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。我们的新数据表明，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，最初的IDO1-KP代谢物，激活了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IDO1的结构性激活，这反过来又以细胞固有的方式促进生长。基于这些观察，我们的主要假设是：“在已建立的CAC的肿瘤上皮中抑制IDO1-Kyurenine通路可以选择性地增强细胞毒治疗，同时不会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将IDO1-KP作为一种新的CAC治疗方法。我们建议解决以下问题。IDO1抑制能否与细胞毒性CAC疗法协同作用来改善结果，而不是毒性？IDO1和KP代谢物促进CAC生长的机制是什么？KP对正常上皮细胞和肿瘤细胞的影响有何不同？是否有更合适的靶点用于IDO1上游或KP内的CAC治疗，以获得更高的疗效或更低的毒性？我们将使用创新的方法，包括肠道特异性IDO1基因敲除(IDO-IKO)小鼠，人类器官培养(肿瘤样、结肠样和肠样)，一种新的高效和特异性的IDO1抑制剂，以及一个独特的人CAC和结肠炎相关异型增生样本的生物库。重要的是，我们研究的完成将确定IDO1-KP如何作为一种新的、精确的CAC治疗方法的靶点，目标是限制对正常肠道的毒性。由于IDO1也在散发性结直肠癌(CRC)中表达，预示着预后不良，我们的发现可能也适用于CAC以外的地方。

 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.