IDO2 Targeting for pancreatic cancer treatment

描述（由申请人提供）：我们试图检查基于机制的概念来治疗胰腺癌（PDAC），该概念基于对新型免疫抑制酶IDO 2的抑制，IDO 2在PDAC细胞中特异性活化。与更广泛表达的色氨酸分解代谢酶吲哚胺2，3-双加氧酶（IDO）相比，IDO 2相对未被探索，IDO被广泛认为可以抑制T细胞活性并介导人类癌症的免疫逃逸。IDO抑制剂的临床前研究促使NCI免疫治疗研讨会将其列为可以治愈癌症的实验药物中的“前10名”。然而，随着先导抑制剂D-1 MT的I期临床试验的进行，关于IDO在药物作用机制中的作用出现了重大问题。这些问题很重要，因为它们阻碍了基于机械理解的深刻临床试验的设计。在这方面，我们的建议通过将机制焦点从IDO重定向到IDO 2来解决该领域的知识差距：在发现IDO 2时，我们发现它是D-1 MT相对于IDO的优先生化靶标。初步研究表明，IDO 2激活支持PDAC，这意味着D-1 MT可能提供了一种治疗策略，特别是在这种疾病的机制相关性。与其他检查的癌症不同，IDO 2是人类PDAC中的活性靶标。值得注意的是，存在于胰腺癌患者中的人IDO 2基因中天然存在的遗传变异的模式支持IDO 2是这种疾病的驱动者或促进者的假设。因此，我们的项目提出了药理学和遗传学目的，以证实IDO 2阻断可以改善PDAC治疗的假设，包括与吉西他滨治疗（标准治疗）的组合。我们的提案提供的概念，免疫学和遗传学创新包括使用独特的IDO 2缺陷小鼠。这项工作将由药物发现和PDAC治疗领域领先的临床前和临床专家组成的多学科协作团队进行。该提案的意义和影响是基于它为合理化和优先考虑D-1 MT在胰腺癌患者中的II期临床试验提供了强大的机会。 公共卫生相关性：该试点提案旨在通过阻断最近发现的可能限制免疫系统抗肿瘤活性的酶来临床前评估治疗胰腺癌（PDAC）的新免疫疗法概念。该项目可能会重新定位现有药物在临床试验中用于PDAC治疗，当与现有标准治疗相结合时，预计会有效。这一创新项目来自一个由药物发现和PDAC治疗领域领先的临床前和临床专家组成的多学科团队，有可能合理化和优先考虑II期试验，以改善胰腺癌治疗，这是迫切需要的。

DESCRIPTION (provided by applicant): We seek to examine a mechanism-based concept to treat pancreatic adenocarcinoma (PDAC), based on inhibition of the novel immunosuppressive enzyme IDO2, which is specifically activated in PDAC cells. IDO2 has been relatively unexplored compared to the more broadly expressed tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO), which is widely recognized to suppresses T cell activity and mediate immune escape in human cancers. Preclinical studies of IDO inhibitors prompted an NCI immunotherapy workshop to rank them a 'top 10' among experimental agents that could cure cancers. However, as Phase I clinical trials of the lead inhibitor D-1MT have gotten underway, significant questions emerged about the role of IDO in the mechanism of action of the drug. These questions are important since they impede the design of an incisive clinical trial based on mechanistic understanding. In this regard, our proposal addresses a gap in knowledge in the field by redirecting mechanistic focus from IDO to IDO2: in discovering IDO2 we found that it was a preferential biochemical target of D-1MT relative to IDO. Pilot studies suggest that IDO2 activation supports PDAC, implying that D-1MT may offer a therapeutic strategy of particular mechanistic relevance in this disease. Unlike other cancers examined, IDO2 is an active target in human PDAC. Notably, the pattern of naturally occurring genetic variations in the human IDO2 gene which exist in pancreatic cancer patients favor the hypothesis that IDO2 is a driver or facilitator in this disease. Accordingly, our project proposes pharmacological and genetic aims to corroborate the hypothesis that IDO2 blockade could improve PDAC treatment, including in combination with gemcitabine treatment (standard of care). The conceptual, immunological, and genetic innovations offered by our proposal include the use of a unique IDO2-deficient mouse. The work will be conducted by a collaborative multidisciplinary team of leading preclinical and clinical experts in drug discovery and PDAC treatment. The significance and impact of this proposal is based on the powerful opportunity it offers to rationalize and prioritize Phase II clinical trials of D-1MT in pancreatic cancer patients. PUBLIC HEALTH RELEVANCE: This pilot proposal seeks to preclinically assess a new immunotherapy concept to treat pancreatic adenocarcinoma (PDAC), by blocking a recently discovered enzyme that may limit anti-tumor activities of the immune system. This project may re-position an existing agent in clinical testing for use in PDAC therapy, one which would be expected to be effective when combined with the existing standard of care. This innovative project from a multidisciplinary team of leading preclinical and clinical experts in drug discovery and PDAC therapy has the potential to rationalize and prioritize Phase II trials to improve pancreatic cancer treatment, which is badly needed.