IDO2 Targeting for pancreatic cancer treatment

描述（由申请人提供）：我们试图研究一种基于机制的治疗胰腺腺癌（PDAC）的概念，该概念基于抑制PDAC细胞中特异性激活的新型免疫抑制酶IDO2。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，IDO2的研究相对较少，IDO被广泛认为在人类癌症中抑制T细胞活性并介导免疫逃逸。IDO抑制剂的临床前研究促使NCI免疫治疗研讨会将其列为治疗癌症的“十大”实验药物之一。然而，随着先导抑制剂D-1MT的I期临床试验的进行，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制理解的精辟临床试验的设计。在这方面，我们的建议通过将机制焦点从IDO重定向到IDO2来解决该领域的知识空白：在发现IDO2时，我们发现它是D-1MT相对于IDO的优先生化靶标。初步研究表明IDO2激活支持PDAC，这意味着D-1MT可能为该疾病提供一种特殊机制相关的治疗策略。与其他癌症不同，IDO2在人类PDAC中是一个活跃的靶标。值得注意的是，胰腺癌患者中存在的人类IDO2基因自然发生的遗传变异模式支持IDO2是该疾病的驱动因素或促进因素的假设。因此，我们的项目提出了药理学和遗传学的目标，以证实IDO2阻断可以改善PDAC治疗的假设，包括与吉西他滨治疗（标准护理）联合。我们的提议在概念上、免疫学上和遗传学上的创新包括使用一种独特的ido2缺陷小鼠。这项工作将由药物发现和PDAC治疗方面的临床前和临床专家组成的多学科合作团队进行。该提案的重要性和影响是基于它为胰腺癌患者D-1MT的II期临床试验提供了合理化和优先排序的强大机会。

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.