IDO2 Targeting for pancreatic cancer treatment

IDO2 靶向治疗胰腺癌

• 批准号: 8338893
• 负责人: GEORGE C PRENDERGAST
• 金额: $ 17.44万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338893
• 关键词: Ablation; Address; Biochemical; Cancer Patient; Cells; Clinical; Clinical Trials; Cytotoxic Chemotherapy; Development; Diagnosis; Disease; Drug effect disorder; Educational workshop; Elements; Enzymes; Evaluation; Excision; Genes; Genetic; Genetic Variation; Genotype; Growth; Human; Immune; Immune system; Immunosuppressive Agents; Immunotherapy; Knowledge; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mus; Operative Surgical Procedures; Outcome; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pattern; Phase I Clinical Trials; Phase II Clinical Trials; Pilot Projects; Positioning Attribute; Regimen; Relapse; Relative (related person); Resistance; Role; T-Lymphocyte; Therapeutic; Translations; Tryptophan; Tryptophan 2,3 Dioxygenase; Work; base; cancer therapy; chemotherapy; cytotoxic; design; drug discovery; drug mechanism; gemcitabine; improved; inhibitor/antagonist; innovation; multidisciplinary; neoplastic cell; novel; pre-clinical; preclinical study; research clinical testing; small molecule; standard of care; therapeutic target; tumor

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.

描述(由申请人提供)：我们试图研究一种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IDO2的抑制，该酶在PDAC细胞中被特异性激活。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，IDO2一直是相对未知的，IDO被广泛认为在人类癌症中抑制T细胞活性和介导免疫逃逸。对IDO抑制剂的临床前研究促使NCI的一个免疫治疗研讨会将它们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-1mt的I期临床试验已经开始，关于IDO在药物作用机制中的作用的重大问题出现了。这些问题很重要，因为它们阻碍了基于机械理解的深入临床试验的设计。在这方面，我们的建议通过将机械焦点从IDO重定向到IDO2来解决该领域的知识缺口：在发现IDO2时，我们发现它是D-1mt相对于IDO的优先生化靶点。初步研究表明，IDO2的激活支持PDAC，这意味着D-1MT可能在这种疾病中提供了一种具有特殊机制相关性的治疗策略。与其他被研究的癌症不同，IDO2是人类PDAC中的一个活跃靶点。值得注意的是，存在于胰腺癌患者中的人类IDO2基因自然发生的遗传变异模式支持这样的假设，即IDO2是这种疾病的驱动或促进因素。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，包括与吉西他滨联合治疗(标准护理)。我们的提议提供的概念、免疫学和遗传学创新包括使用一种独特的IDO2缺陷小鼠。这项工作将由一个由药物发现和PDAC治疗方面的领先临床前和临床专家组成的多学科协作团队进行。这项建议的意义和影响是基于它提供了一个强大的机会，使D-1MT在胰腺癌患者中的第二阶段临床试验合理化并优先考虑。