IDO2 Targeting in Pancreatic Cancer

IDO2 靶向治疗胰腺癌

• 批准号: 8965168
• 负责人: GEORGE C PRENDERGAST
• 金额: $ 40.77万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965168
• 关键词: Ablation; Abraxane; Address; Affect; Biological Markers; Cancer Patient; Caring; Cells; Chemotherapy-Oncologic Procedure; Chronic; Clinical; Clinical Management; Clinical Research; Clinical Treatment; Code; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Dioxygenases; Disease; Enzymes; Evaluation; Excision; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Female; Functional disorder; Genes; Genetic; Genetic study; Genotype; Growth; Human; Immune; Immunotherapy; Individual; Inflammation; Inflammatory; Investigation; KRAS2 gene; Lead; Learning; Licensing; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Molecular; Mus; Mutant Strains Mice; Nature; Operative Surgical Procedures; Outcome; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathology; Pathway interactions; Patients; Pre-Clinical Model; Predisposition; Process; Relapse; Resistance; Role; Solid Neoplasm; Source; Survival Rate; Therapeutic; Translations; Treatment outcome; Variant; Work; base; cancer immunotherapy; cancer type; drug discovery; drug mechanism; enzyme activity; experience; gemcitabine; genetic variant; improved; indoleamine; inhibitor/antagonist; innovation; multidisciplinary; neoplastic cell; oncology; overexpression; pancreatic tumorigenesis; phase II trial; pre-clinical; preclinical study; programs; public health relevance; response; small molecule; theranostics; therapy development; therapy resistant; treatment response; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) eludes immune control by mechanisms that are poorly understood but might be restored to improve clinical outcomes. The primary impact of our proposal is that it addresses the need for theranostic markers to assist the clinical development of IDO inhibitors, a promising new class of small molecule immunotherapy now in Phase II trials. Building upon an earlier R21 award, we will develop our hypothesis that the IDO2 gene can (1) inform the development of pancreatic ductal adenocarcinoma (PDAC) and (2) define a host biomarker to stratify individual PDAC patient responses to an IDO inhibitor, based on natural polymorphic variations in the IDO2 coding region that affect its enzyme activity. In essence, our project seeks to illuminate an immune basis for PDAC development and to identify a theranostic marker that could predict the efficacy of IDO inhibitor treatment in an individual patient. A major source of scientific significance in our proposal is how it approaches the question of "cancer- associated" inflammation: why does chronic inflammation lead to cancer in some individuals but not others? Inflammation and immune escape are well established as causative factors in PDAC, but it is clear that this question has broader general significance in oncology. While variations in a single pathway cannot address this question fully, our focus on IDO2 may inform IDO inhibitor therapy and help tilt some PDAC patients with a suitable IDO2 genotype into a more manageable state. It is in this sense that our project is incisive in the opportunity if offers to improve clinical treatment. Our preliminary results suggest that IDO2 programs a pathogenic process that enforces a powerful mechanism of immune escape in PDAC, thereby licensing its rapid progression and resistance to treatment. We discovered IDO2 and generated a unique conditionally genetic mutant mouse to understand how IDO2 informs the inflammatory tumor microenvironment. Among human cancers, PDAC was a chosen focus because of our discovery that this type of cancer overexpresses IDO2 in both immune cells and solid tumor cells (the latter of which is not usually the case for IDO2 in most tumors). This feature may be relevant to the particularly strong correlates of PDAC with chronic inflammation and aggressive pathology. Aim 1 will continue a clinical study of IDO2 genetic variants in a unique subset of PDAC patients, where pilot investigations to date suggest that a select set of PDAC patients (i.e., late-onset as well as female patients) are more likely to correlate with a WT host IDO2 genotype. Aim 2 will develop a mouse genetic study demonstrating that IDO2 deficiency limits a type of pathogenic inflammation that is critical for K-Ras-induced PDAC. This Aim will explore molecular and cellular mechanisms to learn how IDO2 expression in immune cells and tumor cells contribute to malignant development and treatment response. Aim 3 will compare pathogenic and mechanistic contributions of the naturally occurring human IDO2 genetic variants in the mouse, in terms of their impact on PDAC development and treatment. This project offers the opportunity to leverage an outstanding, experienced team to promote the development of IDO inhibitors for effective combination immunochemotherapy of PDAC.

 描述（由申请方提供）：胰腺导管腺癌（PDAC）通过尚不清楚但可能恢复以改善临床结局的机制逃避免疫控制。我们的提案的主要影响是，它解决了治疗诊断标记物的需求，以协助IDO抑制剂的临床开发，IDO抑制剂是一种有前途的新型小分子免疫疗法，目前正在进行II期试验。基于早期的R21奖项，我们将发展我们的假设，即IDO 2基因可以（1）告知胰腺导管腺癌（PDAC）的发展，以及（2）基于IDO 2编码区中影响其酶活性的天然多态性变异，定义宿主生物标志物以分层个体PDAC患者对IDO抑制剂的反应。从本质上讲，我们的项目旨在阐明PDAC发展的免疫基础，并确定可以预测个体患者中IDO抑制剂治疗疗效的治疗诊断标志物。在我们的提议中，一个具有科学意义的主要来源是它如何处理“癌症相关”炎症的问题：为什么慢性炎症会导致某些个体而不是其他个体的癌症？炎症和免疫逃逸是PDAC的致病因素，但很明显，这个问题在肿瘤学中具有更广泛的普遍意义。虽然在一个单一的变化 虽然IDO通路不能完全解决这个问题，但我们对IDO 2的关注可能会为IDO抑制剂治疗提供信息，并有助于将一些具有合适IDO 2基因型的PDAC患者倾斜到更易于管理的状态。正是在这个意义上，我们的项目是深刻的机会，如果提供改善临床治疗。我们的初步结果表明，IDO 2程序的致病过程，强制执行一个强大的机制，免疫逃逸PDAC，从而许可其快速发展和耐药治疗。我们发现了IDO 2并产生了一种独特的条件遗传突变小鼠，以了解IDO 2如何影响炎症性肿瘤微环境。在人类癌症中，PDAC是一个选择的焦点，因为我们发现这种类型的癌症在免疫细胞和实体瘤细胞中都过表达IDO 2（后者在大多数肿瘤中通常不是IDO 2的情况）。该特征可能与PDAC与慢性炎症和侵袭性病理学的特别强的相关性有关。目标1将继续在PDAC患者的独特子集中进行IDO 2遗传变体的临床研究，其中迄今为止的初步研究表明，一组选定的PDAC患者（即，晚发型以及女性患者）更可能与WT宿主IDO 2基因型相关。目的2将开展小鼠遗传学研究，证明IDO 2缺乏限制了一种对K-Ras诱导的PDAC至关重要的致病性炎症。该目标将探索分子和细胞机制，以了解IDO 2在免疫细胞和肿瘤细胞中的表达如何促进恶性发展和治疗反应。目的3将比较小鼠中天然存在的人IDO 2遗传变异体的致病性和机制贡献，就其对PDAC发展和治疗的影响而言。该项目提供了一个机会，利用一个优秀的，经验丰富的团队，以促进IDO抑制剂的发展，有效的联合免疫化疗的PDAC。