IDO2 Targeting in Pancreatic Cancer

IDO2 靶向治疗胰腺癌

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：胰腺导管腺癌（PDAC）通过人们知之甚少的机制逃避免疫控制，但可能会恢复以改善临床结果。我们提案的主要影响是它解决了治疗诊断标记物协助临床的需求。 IDO 抑制剂的开发，这是一种有前景的新型小分子免疫疗法，目前正在进行 II 期试验，以早期的 R21 奖项为基础，我们将提出这样的假设：IDO2 基因可以 (1) 提供信息。胰腺导管腺癌 (PDAC) 的发展以及 (2) 基于影响其酶活性的 IDO2 编码区的自然多态性变异，定义宿主生物标志物来分层个体 PDAC 患者对 IDO 抑制剂的反应。阐明 PDAC 发展的免疫基础，并确定可以预测 IDO 抑制剂治疗个体患者疗效的治疗诊断标记物。我们提案的主要科学意义在于它如何解决这一问题。 “癌症相关”炎症：为什么慢性炎症会在某些个体中导致癌症，而在其他个体中却不会？在一个单一的途径不能完全解决这个问题，我们对 IDO2 的关注可能会为 IDO 抑制剂治疗提供信息，并帮助一些具有合适 IDO2 基因型的 PDAC 患者进入更容易控制的状态。从这个意义上说，我们的项目在提供改善的机会方面是敏锐的。我们的初步结果表明，IDO2 编程了一种致病过程，在 PDAC 中强制执行强大的免疫逃逸机制，从而许可其快速进展和对治疗的抵抗力。 IDO2 影响炎症肿瘤微环境。在人类癌症中，PDAC 成为我们关注的焦点，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度表达 IDO2（后者在大多数肿瘤中通常不会出现 IDO2 的情况）。这一特征可能与 PDAC 与慢性炎症和侵袭性病理学之间特别强的相关性有关，目标 1 将继续在一个独特的 PDAC 患者亚群中进行 IDO2 基因变异的临床研究，迄今为止的初步研究表明，选择一组 PDAC 患者（即晚发患者和女性患者）更有可能与 WT 宿主 IDO2 基因型相关。目标 2 将开展一项小鼠遗传学研究，证明 IDO2 缺乏限制了一种至关重要的致病性炎症。该目标将探索分子和细胞机制，以了解免疫细胞和肿瘤细胞中的 IDO2 表达如何促进恶性发展和治疗反应。目标 3 将比较致病和机制贡献。该项目提供了利用优秀、经验丰富的团队来促进 IDO 抑制剂开发的机会，以实现 PDAC 的有效联合免疫化疗。