Efficacy of PDI inhibitors in glioblastoma

PDI 抑制剂对胶质母细胞瘤的疗效

基本信息

批准号：
9086289
负责人：
NOURI NEAMATI
金额：
$ 48.61万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2015-06-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9086289
关键词：
ABCB1 gene Advanced Development Binding Cell Line Cells Cessation of life Clinic Clinical Collaborations Development Doxycycline Drug Targeting Drug resistance Endoplasmic Reticulum Genes Glioblastoma Glioma Health Homeostasis In Vitro Lead Malignant Neoplasms Malignant neoplasm of brain Mediating Molecular Chaperones Normal Cell Normal tissue morphology Pathway interactions Patients Pharmaceutical Preparations Physiological Process Property Protein Biosynthesis Protein Disulfide Isomerase Proteins Radiation Reactive Oxygen Species Reagent Recurrence Resistance Role Safety Sampling Signal Transduction Structure Survival Rate Technology Toxic effect Translations Tumor Escape Xenograft Model analog anticancer activity base cancer cell cancer therapy cancer type chemotherapy coping cytotoxicity design disulfide bond endoplasmic reticulum stress high throughput screening improved in vivo inhibitor/antagonist novel novel marker oncology outcome forecast overexpression predictive marker protein folding protein misfolding systemic toxicity targeted treatment temozolomide therapeutic target tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Protein disulfide isomerase (PDI) has a key role in maintaining cellular homeostasis by mediating oxidative protein folding. It catalyzes disulfide bond formation, breakage and rearrangement in the endoplasmic reticulum (ER), and possesses chaperone protein activity. Increasing evidence suggests that PDI supports the survival and progression of several cancers and most significantly brain cancer. Cancer cells require higher levels of PDI to cope with significant ER stress and global increase in protein synthesis to sustain rapid proliferation. Increased protein synthesis leads to an abundant presence of misfolded proteins in the ER that need to be refolded by PDI. As such, cancer cells are more vulnerable to PDI inhibition than normal cells making PDI a new and exciting target to treat brain cancer. Although PDI remains a very promising oncology target, currently there are no PDI inhibitors under clinical development. There is an urgent need to develop drugs targeting essential pathways in brain cancer. Previous attempts at targeted therapy for glioma did not produced cures. Since PDI is a hub for orchestrating an entire process essential for rapid proliferation, selective blockade of its function will result in increased ER stress leading to the death of cancer cells. This approach is drastically different from previous attempts that target a single protein leading to facile escape and tumor recurrence. Previously, we discovered a class of novel and irreversible PDI inhibitors that selectively bind to PDI and demonstrated significant in vivo efficacy with no apparent systemic toxicity. More recently, we performed a high throughput screen and have identified several nM inhibitors of PDI representing the most potent PDI inhibitors discovered to date. We propose to optimize and characterize these compounds to select clinical leads for the treatment of glioblastoma multiforme (GBM). To determine the significance of PDI signaling in cancer progression and the effect of its inhibition on tumor growth, we propose the following aims. Aim 1: To validate PDI as a target and to determine the expression levels of PDI and select ER stress genes in GBM cell lines. Aim 2: To perform a structure-based and ADMET-guided lead optimization campaign to select the top 5 compounds with desirable potency, selectivity, and PK properties. Aim 3: To perform mechanistic studies of top 5 compounds from Aim 2 as single agents and in combination with temozolomide and radiation (TMZ/IR) using Bru-Seq technology in a panel of GBM cell lines. Aim 4: To determine in vivo efficacy of PDI inhibitors, as a single agent and in combination with TMZ/IR in patient-derived xenograft (PDX) models.

描述（申请人提供）：蛋白质二硫键异构酶（PDI）通过介导氧化蛋白质折叠在维持细胞稳态中发挥关键作用，它催化内质网（ER）中二硫键的形成、断裂和重排，并具有伴侣蛋白活性。越来越多的证据表明，PDI 支持多种癌症的生存和进展，最重要的是，癌细胞需要更高水平的 PDI。 PDI 应对显着的 ER 应激和蛋白质合成的整体增加以维持快速增殖。蛋白质合成的增加导致 ER 中存在大量错误折叠的蛋白质，这些蛋白质需要 PDI 重新折叠，因此，癌细胞更容易受到 PDI 的影响。尽管 PDI 仍然是一个非常有前途的肿瘤学靶点，但目前尚无正在临床开发的 PDI 抑制剂，因此迫切需要开发针对脑癌重要途径的药物。之前的尝试神经胶质瘤的靶向治疗并没有治愈，因为 PDI 是协调快速增殖所必需的整个过程的枢纽，选择性阻断其功能将导致 ER 应激增加，从而导致这种方法与之前针对单一蛋白质导致轻易逃逸和肿瘤复发的尝试截然不同，我们发现了一类新型且不可逆的 PDI 抑制剂，它们选择性地与 PDI 结合，并表现出显着的体内疗效。最近，我们进行了高通量筛选，并鉴定了几种 nM PDI 抑制剂，代表了迄今为止发现的最有效的 PDI 抑制剂，我们建议优化和表征这些化合物，以选择用于治疗的临床先导药物。多形性胶质母细胞瘤 (GBM)。为了确定 PDI 信号在癌症进展中的重要性及其对肿瘤生长的抑制作用，我们提出以下目标：验证 PDI 作为靶点并确定 PDI 和 PDI 的表达水平。选择 GBM 细胞系中的 ER 应激基因目标 2：进行基于结构和 ADMET 指导的先导化合物优化活动，以选择具有理想效力、选择性和 PK 特性的前 5 种化合物。使用 Bru-Seq 技术在一组 GBM 细胞系中对 Aim 2 中的前 5 种化合物作为单一药物以及与替莫唑胺和辐射 (TMZ/IR) 组合进行机制研究。目标 4：确定 PDI 抑制剂的体内功效。，在患者来源的异种移植 (PDX) 模型中作为单一药物并与 TMZ/IR 联合使用。