Targeting the Unfolded Protein Response in PanNETs

针对 PanNET 中未折叠的蛋白质反应

• 批准号: 10314073
• 负责人: Scott A. Oakes
• 金额: $ 48.46万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-12 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314073
• 关键词: American; Apoptosis; Apoptotic; Blood Circulation; Carcinoid Tumor; Cell Death; Cell Fate Control; Cell Nucleus; Cells; Client; Data; Diagnosis; Disease; Disease Progression; Drug Targeting; Endocrine; Endoplasmic Reticulum; Functional disorder; Gastrointestinal tract structure; Genetic; Genetic Models; Genetic Transcription; Growth; Homeostasis; Hormones; Human; Hypoxia; Insulin; Intervention; Islet Cell Tumor; Laboratories; Lead; Lung Neoplasms; Malignant Neoplasms; Measures; Modeling; Molecular; Monitor; Mus; Neoplasms; Neuroendocrine Tumors; OmpR protein; Operative Surgical Procedures; Organelles; Output; Pancreas; Pathway interactions; Patients; Pharmacology; Phosphotransferases; Pre-Clinical Model; Protein Secretion; Protein-Serine-Threonine Kinases; Proteins; Research Project Grants; Ribonucleases; Role; Sampling; Secretory Cell; Signal Pathway; Signal Transduction; Site; Solid; Solid Neoplasm; Somatic Mutation; Stress; Therapeutic; Toxic effect; Tumor-Derived; Work; Xenograft Model; antitumor effect; arm; base; cancer cell; cancer therapy; cell growth; chemical genetics; curative treatments; endoplasmic reticulum stress; human model; in vivo; insight; misfolded protein; mouse model; multicatalytic endopeptidase complex; neoplastic cell; novel therapeutics; nutrient deprivation; patient derived xenograft model; peptide hormone; pre-clinical; protein folding; response; secretory protein; small molecule; tool; tumor; tumor growth

The unfolded protein response (UPR) is an intracellular signaling pathway largely controlled by two ER transmembrane kinases—IRE1 and PERK—that communicate the protein folding status of the endoplasmic reticulum (ER) to the nucleus in order to maintain homeostasis within this organelle. Hypoxia, nutrient deprivation, proteasome dysfunction, or sustained demands on the secretory pathway--conditions often encountered by solid tumor cells--lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” Under remediable levels of ER stress, the UPR activates transcriptional and translational changes that promote adaptation (Homeostatic UPR). But when confronted with irremediable levels of ER stress, these adaptive measures fail, and the UPR instead switches strategies to trigger cell death (Terminal UPR). Neuroendocrine tumors (e.g. carcinoids) are one class of solid tumor that may be particularly sensitive to protein folding stress due to their high protein secretory activity. Derived from professional secretory cells, neuroendocrine tumors can arise in many sites (e.g. gastrointestinal tract, lung), but these tumors universally hypersecrete one or more peptide hormone(s). For the nearly 12,000 Americans diagnosed with a neuroendocrine tumor each year, surgery is the only potentially curative treatment. Unfortunately, the five year survival is extremely low for the ~25% of patients who develop metastatic disease. We have evidence that the UPR is upregulated and required for the growth of pancreatic neuroendocrine tumors (PanNETs), a representative model for this class of secretory solid tumors. Based on our preliminary data, we hypothesize that PanNETs are reliant on elevated levels of Homeostatic UPR signaling to avoid the toxic effects of protein folding stress, and that targeted interventions to either reduce Homeostatic UPR outputs or alternatively trigger the Terminal UPR will have potent antitumor effects. We will use a variety of genetic, chemical-genetic, and pharmacological tools developed in our laboratory to selectively activate or disable the UPR master regulators (IRE1 and PERK) in order to accomplish two specific aims. (1): Define the activation status, signaling outputs, and cell growth effects of the UPR regulators IRE1 and PERK in primary human samples and murine xenograft models of PanNETs. (2): Determine the effects of pharmacologic inhibition of IRE1 and/or PERK on the growth of PanNETs in murine xenograft and genetic models of PanNETs. Our research project will provide powerful mechanistic insights into the role of the UPR on PanNET growth and the use of small molecules to manipulate this pathway to control cell fate. If successful, our work promises to validate drug targets to modify progression of PanNET and other neuroendocrine tumors.

未折叠蛋白反应 (UPR) 是一种细胞内信号传导途径，主要由两个 ER 控制 跨膜激酶 - IRE1 和 PERK - 传达内质蛋白折叠状态 网状结构（ER）连接到细胞核，以维持该细胞器内的稳态。缺氧、营养 剥夺、蛋白酶体功能障碍或对分泌途径的持续需求——这些情况通常 实体瘤细胞遇到的情况——导致内质网中错误折叠的蛋白质积累并引起“内质网应激”。 在可修复的 ER 应激水平下，UPR 激活转录和翻译变化，从而促进 适应（稳态UPR）。但当面临无法挽回的内质网压力时，这些适应性 措施失败，UPR 转而切换策略来触发细胞死亡（终端 UPR）。 神经内分泌肿瘤（例如类癌）是一类可能对蛋白质特别敏感的实体瘤 由于其高蛋白质分泌活性而产生折叠应力。源自专业分泌细胞， 神经内分泌肿瘤可发生在许多部位（例如胃肠道、肺），但这些肿瘤普遍存在 过度分泌一种或多种肽激素。对于近 12,000 名被诊断患有这种疾病的美国人来说 神经内分泌肿瘤每年都会出现，手术是唯一可能治愈的治疗方法。不幸的是，这五年 大约 25% 的发生转移性疾病的患者的生存率极低。 我们有证据表明 UPR 上调并且是胰腺神经内分泌肿瘤生长所必需的 （PanNETs），此类分泌性实体瘤的代表性模型。根据我们的初步数据，我们 假设 PanNET 依赖于稳态 UPR 信号水平的升高来避免毒性作用 蛋白质折叠应激的影响，以及有针对性的干预措施，以减少稳态 UPR 输出或 或者触发末端UPR将具有有效的抗肿瘤作用。我们将利用多种基因、 我们实验室开发的化学遗传和药理学工具可以选择性地激活或禁用 UPR 主调节器（IRE1 和 PERK）为了实现两个特定目标。 (1): 定义激活 UPR 调节因子 IRE1 和 PERK 在原代人类中的状态、信号输出和细胞生长效应 PanNET 的样本和小鼠异种移植模型。 (2)：确定药物抑制的效果 IRE1 和/或 PERK 对小鼠异种移植物和 PanNET 遗传模型中 PanNET 生长的影响。 我们的研究项目将为 UPR 对 PanNET 增长和发展的作用提供强有力的机制见解。 使用小分子操纵该途径来控制细胞命运。如果成功，我们的工作有望 验证药物靶标以改变 PanNET 和其他神经内分泌肿瘤的进展。