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.

展开的蛋白质反应（UPR）是一个细胞内信号通路，主要由两个ER控制 跨膜激酶-IRE1和PERK-传达内质的蛋白质折叠状态 网状（ER）到细胞核，以维持该细胞器中的体内稳态。缺氧，营养素 剥夺，蛋白酶体功能障碍或对秘书道路的持续需求 - 条件通常 实体肿瘤细胞遇到的 - 领先于ER中错误折叠的蛋白的积累并引起“ ER应激”。 在可补充的ER应力水平下，UPR激活转录和翻译变化，以促进 适应（稳态UPR）。但是，当面对不可恢复的ER应力水平时，这些适应性 措施失败，而UPR则切换了触发细胞死亡（终端UPR）的策略。 神经内分泌肿瘤（例如类癌）是一类实体瘤，可能对蛋白质特别敏感 由于其高蛋白质的秘密活性，折叠应力。来自专业秘密细胞， 神经内分泌肿瘤可以在许多部位（例如胃肠道，肺）出现，但是这些肿瘤普遍存在 超副反应一个或多个肽马酮。对于被诊断出患有的近12,000名美国人 每年神经内分泌肿瘤，手术是唯一的潜在治疗方法。不幸的是，五年 对于发生转移性疾病的患者中，约25％的生存率极低。 我们有证据表明胰腺神经内分泌肿瘤的生长是上调的，并且需要 （Pannets），这类秘密实体瘤的代表性模型。根据我们的初步数据，我们 假设Pannets对稳态UPR信号升高以避免有毒作用敏感 蛋白质折叠应力，以及针对性的干预措施，以减少稳态UPR输出或 或者，触发末端UPR将具有潜在的抗肿瘤作用。我们将使用各种遗传， 化学遗传学和药物工具在我们的实验室中开发的，以选择性激活或禁用 UPR主监管机构（IRE1和PERK）为了实现两个具体目标。 （1）：定义激活 UPR调节剂IRE1和PERK的状态，信号输出和细胞生长效应在原代人中 Pannets的样品和鼠色谱模型。 （2）：确定药理学抑制的影响 IRE1和/或PERK关于Pannets的鼠类特征和遗传模型的生长。 我们的研究项目将为UPR在Pannet增长和 使用小分子来操纵这种控制细胞命运的途径。如果成功，我们的工作承诺 验证药物靶标，以改变Pannet和其他神经内分泌肿瘤的进展。